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The effects of lamotrigine on alcohol seeking and relapse
Abstract
Lamotrigine is a clinically used drug, which inhibits Na(+) channel activity that in turn reduces glutamate release. Its downstream activity on other neurotransmitter systems such as serotonergic and dopaminergic has also been reported. Since both glutamate and monoamines might be involved in alcohol craving and relapse, our aim was to examine the effects of lamotrigine on alcohol seeking and relapse-like drinking behaviour. Thus, lamotrigine (5 and 15mg/kg) was tested in two behavioural models for alcohol seeking and relapse - the model of cue-induced reinstatement of alcohol-seeking behaviour and the alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats. Administration of 5mg/kg of lamotrigine caused a significant decrease of cue-induced reinstatement of alcohol-seeking behaviour. The ADE was significantly reduced with both doses tested. However, the highest dose of lamotrigine produced sedation. The ability of lamotrigine to reduce alcohol seeking as well as relapse-like drinking behaviour provides further support for the proposed involvement of the glutamatergic and dopaminergic/serotonergic systems in alcohol craving and relapse, hence suggesting a good rationale for pharmacological intervention that may reduce craving and relapse in alcohol dependent patients.
... To assess the potential of antirelapse effects of pharmacological treatment, we used lamotrigine as a reference compound. Lamotrigine-which acts on voltage-gated Na + -channels (Tarnawa et al., 2007)-has a robust effect on relapse-like drinking in rats (Vengeliene et al., 2007). In rats that had long-term voluntary access to EtOH followed by deprivation for several weeks, the re-presentation of EtOH leads to relapse-like drinking, a temporal increase in EtOH intake over baseline drinking. ...
... The pharmacological study using 5 mg/kg of lamotrigine-this was an optimal dose in our previous study (Vengeliene et al., 2007) -was introduced at the end of the seventh EtOH deprivation phase of 15-day duration. Thus, before drug treatment, all animals had 44 weeks of access to EtOH interrupted with several 2-to 3-week withdrawal phases. ...
... In line with our previous report (Vengeliene et al., 2007), this study demonstrates that repeated administration of lamotrigine reduces daily EtOH intake during the ADE in a 4-bottle free-choice paradigm in rats. Our Fourier analysis further shows that on the first postabstinence day, drinking frequency in lamotrigine-treated animals was significantly increased when compared to baseline condition but was not different from that seen in vehicle-treated animals. ...
Background:
There are numerous studies in the preclinical alcohol research field showing that pharmacological interventions and many other manipulations can influence ethanol (EtOH) consumption in a free-choice paradigm in rats. Most of these studies are based on 24-hour measurements. These studies provide a measure of the total amount of EtOH consumed per day, but do not provide information on the drinking patterns within this period of measurement. Here, we used a novel drinkometer system in combination with Fourier analysis to provide detailed information on drinking patterns.
Methods:
Our automated drinkometer system measures fluid consumption by means of high-precision sensors attached to the drinking bottles in the home cage of the rat and thereby ameliorates several limitations of a classical lickometer-based drinkometer system. As an example of its application, we used the alcohol deprivation effect (ADE) model for relapse-like drinking and tested as a reference compound lamotrigine, which has a robust effect on the ADE. Fourier analysis was chosen as the main strategy for 24-hour drinking pattern recognition during water/EtOH drinking.
Results:
Under baseline conditions, voluntary EtOH consumption in rats can be expressed as characteristic oscillations that follow diurnal activity and differ in their amplitude, depending on the EtOH concentration. This diurnal drinking rhythmicity was altered during a relapse condition. Furthermore, lamotrigine given during the ADE did not significantly affect the drinking frequency or the number of approaches to the EtOH bottles when compared to vehicle-treated animals. However, EtOH intake during a drinking approach was dramatically reduced.
Conclusions:
The use of the drinkometer system and mathematical modeling allows the characterization of treatment effects on relapse-like drinking with a great level of detail. One use of such detailed information may lie in its translational predictability. For instance, owing to lamotrigine treatment's lack of effect on EtOH drinking frequency or the number of approaches to the EtOH bottles, this compound might not be effective in relapse prevention per se but may reduce hedonic EtOH effects and could therefore be used in alcohol-dependent patients if harm reduction is the primary goal of treatment.
... Relapse-like alcohol drinking. All rats underwent a long-term alcohol-drinking procedure interrupted with repeated deprivation phases, as previously described (Vengeliene et al, 2005Vengeliene et al, , 2006Vengeliene et al, , 2007). Briefly, rats were given ad libitum access to tap water, 5%, 10%, and 20% ethanol solutions (v/v). ...
... In addition, the schedule of five injections given 12 h apart was chosen to avoid stress effects induced by more frequent injections. Furthermore, numerous studies on the alcohol deprivation effect conducted in our long-term drinking rats with different compounds have demonstrated effectiveness in our model using the same treatment schedule (eg, Hölter and Spanagel, 1999; Hölter et al, 2000; Vengeliene et al, 2005 Vengeliene et al, , 2006 Vengeliene et al, , 2007 Vengeliene et al, , 2010). Alcohol bottles were reintroduced after the second injection at the onset of the light phase. ...
... Furthermore, the higher dose significantly decreased alcohol intake below baseline levels for the 6 days after alcohol re-exposure. In order to maintain overall liquid intake and as previously observed (Vengeliene et al, 2006Vengeliene et al, , 2007Vengeliene et al, , 2010), a compensatory decrease in the consumption of water occurred upon alcohol re-exposure in vehicletreated rats (Figure 1b and SupplementaryFigure S2). In contrast, 30 mg/kg PF-670462-treated rats did not reduce their total water intake during the first postabstinence days. ...
During the past decade, it has been shown that circadian clock genes have more than a simple circadian time-keeping role. Clock genes also modulate motivational processes and have been implicated in the development of psychiatric disorders such as drug addiction. Recent studies indicate that casein-kinase 1ε/δ (CK1ε/δ)--one of the components of the circadian molecular clockwork-might be involved in the etiology of addictive behavior. The present study was initiated to study the specific role of CK1ε/δ in alcohol relapse-like drinking using the 'Alcohol Deprivation Effect' model. The effect of CK1ε/δ inhibition was tested on alcohol consumption in long-term alcohol-drinking rats upon re-exposure to alcohol after deprivation using a four-bottle free-choice paradigm with water, 5%, 10%, and 20% ethanol solutions, as well as on saccharin preference in alcohol-naive rats. The inhibition of CK1ε/δ with systemic PF-670462 (0, 10, and 30 mg/kg) injections dose-dependently decreased, and at a higher dosage prevented the alcohol deprivation effect, as compared with vehicle-treated rats. The impact of the treatment was further characterized using nonlinear regression analyses on the daily profiles of drinking and locomotor activity. We reveal that CK1ε/δ inhibition blunted the high daytime alcohol intake typically observed upon alcohol re-exposure, and induced a phase shift of locomotor activity toward daytime. Only the highest dose of PF-670462 shifted the saccharin intake daily rhythm toward daytime during treatment, and decreased saccharin preference after treatment. Our data suggest that CK1 inhibitors may be candidates for drug treatment development for alcoholism.
... Animal studies reveal that systemically administered glutamate receptor antagonists attenuate cue-induced reinstatement of alcohol-seeking behavior. Such compounds include various non-competitive NMDA receptor antagonists (Backstrom and Hyytia, 2004;Bachteler et al., 2005), the NMDA receptor modulator acamprosate (Bachteler et al., 2005), the mGluR2/3 agonist LY379268 (Backstrom and Hyytia, 2005;Zhao et al., 2006), the mGluR5 receptor antagonist MPEP (Backstrom et al., 2004;Adams et al., 2008;Schroeder et al., 2008), and the glutamate release inhibitor lamotrigine (Vengeliene et al., 2007). A recent human study has shown that the anticonvulsant drug topiramate can reduce the percentage of heavy drinking days and improve self-reported drinking outcomes in alcoholdependent individuals (Johnson et al., 2007). ...
... In addition, dampening of glutamate transmission via stimulation of presynaptic mGluR2/3 autoreceptors or antagonism of postsynaptic mGluR5 receptors attenuates cue-induced alcohol-seeking behavior (Backstrom and Hyytia, 2005;Zhao et al., 2006;Schroeder et al. 2008;Adams et al., 2008;Adams et al., 2010). Suppression of glutamate release by anticonvulsant drugs such as lamotrigine also attenuates cue-induced alcohol-seeking (Vengeliene et al., 2007). Combined with our observations that cue-evoked alcohol-seeking is associated with elevated extracellular levels of glutamate in the NAc core and BLA, two regions that are known to be involved in regulated goal-directed drug-seeking behavior and stimulus-reward associations (Grant et al., 1996;Meil & See, 1997;Childress et al., 1999;Cornish & Kalivas, 2000;Kilts et al., 2001;Kruzich & See, 2001;Bonson et al., 2002;Fuchs & See, 2002;McLaughlin & See, 2003;Di Ciano & Everitt, 2004;Fuchs et al., 2004;Dayas et al., 2007;Di Ciano et al., 2008;Rogers et al., 2008), respectively, these various lines of study indicate that increased glutamate transmission mediates cue-induced alcohol-seeking behavior. ...
Relapse is one of the most problematic aspects in the treatment of alcoholism and is often triggered by alcohol-associated environmental cues. Evidence indicates that glutamate neurotransmission plays a critical role in cue-induced relapse-like behavior, as inhibition of glutamate neurotransmission can prevent reinstatement of alcohol-seeking behavior. However, few studies have examined specific changes in extracellular glutamate levels in discrete brain regions produced by exposure to alcohol-associated cues. The purpose of this study was to use glutamate oxidase (GluOx)-coated biosensors to monitor changes in extracellular glutamate in specific brain regions during cue-induced reinstatement of alcohol-seeking behavior. Male Wistar rats were implanted with indwelling jugular vein catheters and intracerebral guide cannula aimed at the basolateral amygdala (BLA) or nucleus accumbens (NAc) core, and then trained to self-administer alcohol intravenously. A separate group of animals were trained to self-administer food pellets. Each reinforcer was accompanied by the presentation of a light/tone stimulus. Following stabilization of responding for alcohol or food reinforcement, and subsequent extinction training, animals were implanted with pre-calibrated biosensors and then underwent a 1-hour cue-induced reinstatement testing period. As determined by GluOx-coated biosensors, extracellular levels of glutamate were increased in the BLA and NAc core during cue-induced reinstatement of alcohol-seeking behavior. The cumulative change in extracellular glutamate in both regions was significantly greater for cue-induced reinstatement of alcohol-seeking behavior versus that of food-seeking behavior. These results indicate that increases in glutamate transmission in the BLA and NAc core may be a neurochemical substrate of cue-evoked alcohol-seeking behavior.
... Oxcarbazepine (25 and 50 mg/kg) was dissolved in 60% DMSO, which served as the 0 mg/kg dose, and injected i.p. at a (lower) volume of 5 mL/kg body weight. Doses were chosen on the basis of prior behavioral studies in rats and mice: lamotrigine (Brody et al., 2003;Vengeliene et al., 2007), oxcarbazepine (Beijamini et al., 1998), topiramate (Gabriel and Cunningham, 2005;Hargreaves and McGregor, 2007;Knapp et al., 2007a;Nguyen et al., 2007) and pilot work showing that when injected alone (i.e., without EtOH) these doses did not produce significant rotarod ataxia or sedation/hypnosis (effects on core body temperature are described in the Results below). All 3 drugs were obtained from Sigma (St. Louis, MO). ...
... One or more of these actions could potentially contribute to the in vivo effects of these drugs on EtOH-related behaviors along with their anti-glutamatergic properties. In this context, lamotrigine has been found to attenuate cue-induced alcoholseeking in rats (Vengeliene et al., 2007) but has no effect on EtOH-withdrawal anxiety-like behavior (Knapp et al., 2007b). Moreover, while there are to our knowledge no published reports of oxcarbazepine effects on rodent EtOH-related behaviors, topiramate has no effect on EtOH conditioned place preference but does attenuate EtOH withdrawal and drinking, perhaps most robustly after EtOH deprivation (Cagetti et al., 2004;Farook et al., 2007;Gabriel and Cunningham, 2005;Gremel et al., 2006;Hargreaves and McGregor, 2007;Knapp et al., 2007a;Nguyen et al., 2007). ...
Compounds with anti-glutamatergic properties currently in clinical use for various indications (eg Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, and topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (by comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (by chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, whereas oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiate ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J, or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with an NMDAR blocker, genetic background, or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.
... The anticonvulsant drug lamotrigine, which was shown to inhibit Na þ channel activity and in turn reduce glutamate release, was found to significantly decrease cueinduced reinstatement of alcohol-seeking behaviour in rats (Vengeliene et al., 2007). ...
... Administration of the anticonvulsant drug lamotrigine completely abolished the expression of an ADE in Wistar rats (Vengeliene et al., 2007). ...
Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA A , glycine, 5‐hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L‐type Ca ²⁺ channels and G‐protein‐activated inwardly rectifying K ⁺ channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcohol‐seeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long‐term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin‐releasing factor system and a hyperfunctional glutamatergic system being the most important ones.
British Journal of Pharmacology (2008) 154 , 299–315; doi: fn1 ; published online 3 March 2008
... Targeting D3 receptors is a powerful tool to specifically interfere with distinct network nodes within the reward system, because this receptor subtype is very selectively expressed in the nucleus accumbens of rats (Bouthenet et al., 1991;Sokoloff et al., 1990). Importantly, SB-277011-a has been previously shown to reduce seeking and taking of alcohol and other drugs of abuse in rats Vengeliene et al., 2007;Rice et al., 2015;Thanos et al., 2005). The combined results provide proof of concept that a targeted pharmacological intervention can modulate specific nodes in networks involved in addiction and may normalize connectivity, including that between insula and striatal regions. ...
Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol-induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent finding across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this completed round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.
... Lamotrigine elevated intracranial self-stimulation (ICSS) thresholds and also attenuated cocaine-induced reduction of ICSS thresholds (Beguin et al., 2012). In addition, lamotrigine reduced the relapse-like alcohol drinking behaviors, the cue-induced alcohol reinstatement and alcohol deprivation effect in rats (Vengeliene et al., 2007). Repeated treatment with lamotrigine significantly reduced the voluntary alcohol intake in alcohol preferring rats (Zalewska-Kaszubska et al., 2015). ...
Background:
Ketamine has become a popular recreational drug of abuse among young people, resulting in an important medical issue due to its addiction liability. One case report has demonstrated that a ketamine addict experienced a great reduction in craving and ketamine use after taking lamotrigine, an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. The present study determined whether lamotrigine can reduce the reinforcing and motivational effects of ketamine and prevent the relapse to drug seeking behavior in rats.
Methods:
Male Sprague-Dawley rats were submitted to ketamine intravenous self-administration training under fixed ratio schedules. The effects of lamotrigine on the motivation to work for ketamine (0.3 and 0.5 mg/kg) were assessed in the breakpoint test under a progressive ratio (PR) paradigm. The relapse-like behavior in the cue- and ketamine-induced reinstatement test was examined after extinction. In addition, the effect of Lamotrigine on the locomotor activity was monitored. Lamotrigine (10 and 30 mg/kg) was administered 30 min prior to each test.
Results:
Lamotrigine (30 mg/kg) significantly decreased the PR breakpoints and cue- and ketamine-induced reinstatement, but not affect locomotor activity, demonstrating that lamotrigine can reduce the reinforcing effect of ketamine and ketamine-seeking behavior.
Conclusions:
Our data support the hypothesis that lamotrigine is capable of reducing the reinforcing efficacy of ketamine and also lowering the risk of relapse.
... Lamotrigine elevated intracranial self-stimulation (ICSS) thresholds and also attenuated cocaine-induced reduction of ICSS thresholds (Beguin et al., 2012). In addition, lamotrigine reduced the relapse-like alcohol drinking behaviors, the cue-induced alcohol reinstatement and alcohol deprivation effect in rats (Vengeliene et al., 2007). Repeated treatment with lamotrigine significantly reduced the voluntary alcohol intake in alcohol preferring rats (Zalewska-Kaszubska et al., 2015). ...
Background: Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. A case report has demonstrated that a ketamine addict experienced a significant reduction in craving and ketamine use after taking lamotrigine. The present study determined whether lamotrigine can reduce the motivation for ketamine and prevent the relapse to ketamine seeking behavior in rats. Methods: Male Sprague-Dawley rats were trained to respond for intravenous ketamine (0.5 mg/kg/infusion) self-administration or food pellets. The effects of lamotrigine on the motivation for ketamine or food were assessed using breakpoint test under a progressive ratio (PR) paradigm. Furthermore, the effects of lamotrigine on reinstatement of ketamine-seeking and food-seeking behaviors were examined after extinction. Results: Lamotrigine significantly decreased the breakpoint for ketamine and prevented cue- and ketamine priming-induced reinstatement of ketamine seeking behavior. However, lamotrigine did not affect the breakpoint for food reinforcement, cue-induced reinstatement of food-seeking behavior, or spontaneous locomotor activity. Conclusions: Our data reveal that lamotrigine is capable of attenuating the reinforcing efficacy of ketamine and reducing ketamine craving and relapse risk, which lays the foundation for conducting clinical trials in patients with ketamine use disorder.
... In addition to stress, other factors are associated with drug seeking resumption following abstinence. One of such factors is the exposure to environmental cues associated with drug use (Bachteler et al., 2005;Cannella et al., 2009;Ciccocioppo et al., 2001Ciccocioppo et al., , 2004Ciccocioppo et al., , 2003Stopponi et al., 2011;Vengeliene et al., 2007). Although it is well demonstrated that exposure to environmental cues can lead to relapse and that the CRF system is involved in relapse to alcohol use, the relationship between relapse induced by environmental cues and the CRF system has not been sufficiently studied yet. ...
... Finally, the last dopaminergic receptor we evaluated is the DRD3 gene. Some studies have reported this to be a crucial receptor in mediating dopaminedependent processes related to alcohol craving and relapse (Vengeliene et al., 2007), while others have reported no association of DRD3 with alcohol excessive consumption (Wiesbeck et al., 2006;Kim et al., 2007). ...
Aims:
To examine the role of genetic and environmental factors in the pathogenesis of alcohol dependence in a Spanish cohort of women and men.
Methods:
We analyzed the relationship between 56 genetic variants in 7 genes associated with the dopaminergic reward pathway and excessive alcohol consumption. The study sample (N = 1533, of which 746 were women) consisted of 653 heavy consumers and 880 very low consumers from the Spanish subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. Lifestyle variables were also examined to assess associations between genetic and environmental factors.
Results:
No statistically significant differences were found between cases and controls for the allele frequencies in five genes: TH, SLC18A2, DRD1, DRD3 and COMT. Conversely, some alleles of the 12 SNPs from the DRD2 locus and the 5 from the MAOA locus showed significant associations with excessive alcohol consumption. Namely, rs10891556 (DRD2) proved to be the only SNP positively correlated with excessive alcohol consumption in both sexes. DRD2 rs1800497 and rs877138 were significantly associated in men, whereas DRD2 rs17601612 and rs4936271 and MAOA rs5906898 were associated with excessive alcohol consumption in women. A correspondence analysis provided an overall lifestyle profile of excessive drinkers, who were predominantly men who smoked, had large intakes of meat, small intakes of fruit and vegetables, whose jobs did not require high education levels and who engaged in little physical activity.
Conclusions:
It has shown the influence of dopaminergic pathway in the genetics of alcohol dependence with differences between men and women and providing a lifestyle profile of excessive drinkers.
... Responses at the ethanol-associated lever were followed by the activation of the syringe pump and the presentation of the CS (light). The first two lever presses resulted in the delivery of ethanol, ie, ~ 60 μl of liquid that served as an additional olfactory/ gustatory cue (see also Vengeliene et al, 2007, for details). To test the effect of A-705253 on cue-induced reinstatement , animals were injected IP with either vehicle, 3 mg/kg of A-705253, or 10 mg/kg of A-705253 randomized throughout three reinstatement sessions separated by 5 days based on a Latin square design. ...
Preclinical studies revealed contribution of N-methyl-D-aspartate receptors (NMDAR) to a variety of neuropsychiatric diseases including alcoholism, but development of NMDAR antagonists for therapeutic use has been a challenge, in part due to severe side effects. One of the key intracellular events resulting from stimulation of NMDAR is activation of calpains - calcium-dependent cysteine proteases. Here we studied whether inhibition of calpains would produce therapeutic-like effects of NMDAR antagonists but without their NMDAR-mediated side effect profile. The calpain inhibitor A-705253 (3-10 mg/kg) was tested a model of cue-induced reinstatement of alcohol-seeking behavior in post-dependent Wistar rats, and in an alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats, two behavioral models for alcohol-seeking and relapse, respectively. We also tested the effect of A-705253 on the saccharine deprivation effect (SDE) as a selectivity measure. Acute treatment with A-705253 dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior. Repeated administration of A-705253 caused significant reductions of relapse-like excessive alcohol intake during the post-abstinence drinking days, an effect that persisted during two more successive drug-free drinking weeks, that was selective for the ADE since the SDE was unaffected. However, A-705253 did not produce psychostimulant, cognition impairing (delayed-matching-to-position), or psychotomimetic effects (specifically, phencyclidine discriminative stimulus effects). Taken together, these results demonstrate the involvement of calpains in alcohol-seeking and relapse and present a rationale for a novel pharmacological intervention that may reduce craving and relapse with minimal side effects in alcohol dependent patients.Neuropsychopharmacology accepted article preview online, 28 July 2015. doi:10.1038/npp.2015.225.
... In terms of modeling relapse behavior, the procedure termed 'alcohol deprivation effect' (ADE) appears to have appropriate face validity for several aspects of the relapse process, such as high motivation to seek/consume alcohol and loss of control. The ADE refers to a phenomenon that is observable across many species including mice, rats, monkeys and humans (Spanagel 2009), and describes a marked increase in voluntary alcohol intake following either forced short (≤24 hours) or long (≥7 days) periods of alcohol deprivation (Sinclair & Li 1989;McBride, Le & Noronha 2002;Vengeliene, Heidbreder & Spanagel 2007). In unselected male rats, daily intake increase from baseline drinking 1-2 g/kg alcohol to above 6 g/kg for a few days after the deprivation. ...
Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a ‘Diagnostic and Statistical Manual of Mental Disorders IV/V-like’ diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review.
... Lamotrigine is a sodium channel blocker with many indeterminate mechanisms of action. Lamotrigine reduced craving both in preclinical models (178) and in human trials (142). In combination with clozapine, lamotrigine was shown to reduce craving among patients suffering from schizophrenia and comorbid alcohol dependence (142). ...
Research on the concept of craving may lead to better understanding of the biobehavioural circuitries that contribute to the complexity of alcohol use disorders (AUDs). The experiences described as craving or desire to drink are often associated with physical responses such as increased salivation and heart rate, and alteration of stress hormones, as well as psychological responses such as anxiety and depression. Greater craving has been associated with an increased probability of alcohol relapse. Reversal of craving, which is understood as a symptom of protracted abstinence, offers the possibility of preventing relapses and treating alcoholism. Various medications have been studied to establish whether they are able to reduce craving; however, the results obtained from clinical studies have been inconsistent. Here, we review the interdisciplinary models developed to evaluate craving, then the different approaches used to assess and measure craving and, finally, the medications utilized and tested to lessen craving in patients suffering from AUDs.
... Recently, Vengeliene and colleagues demonstrated that lamotrigine has potential for treatment of AUDs. Their studies show that treatment of Wistar rats with lamotrigine attenuated the ADE (increased consumption after a period of abstinence/deprivation) (13,14). Using a drinkometer system, they also demonstrated that the normal pattern of alcohol intake was disrupted by the ADE (14). ...
Alcohol use disorders (AUDs) are a major public health issue and have an enormous social and economic burden in developed, developing, and third-world countries. Current pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in preventing relapse in a subset of individuals. This signifies an essential need for improved medications to reduce heavy episodic drinking and alcohol-related problems. Growing literature has provided support for the use of anticonvulsants in suppressing symptoms induced by alcohol withdrawal. Emerging clinical and preclinical evidence suggests that a number of well-tolerated anticonvulsants may also decrease alcohol drinking. This review will focus on recent evidence supporting the efficacy of novel anticonvulsants in reducing voluntary alcohol consumption in rodent models. The data demonstrate that anticonvulsants reduce drinking in standard home cage two-bottle choice paradigms, self-administration of alcohol in operant chambers, and cue- and stress-induced reinstatement of alcohol seeking behaviors in rats and mice. This review also highlights evidence that some anticonvulsants were only moderately effective in reducing drinking in select strains of rodents or models. This suggests that genetics, possible neuroadaptations, or the pharmacological target affect the ability of anticonvulsants to attenuate alcohol consumption. Nonetheless, anticonvulsants are relatively safe, have little abuse potential, and can work in combination with other drugs. The results from these preclinical and clinical studies provide compelling evidence that anticonvulsants are a promising class of medication for the treatment of AUDs.
... Ethanol was not delivered upon task completion despite the presence of cues. Prior to the reinstatement session the left dispenser was flushed with 10% ethanol and the reservoir was removed, allowing a residual 80 μl to provide an olfactory/ gustatory cue (Bäckström and Hyytiä, 2004; Vengeliene et al., 2007). Rats were randomly allocated to vehicle or drug-treatment groups. ...
Orexins are hypothalamic neuropeptides which bind to two G-protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor. While a role for OX1R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX2R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX2R in ethanol-taking and ethanol-seeking behaviour. Indiana ethanol-preferring rats were trained to self-administer ethanol (10% w/v) or sucrose (0.7-1% w/v) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. The selective OX2R antagonist TCS-OX2-29 was administered i.c.v. to assess its effect on operant self-administration and cue-induced reinstatement following extinction. Following i.c.v. injection TCS-OX2-29 reduced self-administration of ethanol, but not sucrose. Despite reducing ethanol self-administration, TCS-OX2-29 had no impact on cue-induced reinstatement of ethanol seeking. To determine where in the brain OX2R were acting to modulate ethanol self-administration, TCS-OX2-29 was microinjected into either the shell or core of the nucleus accumbens (NAc). Intra-NAc core, but not shell, infusions of TCS-OX2-29 decreased responding for ethanol. Importantly, the doses of TCS-OX2-029 used were non-sedating. Collectively, these findings implicate OX2R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX2R had no impact on sucrose self-administration. Thus, OX2R in addition to OX1R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX1R, no impact of OX2R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX2R in ethanol self-administration compared to cue-conditioned ethanol-seeking.
... Despite these encouraging results, very little other research has been conducted with lamotrigine. The only other study that has examined the effects of lamotrigine on drinking behavior was conducted with animals (rats), in which, lamotrigine was associated with reduced alcohol seeking and relapse-like drinking behaviors (Vengeliene, Heidbreder, & Spanagel, 2007). ...
There is a high degree of comorbidity between borderline personality disorder (BPD) and alcohol use disorders (AUDs). There is some evidence that this pattern of comorbidity may be associated with poorer prognosis. Although there are many different psychotherapeutic and pharmacological treatments for BPD and AUDs when they occur alone, there are very few treatment options when they occur together. The objective of this article was to review the existing treatment options-both psychotherapeutic and pharmacological-for patients with dual diagnoses of BPD and AUDs and to explore alternative treatment options that warrant further study. There have been a number of studies that have examined the efficacy of specific psychotherapies targeting drinking among patients with comorbid BPD; however, their efficacy in reducing BPD symptoms is unknown. There are also three psychotherapies that were specifically developed for patients with BPD and substance use disorders (SUDs), but only one of these (Dynamic Deconstructive Psychotherapy) has been tested among patients with dual diagnoses of BPD and AUDs. Research on pharmacotherapy for dual diagnoses of BPD and AUD is scarce, and no study has yet explored medication options that can concurrently manage symptoms of BPD and decrease alcohol consumption. Interestingly, there is growing evidence that anticonvulsants and second generation antipsychotics, the recent medications of choice for the management of BPD symptoms, may also reduce alcohol craving and consumption. Although premature, these findings are encouraging especially for this population of patients for whom treatment options are very limited.
... Some of the so-called new anticonvulsants that appeared in the 1990s (Bourgeois, 1996;Wilson and Brodie, 1996) have demonstrated efficacy in the treatment of drug abuse disorders by alleviating withdrawal symptoms (Zullino et al., 2004), reducing craving (urge to consume) (Furieri and Nakamura-Palacios, 2007;Vengeliene et al., 2007;Miranda et al., 2008;Reis et al., 2008) or attenuating the pleasurable effects of drug intake, thus avoiding relapse (Bisaga et al., 2006;Martinotti et al., 2007). Among these new antiepileptic drugs, topiramate stands out in substance abuse intervention (mainly alcohol dependence) due to its ability to reduce consumption and relapse (Kampman et al., 2004;Cubells, 2006;Nguyen et al., 2007;Kenna et al., 2009;Johnson and Ait-Daoud, 2010). ...
Impulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice.
The effects of acute and chronic administration of pregabalin (10, 20 and 40 mg·kg(-1) ) and topiramate (12.5, 25 and 50 mg·kg(-1) ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). α(2A) -Adrenoceptor, D(2) -receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively.
Acute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA.
These results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively.
... Ethanol selfadministration is reduced by competitive and non-competitive NDMA receptor antagonists (Rassnick et al., 1992; Bienkowski et al., 1999; Holter et al., 2000; Malpass et al., 2010) and competitive AMPA/kainate receptor antagonists (Stephens and Brown, 1999). Cue-induced reinstatement of ethanol maintained responding is reduced by lamotrigine, a glutamate release inhibitor (Vengeliene et al., 2007), competitive NMDA receptor antagonists (Backstrom and Hyytia, 2004; Bachteler et al., 2005), the NMDA receptor modulator acamprosate (Bachteler et al., 2005 ) as well as competitive AMPA/kainate antagonists (Backstrom and Hyytia, 2004; Sanchis-Segura et al., 2006), including topiramate (Knapp et al., 2007; Lynch et al., 2011). Previous studies in humans demonstrate clearly the potential role of iGluR modulators in the regulation of alcohol intake, craving, withdrawal symptoms and other outcome measures (Krupitsky et al., 2007; Johnson, 2010 ). ...
Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical communication and alcohol-induced changes in the abundance of the receptor subunits and/or their splice variants may result in critical functional impairments of prefrontal cortex in alcohol dependence. To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit variant and kainate (GRIK) subunit mRNA expression were studied in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were positively correlated with daily ethanol intake and blood ethanol concentrations (BEC) averaged over the 6 months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and BEC averaged over the 6 months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional studies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted.
... Lamotrigine, which inhibits sodium channel activity, is used clinically to treat epilepsy. In rodents, lamotrigine reduces alcohol relapse and reinstatement (Vengeliene et al, 2007). Also, bipolar disorder is associated with high rates of substance abuse, and preliminary studies show that lamotrigine reduces alcohol craving and intake in human alcoholics with bipolar disorder (Rubio et al, 2006) and cocaine craving and intake in addicts with bipolar disorder (Brown et al, 2006). ...
Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism.
... presented with S/CS), except that the ethanol was not made available. Additionally, the first two presses on the formerly active lever were reinforced by 30 µl of ethanol, it served as an additional olfactory/gustatory ethanol cue (Vengeliene et al. 2007). The duration of a memory retrieval session was assessed in a pilot study in which two animal groups were subjected to either a 5-or 10-min memory reactivation session and their behaviour during subsequent cue-induced ethanol-seeking testing (see below) was compared with the behaviour of animals that had not received memory reactivation procedure ('no-retrieval' control group). ...
In humans, the retrieval of memories associated with an alcohol-related experience frequently evokes alcohol-seeking behaviour. The reconsolidation hypothesis states that a consolidated memory could again become labile and susceptible to disruption after memory retrieval.
The aim of our study was to examine whether retrieval of alcohol-related memories undergoes a reconsolidation process.
For this purpose, male Wistar rats were trained to self-administer ethanol in the presence of specific conditioned stimuli. Thereafter, animals were left undisturbed in their home cages for the following 21 days. Memory retrieval was performed in a single 5-min exposure to all alcohol-associated stimuli. The protein synthesis inhibitor anisomycin, the non-competitive N-methyl-D: -aspartate (NMDA) receptor antagonist MK-801 and acamprosate, a clinically used drug known to reduce a hyper-glutamatergic state, were given immediately after retrieval of alcohol-related memories. The impact of drug treatment on cue-induced alcohol-seeking behaviour was measured on the following day and 7 days later.
Administration of both anisomycin and MK-801 reduced cue-induced alcohol-seeking behaviour, showing that memory reconsolidation was disrupted by these compounds. However, acamprosate had no effect on the reconsolidation process, suggesting that this process is not dependent on a hyper-glutamatergic state but is more related to protein synthesis and NMDA receptor activity.
Pharmacological disruption of reconsolidation of alcohol-associated memories can be achieved by the use of NMDA antagonists and protein synthesis inhibitors and may thus provide a potential new therapeutic strategy for the prevention of relapse in alcohol addiction.
... The ERK1/2 pathway is downstream from mGluR5 receptors (as well as others such as NMDA) and the blockade of mGluR5 receptors with MPEP and subsequent attenuation of reinstatement of alcohol-seeking was associated with a decrease in p-ERK1/2 expression in both the shell and the BLA. Lamotrigine inhibits the release of glutamate [45], and systemic administration attenuates cue-induced reinstatement of alcohol seeking [46], further supporting a role for glutamate in relapse to alcohol-seeking. ...
The importance of glutamate in the reinstatement of cocaine-seeking behavior has been established. New molecular and neurochemical adaptations in the glutamatergic system which drive cocaine relapse have been identified, such as the ability of CB1 receptor stimulation to reduce basal glutamate levels and the involvement of the GluR1 receptor subunit in reinstatement. Furthermore, it is apparent that similar glutamatergic neuroadaptations arise after self-administration of cocaine, heroin, nicotine, and alcohol. For example, reinstatement to cocaine, nicotine, and alcohol can be prevented both by the stimulation of group II mGluR receptors and by the blockade of group I mGluR receptors. The similarities in the neurochemistry behind relapse to these varied drug classes indicate that drugs that target the glutamate system could be effective at treating relapse to multiple types of drugs.
Background
For most psychiatric conditions, including alcohol use disorder (AUD), FDA-approved pharmacological treatments are limited and their efficacy is restricted to only certain subgroups of patients. Scientific interest in the potential of psychedelic drugs has dramatically increased because of clinical preliminary evidence of efficacy in treating various psychiatric disorders. One of the most promising compounds belonging to this class of molecules is psilocybin. Here, to elucidate the therapeutic potential and treatment modalities of this drug, we investigated the effect of psilocybin on alcohol drinking and seeking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, a well validated animal model of AUD characterized by excessive drinking and seeking.
Methods
Using male and female msP rats, we tested the effect of psilocybin on home cage voluntary alcohol consumption. We also tested the effect of the drug on the alcohol deprivation effect (ADE) model of relapse and on cue-induced reinstatement of alcohol seeking after a period of abstinence. Finally, we evaluated if psilocybin may disrupt the reconsolidation process of alcohol-related memory.
Results
Psilocybin did not reduce alcohol consumption, nor it prevented increased alcohol drinking after a period of forced abstinence and cue-induced reinstatement of alcohol-seeking. Noteworthy, in a memory retrieval-reconsolidation paradigm, psilocybin markedly attenuated resumption of alcohol seeking.
Conclusions
Altogether these data suggest that, despite psilocybin does not affect alcohol drinking and relapse, it may be highly effective if used to block the reconsolidation process of alcohol-related memories. This opens to the possibility of using this psychedelic drug in clinical settings in which AUD patients undergo procedures to recall the memory of alcohol and are then treated with psilocybin during the memory reconsolidation phase.
Understanding factors that contribute to the escalation of alcohol consumption is key to understanding how an individual transitions from non/social drinking to AUD and to providing better treatment. In this review, we discuss how the way ethanol is consumed as well as individual and environmental factors contribute to the escalation of ethanol consumption from intermittent low levels to consistently high levels. Moreover, we discuss how these factors are modelled in animals. It is clear a vast array of complex, interacting factors influence changes in alcohol consumption. Some of these factors act early in the acquisition of ethanol consumption and initial escalation, while others contribute to escalation of ethanol consumption at a later stage and are involved in the development of alcohol dependence. There is considerable need for more studies examining escalation associated with the formation of dependence and other hallmark features of AUD, especially studies examining mechanisms, as it is of considerable relevance to understanding and treating AUD.
Objective:
Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials.
Method:
In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial.
Results:
We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies.
Conclusion:
This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers.
The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study.
Understanding the psychological mechanisms and underlying neurobiology of relapse behavior is essential for improving the treatment of addiction. Because the neurobiology of relapse behavior cannot be well studied in patients, we must rely on appropriate animal models. The alcohol deprivation effect (ADE) is a phenomenon in laboratory animals that models a relapse-like drinking situation, providing excellent face and predictive validity. In rodents, relapse-like behavior is largely influenced by the genetic make-up of an animal. It is not clear which other factors are responsible for variability of this behavior, but there seems to be no correlation between levels of baseline alcohol intake and the occurrence, duration, and robustness of the ADE. Rats that undergo long-term alcohol drinking for several months with repeated deprivation phases develop a compulsive drinking behavior during a relapse situation, characterized by insensitivity to taste adulteration with quinine, a loss of circadian drinking patterns during relapse-like drinking, and a shift toward drinking highly concentrated alcohol solutions to rapidly increase blood alcohol concentrations and achieve intoxication. Some mouse strains also exhibit an ADE, but this is usually of shorter duration than in rats. However, compulsive drinking in mice during a relapse situation has yet to be demonstrated. We extend our review section with original data showing that during long-term alcohol consumption, mice show a decline in alcohol intake, and the ADE fades with repeated deprivation phases. Furthermore, anti-relapse compounds that produce reliable effects on the ADE in rats produce paradoxical effects in mice. We conclude that the rat provides a better model system to study alcohol relapse and putative anti-relapse compounds.
Environmental stimuli are powerful mediators of craving and relapse in substance‐abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug‐seeking behaviour. We address how animal models can describe the way drug‐associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance‐abuse disorders. Drug‐associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug‐seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug‐associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour.
Linked Articles
This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐20
Pharmacokinetic studies concerning D-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose D-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on D-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on D-penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of D-penicillamine were performed using young or adult ethanol-naïve rats or adult ethanol-experienced (subjected to a long-term ethanol self-administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalizedAUC0∞, V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non-linear both in young ethanol-naïve and in adult ethanol-experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2 . D-penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non-linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters DP disposition but, again, does not modify t1/2 . This article is protected by copyright. All rights reserved.
Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as 'delayed ADE'. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be triggered by acetaldehyde after ethanol consumption. Hence, we conjecture that the combination of NTX and DP, due to their distinct but complementary mechanisms to impede OR activation, may be more efficacious in the prevention of the ADE and, specifically, the 'delayed ADE'. Herein, we compare the effects of the combination NTX/DP (NTX: 2×5 mg/kg SC injection daily/DP: SC infusion (0.25 mg/h)) versus NTX on the ADE in long-term ethanol-experienced rats. As expected, NTX-treated animals displayed a delayed ADE. However, NTX/DP treatment prevented this delayed effect. Our present data indicate that this combination therapy shows an adequate anti-relapse preclinical efficacy being able to overcome the preclinical limitations of NTX alone.
Rationale
Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as d-penicillamine (DP), in relapse prevention has not been studied yet.
Objectives
The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment.
Methods
Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated.
Results
One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3–4 μg/ml, and brain DP levels in these conditions were about 2–3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE.
Conclusion
DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.
Many recent researches have confirmed the effectiveness of antiepileptic drugs in preventing alcohol dependency, whereas our previous study showed that repeated treatment with topiramate, a new antiepileptic drug, was effective in increasing the plasma levels of beta-endorphin (an endogenous opioid peptide) in rats. It is well documented that in humans a genetic deficit of beta-endorphin is often associated with alcohol addiction as alcohol consumption elevates the level of this peptide. The aim of the present study is multifaceted: to investigate the effect of repeated treatment of levetiracetam (50 or 100mg/kg b.w., twice daily) on voluntary alcohol intake in alcohol preferring rats (Warsaw High Preferring; WHP) and to assess changes in plasma beta-endorphin levels while alcohol is available and when it is not available for an extended period of time. We observed a noticeable increase in the levels of beta-endorphin in rats with free access to alcohol whether in a prolonged levetiracetam-treated or vehicle-treated group. However, in the levetiracetam group, a voluntary intake of alcohol diminished in comparison with both the pretreatment period and in comparison with the vehicle-treated rats. A similar increase in the plasma beta-endorphin levels was observed in levetiracetam-treated rats that did not have access to ethanol. This finding lets us to believe that levetiracetam may be a promising medication in treatment of alcohol dependency as its application leads to the increase in the beta-endorphin concentration and ultimately results in reducing deficiency of this peptide.
Methamphetamine is a potent psychomotor stimulant and a major drug of abuse. There is currently no effective medication available for treatment for methamphetamine addiction. The present study investigated the role of the dopamine D3 receptor on IV methamphetamine self-administration and its effect on methamphetamine induced neurochemical changes. Acute administration of the putative D3 receptor antagonists PG-01037 (10, 30 mg/kg, ip) and SB-277011A (12, 24, mg/kg, ip) significantly decreased the break-point for methamphetamine self-administration under a progressive-ratio (PR) schedule by 45 - 70%. Furthermore, both drugs dose dependently attenuated methamphetamine -triggered reinstatement of drug-seeking behavior in the reinstatement model of relapse. As with other drugs of abuse, the rewarding effects of methamphetamine are believed to be mediated by elevated levels of extracellular dopamine in the mesocorticolimbic system. The present study utilized in vivo microdialysis to examine the neurochemical mechanisms modulating the rewarding effects of methamphetamine actions evident in the various animal models of addiction. In the nucleus accumbens and ventral pallidum, acute methamphetamine (1.0 mg/kg, i.p.,) increased extracellular dopamine by 800 - 900% and decreased GABA by 60 – 65 % in the nucleus accumbens and ventral pallidum. Pretreatment with SB-277011A (12, 24 mg/kg) potentiated the methamphetamine induced dopamine increase but attenuated the methamphetamine-induced GABA decrease. Take together these data suggest that D3 selective antagonists’ pharmacotherapeutic potential in the treatment of methamphetamine addiction may involve a GABAergic mechanism. National Institute of Health National Institute of Drug Abuse Intramural Research Program Doctor of Philosophy Doctoral Department of Psychology Stephen W. Kiefer
One strategy to understand bipolar disorder is to study the mechanism of action of mood-stabilizing drugs, such as valproic acid and lithium. This approach has implicated a number of intracellular signalling elements, such as GSK3beta (glycogen synthase kinase 3beta), ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) or protein kinase C. However, lamotrigine does not seem to modulate any of these targets, which is intriguing given that its profile in the clinic differs from that of valproic acid or lithium, with greater efficacy to prevent episodes of depression than mania. The primary target of lamotrigine is the voltage-gated sodium channel, but it is unclear why inhibition of these channels might confer antidepressant efficacy. In healthy volunteers, we found that lamotrigine had a facilitatory effect on the BOLD (blood-oxygen-level-dependent) response to TMS (transcranial magnetic stimulation) of the prefrontal cortex. This effect was in contrast with an inhibitory effect of lamotrigine when TMS was applied over the motor cortex. In a follow-up study, a similar prefrontal specific facilitatory effect was observed in a larger cohort of healthy subjects, whereas valproic acid inhibited motor and prefrontal cortical TMS-induced BOLD response. In vitro, we found that lamotrigine (3-10 microM) enhanced the power of gamma frequency network oscillations induced by kainic acid in the rat hippocampus, an effect that was not observed with valproic acid (100 microM). These data suggest that lamotrigine has a positive effect on corticolimbic network function that may differentiate it from other mood stabilizers. The results are also consistent with the notion of corticolimbic network dysfunction in bipolar disorder.
Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societies. The World Health Organization ranks alcohol as one of the primary causes of the global burden of disease in industrialized countries. Alcohol-related diseases, especially alcoholism, are the result of cumulative responses to alcohol exposure, the genetic make-up of an individual, and the environmental perturbations over time. This complex gene x environment interaction, which has to be seen in a life-span perspective, leads to a large heterogeneity among alcohol-dependent patients, in terms of both the symptom dimensions and the severity of this disorder. Therefore, a reductionistic approach is not very practical if a better understanding of the pathological processes leading to an addictive behavior is to be achieved. Instead, a systems-oriented perspective in which the interactions and dynamics of all endogenous and environmental factors involved are centrally integrated, will lead to further progress in alcohol research. This review adheres to a systems biology perspective such that the interaction of alcohol with primary and secondary targets within the brain is described in relation to the behavioral consequences. As a result of the interaction of alcohol with these targets, alterations in gene expression and synaptic plasticity take place that lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, alcohol-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior.
Mesocorticolimbic dopamine (DA) transmission has been implicated in the consummatory and, more recently, the incentive-motivational aspect of ethanol's actions. The purpose of this study was to test whether ethanol-seeking behavior induced by an ethanol-associated contextual stimulus is sensitive to antagonism of DA transmission. Male Wistar rats were trained to orally self-administer 10% ethanol and to associate olfactory discriminative stimuli with the availability of ethanol (S(+)) versus nonreward (S(-)). Ethanol-reinforced operant responding then was extinguished by withholding ethanol and the associated S(+). After reaching a predetermined extinction criterion, reinstatement tests were conducted in which the animals were presented noncontingently with only the S(+) or S(-). Exposure to the S(+) but not the S(-) reinstated responding at the previously active lever. The D1 antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 5, 10, 50 microg/kg s.c.) and the D2 antagonist eticlopride (5, 10, 50 microg/kg s.c.) dose dependently decreased the number of S(+)-induced responses and increased response latency. During a second test, conducted in the same rats, 3 weeks after withdrawal from a 12-day ethanol vapor inhalation procedure, the response-reinstating efficacy of the S(+) remained unaltered. However, the potency of both DA antagonists to inhibit the S(+)-induced drug-seeking response was significantly increased. The results confirm that ethanol-related contextual stimuli reliably elicit drug-seeking behavior and suggest that this effect requires activation of DA neurotransmission. The results also indicate that chronic ethanol exposure produces changes in D1 and D2 receptor function that lead to enhanced sensitivity to the behavioral effects of antagonists for these receptors.
Rational and objectives.
The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking.
Conclusions.
The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.
Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2(Brdm1) mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2(Brdm1) mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.
Chronic vulnerability to relapse is a formidable challenge for the treatment of drug addiction. The neurobiological basis of relapse and its prevention has, therefore, attracted major attention in addiction research. Current conceptualizations of addiction recognize craving as a central driving force for ongoing drug use, as well as for relapse following abstinence. Progress has been made in understanding experiential factors, neurocircuitry components and signaling mechanisms that mediate conditioned drug-seeking behaviour, craving and long-lasting susceptibility to relapse. Importantly, stress contributes to drug craving, and there is evidence for overlap between the neural and neuroendocrine mechanisms implicated in drug desire evoked by drug cues and stress. Recent research has substantially advanced our understanding of the neurobiological factors responsible for drug craving and relapse, with promising therapeutic implications.
This study examines, for the first time, the effects of acamprosate and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist neramexane on ethanol-seeking induced by alcohol-related environmental stimuli in an animal model of relapse. Wistar rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol availability was signaled by an olfactory discriminative stimulus of orange extract (S+). In addition, each lever press was accompanied by a 5-s illumination of the operant chamber's house light (CS+). Water availability was signaled by anise odor (S-) and 5-s white noise stimulus (CS-). After completion of the conditioning phase, indicated by stable levels of responding, operant behaviors were extinguished. Prior to reinstatement tests, animals were divided into groups according to either treatment with acamprosate (100, 200 mg/kg given twice), neramexane (1.0, 2.0, 4.0 mg/kg), or vehicle. In vehicle-treated rats, re-exposure to the S+/CS+ in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of water-paired cues (S-/CS-). Acamprosate dose-dependently attenuated recovery of responding elicited by ethanol-paired cues (S+/CS+), whereas responding under S-/CS- was not modified by drug administration. Treatment with 1.0 and 2.0 mg/kg of neramexane did not significantly modify responding under both S+/CS+ and S-/CS- conditions. However, a slight reduction of cue-induced reinstatement of alcohol seeking was observed. At the dose of 4.0 mg/kg, neramexane elicited a marked inhibition of responding following presentation of both ethanol- and water-paired cues. In conclusion, acamprosate significantly and selectively reduced alcohol-seeking elicited by environmental stimuli predictive of alcohol availability. Treatment with neramexane that shares part of the pharmacological effects of acamprosate on NMDA receptors, however, resulted in a nonselective reduction of lever responding.
Our study aimed to identify new candidate genes, which might be involved in alcohol craving and relapse. To find changes in gene expression after long-term alcohol consumption, we studied gene expression profiles in the striatal dopamine system by using DNA microarrays of two different alcohol-preferring rat lines (HAD and P). Our data revealed an up-regulation of the dopamine D3 receptor (D3R) after 1 yr of voluntary alcohol consumption in the striatum of alcohol preferring rats that was confirmed by qRT-polymerase chain reaction. This finding was further supported by the finding of up-regulated striatal D3R mRNA in nonselected Wistar rats after long-term alcohol consumption when compared with age-matched control animals. We further examined the role of the D3R in mediating alcohol relapse behavior using the alcohol deprivation effect (ADE) model in long-term alcohol drinking Wistar rats and the model of cue-induced reinstatement of alcohol-seeking behavior using the selective D3R antagonist SB-277011-A (0, 1, 3, and 10 mg/kg) and the partial agonist BP 897 (0, 0.1, 1, and 3 mg/kg). Both treatments caused a dose-dependent reduction of relapse-like drinking in the ADE model as well as a decrease in cue-induced ethanol-seeking behavior. We conclude that long-term alcohol consumption leads to an up-regulation of the dopamine D3R that may contribute to alcohol-seeking and relapse. We therefore suggest that selective antagonists of this pharmacological target provide a specific treatment approach to reduce alcohol craving and relapse behavior.
Lamotrigine (LTG) is a novel antiepileptic drug (AED) with a spectrum of activity in animal models of epilepsy similar to that of phenytoin and carbam-azepine. In some models it appears to have a broader spectrum and better tolerability than these agents, however. One mechanism of action of LTG is the marked inhibition of release of the excitatory neurotransmitters glutamate and aspartate under conditions of sustained repetitive firing. LTG appears to do this by blocking voltage-sensitive sodium channels and has no direct effect on JV-methyl-D-aspartate (NMDA) receptors. In clinical trials as add-on therapy in medically refractory partial seizure patients, LTG has consistently produced a 50% reduction in seizure frequency in 25–34% of subjects. LTG is well tolerated, even in the add-on situation. In part, this appears to be related to positive behavioral effects. Desirable pharmacologic properties of LTG include low protein binding (55%), an absence of enzyme induction, and linear pharmacokinetics. The most significant adverse effect is rash, leading to a withdrawal rate of 2% of patient exposures in clinical trials.
Anti-craving compounds have recently been registered for relapse prophylaxis in weaned alcoholics in various European countries (acamprosate), and in the United States (naltrexone). Acamprosate, the Ca(2+)-salt of N-acetyl-homotaurinate, interacts with NMDA receptor-mediated glutamatergic neurotransmission in various brain regions and reduces Ca2+ fluxes through voltage-operated channels. The opioid receptor antagonist naltrexone most likely interferes with alcohol-induced reinforcement via the block of opioid receptors. In this article Rainer Spanagel and Walter Zieglgänsberger discuss the pivotal role of incremental neuroadaptation to alcohol and alcohol-associated stimuli for craving, and the possible mechanisms of action underlying the anti-craving properties of acamprosate and naltrexone.
Whole cell and perforated patch clamp experiments were conducted on cultured cortical rat neurones (7–21 days in vitro) in order to determine the effects of the anticonvulsant and glutamate release inhibitor Lamotrigine (10–100 μM), on CNS receptors and ion channels. The compound inhibited, indiscriminately, both excitatory and inhibitory synaptic events which occurred spontaneously in cultured neural circuits. The drug did not mimic diazepam as a positive modulator of GABAA currents. In the presence of tetrodotoxin, voltage-gated potassium currents and composite currents evoked byl-glutamate were not significantly modulated even at the highest dose. Unitary, fast, presumptive-sodium spikes, evoked at low frequencies, were not blocked significantly by lamotrigine. In contrast, burst firing induced by pulsed application ofl-glutamate or potassium ions was markedly depressed at 10 μM. Presumptive calcium were inhibited by lamotrifine at 100 μM. It is proposed that the drug inhibits epileptiform burst firing preferentially by state/activity dependent interactions with voltage gated cation channels. Potential mechanisms for inhibition of glutamate release are discussed.
Rats consuming alcohol voluntarily for a long time show increased alcohol consumption after a phase of alcohol deprivation and this might reflect increased craving for alcohol. Administration of memantine (1-amino-3,5-dimethyl-adamantane), a clinically used uncompetitive NMDA receptor antagonist, resulted in a significant reduction of the alcohol deprivation effect without any sedative, dysphoric or stimulant side-effects. The dose of memantine used (4.8 mg/day) resulted in serum levels close to the therapeutic range in humans. These results indicate that memantine may have therapeutic potential as an anti-craving drug for alcohol.
Theoretical considerations as well as pre-clinical data suggest a potential role for glutamate-inhibiting agents in the treatment of cocaine addiction. At present, however, there is little clinical data to inform the use of these agents for this application. In this preliminary study eighteen HIV-seropositive cocaine dependent, opiate-agonist maintained patients received lamotrigine (300 mg/day), an indirect glutamate release inhibitor, on either a standard (n = 8) or accelerated (n = 10) induction schedule for 12 weeks. Results showed a significant decrease in percentage of cocaine-positive urine screens in the standard induction lamotrigine group but not in the accelerated induction group. There were fewer reports of side-effects and fewer dropouts in the standard-induction lamotrigine group compared to the accelerated induction group. Neuropsychological assessments suggested a decrement in the Trail Making Tests, but no other decreases in cognitive functioning. We conclude that standard-induction lamotrigine warrants further investigation for the treatment of cocaine abuse in this patient population.
Rats, maintained on free access to both food and water, were trained to press a lever to obtain a 20% sucrose solution. When presentation of the sucrose solution was maintaining responding, low ethanol concentrations were added to the solution. Over 25 sessions, the solution presented as reinforcement was gradually reduced in sucrose concentration until a 10% ethanol solution with no sucrose was presented. Following this initiation procedure, ethanol concentrations up to and including 40% ethanol were found to maintain responding. At the higher ethanol concentrations, the rats consumed doses of ethanol between 0.90 and 0.95 g/kg in the 30-min session. When a concurrent choice between ethanol and water was available in the operant chamber, the rats responded on the lever associated with 10% ethanol presentation. Home cage preference between ethanol and water was found to be altered following the operant ethanol experience with the rats acceptability for 10% ethanol increased prior to the start of the experiment. This initiation procedure provides another manner in which ethanol reinforcement can be instigated in animals that have not been either food- or fluid-deprived. It is hypothesized that mechanisms which may regulate the intravascular and intragastric self-administration of ethanol may also be operating when the oral route is employed.
Actions of the new antiepileptic drug lamotrigine (LTG, Lamictal) were characterised using recombinant rat brain type IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells and native Na+ channels in rat hippocampal pyramidal neurones, using whole-cell recording and intracellular recording techniques. In CHO cells, LTG caused a tonic inhibition of Na+ currents in a concentration-dependent and voltage-dependent manner. The half-maximal inhibitory concentration (IC50) of approximately 500 μM was obtained at a holding potential (V
h) of −90 mV compared with an IC50 of 100 μM at a V
h of −60 mV. LTG (50 μM) caused a 10−mV negative shift in the slow, steady-state inactivation curve and delayed considerably the recovery from inactivation, but had no significant effects on the voltage dependence of activation or fast inactivation, suggesting that LTG acts mainly on the slow inactivated state. The affinity for the inactivated channels was estimated at 12 μM. The tonic inhibition was augmented by a use-dependent action in which a further inhibition by the drug developed during rapid repetitive stimulation using a train of 20-ms duration pulses (11 Hz). These results were consistent with the drug action being on firing properties of pyramidal neurones. Only in those epileptiform bursts which caused cumulative inactivation of Na+ spikes did LTG produce a potent inhibition. Our data suggest that the inactivated channel is a primary target for LTG action at therapeutic concentrations.
Lamotrigine (LTG) is a novel antiepileptic drug (AED) with a spectrum of activity in animal models of epilepsy similar to that of phenytoin and carbamazepine. In some models it appears to have a broader spectrum and better tolerability than these agents, however. One mechanism of action of LTG is the marked inhibition of release of the excitatory neurotransmitters glutamate and aspartate under conditions of sustained repetitive firing. LTG appears to do this by blocking voltage-sensitive sodium channels and has no direct effect on N-methyl-D-aspartate (NMDA) receptors. In clinical trials as add-on therapy in medically refractory partial seizure patients, LTG has consistently produced a 50% reduction in seizure frequency in 25-34% of subjects. LTG is well tolerated, even in the add-on situation. In part, this appears to be related to positive behavioral effects. Desirable pharmacologic properties of LTG include low protein binding (55%), an absence of enzyme induction, and linear pharmacokinetics. The most significant adverse effect is rash, leading to a withdrawal rate of 2% of patient exposures in clinical trials.
Anti-craving compounds have recently been registered for relapse prophylaxis in weaned alcoholics in various European countries (acamprosate), and in the United States (naltrexone). Acamprosate, the Ca(2+)-salt of N-acetyl-homotaurinate, interacts with NMDA receptor-mediated glutamatergic neurotransmission in various brain regions and reduces Ca2+ fluxes through voltage-operated channels. The opioid receptor antagonist naltrexone most likely interferes with alcohol-induced reinforcement via the block of opioid receptors. In this article Rainer Spanagel and Walter Zieglgänsberger discuss the pivotal role of incremental neuroadaptation to alcohol and alcohol-associated stimuli for craving, and the possible mechanisms of action underlying the anti-craving properties of acamprosate and naltrexone.
Acamprosate (calcium-acetyl homotaurinate) is a relatively new compound developed for the treatment of alcoholism and has been shown to be effective in attenuating relapse in human alcoholics. In the current study, the effects of this drug were further examined using an animal model of oral ethanol self-administration in a limited access paradigm. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice operant condition. Acute administration of acamprosate (400 mg/kg) reduced ethanol consumption and increased responding for water. Chronic administration of lower daily doses of acamprosate (100 and 200 mg/kg) blocked the increased ethanol consumption typically observed in rats after an imposed abstinence period. This effect of acamprosate was selective for ethanol, as responding for water was unaffected at any dose tested. These results with rats suggest a model by which to explore the mechanisms for anti-relapse effects of acamprosate.
Recent evidence suggests that ethanol abuse produces its diverse effects on the brain to a substantial degree by disrupting the function of the major excitatory neurotransmitter, glutamate. Ethanol, at concentrations associated with behavioral effects in humans, inhibits the N-methyl-D-aspartate (NMDA) receptor, which mediates the post-synaptic excitatory effects of glutamate. Tolerance to ethanol results in up-regulation of the NMDA receptor so that abrupt withdrawal produces a hyperexcitable state that leads to seizures, delerium tremens, and excitotoxic neuronal death. Ethanol's inhibition of the NMDA receptor in the fetal brain likely contributes to the CNS manifestations of fetal alcohol syndrome. Therapeutic strategies aimed at correcting glutamatergic dysregulation in alcoholism need to be explored.
In order to study the dynamics of ethanol drinking behaviour, male Wistar rats were given the free choice between tap water, and 5, 10 and 20% ethanol solutions. After 8 weeks of continuous access, the animals were repeatedly deprived of the ethanol solutions for 3 days every 4 weeks. In the first experiment, drinking patterns were recorded for 24 h with an electronic drinkometer device, at different time-points of ethanol experience and after an ethanol deprivation episode. The preference for more highly concentrated ethanol solutions as well as ethanol consumption increased with continuing ethanol experience. Furthermore, after the ethanol deprivation episode, the animals immediately and preferentially drank from the 20% ethanol solution, the most highly concentrated ethanol solution offered. Additionally, the number of drinking bouts, particularly at the 10 and 20% ethanol solutions, was increased during the first hour after ethanol re-presentation. In a second experiment, the effects of repeated ethanol deprivation experience, inherent in this self-administration paradigm, on anxiety-related behaviour were tested on the elevated plus-maze. Repeated ethanol deprivation proved to be more anxiogenic than the first deprivation experience. Taken together, these findings suggest that ethanol deprivation is anxiogenic in long-term voluntarily ethanol-drinking rats, which is increased by repeated ethanol deprivation experience. The possibility that anxiety during ethanol deprivation might contribute to the 'relapse'-like drinking behaviour is discussed.
We have recently shown that priming injections of alcohol and footshock stress reinstate alcohol seeking in drug-free rats. Here we tested whether naltrexone and fluoxetine, two drugs used in the treatment of alcohol dependence, would affect reinstatement of alcohol seeking induced by these events. We also determined the effects of these drugs on alcohol self-administration during the maintenance phase. Rats were trained to press a lever for a 12% w/v alcohol solution. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished. Reinstatement of drug seeking was then determined after priming injections of alcohol (0.24-0.96 g/kg) or exposure to intermittent footshock (5 and 15 min). Rats were pretreated with naltrexone (0.2-0.4 mg/kg) or fluoxetine (2.5-5 mg/kg) during maintenance or during tests for reinstatement. Both naltrexone and fluoxetine decreased lever presses for alcohol during the maintenance phase. Naltrexone blocked alcohol-induced, but not stress-induced reinstatement. In contrast, fluoxetine blocked stress-induced reinstatement, while its effect on alcohol-induced reinstatement was less consistent. The implications of these data to the understanding of relapse to alcohol are discussed.
Mesolimbic dopaminergic neurons are thought to serve as a final common neural pathway for mediating reinforcement processes. However, several recent findings have challenged the view that mesolimbic dopamine has a crucial role in the maintenance of reinforcement processes, or the subjective rewarding actions of natural rewards and drugs of abuse. Instead, there is growing evidence that dopamine is involved in the formation of associations between salient contextual stimuli and internal rewarding or aversive events. This evidence suggests that dopaminergic-neuron activation aids the organism in learning to recognize stimuli associated with such events. Thus, mesolimbic dopaminergic neurons have an important function in the acquisition of behavior reinforced by natural reward and drug stimuli. Furthermore, long-lasting neuroadaptive changes in mesolimbic dopamine-mediated transmission that develop during chronic drug use might contribute to compulsive drug-seeking behavior and relapse.
Previous findings suggested that drugs modulating glutamatergic neurotransmission could be useful in the treatment of alcohol dependence. This study examined the effects of chronic and acute treatment with MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), a novel uncompetitive N-methyl-D-aspartate receptor antagonist, on voluntary ethanol intake in long-term ethanol-experienced rats. Rats were implanted with mini-osmotic pumps delivering either 9.6 mg/day MRZ 2/579 or vehicle, and the effects of treatment on the alcohol deprivation effect (ADE) were studied in a four-bottle home cage-drinking paradigm. The same rats were tested for a second ADE 3 weeks later in the absence of the drug. In a second experiment long-term ethanol-experienced rats trained in an operant free-choice ethanol self-administration paradigm with concurrent water received acute MRZ 2/579 treatment (0-4 mg/kg i.p.) before a 23-h session either during basal drinking or during the ADE. In an additional experiment, MRZ 2/579 (0.5-4 mg/kg i.p.) was tested for generalization to the ethanol cue in a drug discrimination procedure. Chronic MRZ 2/579 treatment selectively abolished the increased ethanol intake during the ADE. This effect depended on the presence of the drug. Acute MRZ 2/579 treatment (2 and 4 mg/kg) had a short-lasting reductive effect on lever pressing for ethanol, but not for water, both during the ADE and basal drinking. MRZ 2/579 dose dependently generalized to the ethanol cue in the drug discrimination experiment. It is concluded that MRZ 2/579 might exert its reducing effect on ethanol intake by substituting for some of the stimulus properties of ethanol.
Previous research indicated that 5-HT(3) antagonists can reduce ethanol drinking in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT(3) antagonists MDL 72222 (MDL) or ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisition, maintenance, and following a period of deprivation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL (1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 10 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT(3) antagonist. To examine the effects of a 5-HT(3) antagonist on relapse of ethanol drinking, another group of P rats was allowed access to ethanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to ethanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 mg/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60-80%) and during maintenance drinking (35-70%) in P rats pretreated with saline during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of either MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with 1 mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) or ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observed on the first day of reinstatement. Overall, the results suggest that 5-HT(3) receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treatment with 5-HT(3) antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat.
This paper reviews the literature on maternal influences on smoking behaviors of offspring from the perspective of neuropsychiatric deficits that may be transmitted from mother to child. In particular, we review what is known regarding associations between: (1) in-utero exposure to smoking, (2) adolescent neurocognitive functioning and psychiatric comorbidity, and (3) the patterns of smoking and progression of nicotine dependence. Furthering our knowledge of these differences in susceptibility to nicotine dependence among youth will provide additional avenues for prevention and intervention efforts targeted toward those at high risk for dependence.
Some anticonvulsants have been shown to be as effective as some benzodiazepines for the treatment of alcohol withdrawal. Anticonvulsants may offer advantages over benzodiazepines in the outpatient treatment of alcohol withdrawal: they lack abuse potential, have minimal interactions with alcohol, and may be more effective in ameliorating psychiatric symptoms of alcohol withdrawal. Carbamazepine appears to be as effective as lorazepam and oxazepam in ameliorating the symptoms of alcohol withdrawal. In addition, a recent study indicates that carbamazepine may suppress post-withdrawal alcohol use. Divalproex may also reduce symptoms of alcohol withdrawal, based on several open-label studies. However, both carbamazepine and divalproex have limited usefulness in alcoholics with severe hepatic or hematologic complications. Newer anticonvulsants, such as gabapentin and vigabatrin, also appear to reduce alcohol withdrawal symptoms in preclinical and open-label clinical trials while lacking the toxicities of carbamazepine and divalproex. Controlled trials are underway exploring the efficacy and safety of newer anticonvulsants for the treatment of alcohol withdrawal.
Lamotrigine (LAG) is an antiepileptic drug which is believed to suppress seizures by inhibiting the release of excitatory neurotransmitters. The present study was aimed at investigating the effect of LAG on the 4-aminopyridine (4AP)-evoked glutamate release in cerebrocortical nerve terminals (synaptosomes). LAG inhibited the release of glutamate evoked by 4AP in a concentration-dependent manner. This inhibitory effect was associated with a reduction in the depolarization-evoked increase in the cytoplasmic free Ca2+ concentration ([Ca2+]C). In addition, LAG did not alter the resting synaptosomal membrane potential or 4AP-evoked depolarization. Furthermore, ionomycin-evoked glutamate release was not affected by LAG. Based on these results, we suggest that presynaptic calcium influx blockade and inhibition of glutamate release may underlie the mechanism of action of LAG. These action may also contribute to their neuroprotective properties in excitotoxic injury.
This study examined the effects of a nonselective opiate antagonist and antagonists selective for the mu(1) versus delta opioid receptor on ethanol-seeking behavior induced by alcohol-related environmental stimuli in an animal model of relapse. Rats were trained to self-administer ethanol (10% w/v) or water on an FR 1 schedule in 30-min daily sessions. The availability of ethanol was signaled by an olfactory discriminative stimulus (S(+)). A different olfactory stimulus (S(-)) signaled water availability. In addition, each lever-response resulting in delivery of ethanol was paired with illumination of a visual cue for 5 s (SC(+)), whereas a 5-s white noise (SC(-)) was associated with water. The rats were then subjected to a 20-day extinction phase where lever presses had no programmed consequences. Reexposure to the S(+)/CS(+) stimulus condition in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of S(-)/CS(-). Subsequently, ethanol-seeking behavior associated with the S(+)/CS(+) stimulus condition was studied in rats treated with the nonselective opiate antagonist naltrexone (0.25-1 mg/kg, SC), the delta selective antagonist naltrindole (1-5 mg/kg, IP), and the mu(1) selective antagonist naloxonazine (1-15 mg/kg, IP). Naltrexone (1 mg/kg) and naltrindole (5 mg/kg) selectively inhibited alcohol-seeking behavior. Naloxonazine (15 mg/kg) also reduced ethanol-seeking behavior but produced some nonselective behavioral suppression as well. The results provide evidence that selective blockade of either mu(1) or delta opioid receptors inhibits ethanol-seeking behavior elicited by drug-related environmental stimuli. Moreover, the data suggest that drugs aimed at the delta opioid receptor may offer advantages in the treatment and prevention of relapse compared with agents that also block the mu(1) receptor.
This review takes a translational neuroscience perspective on the role of glutamate systems in human ethanol abuse and dependence. Ethanol is a simple molecule with profound effects on many chemical systems in the brain. Glutamate is the primary excitatory neurotransmitter in the brain. Glutamatergic systems are targets for the actions of ethanol via its antagonism of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor and other mechanisms. The modulation of glutamatergic function by ethanol contributes to both euphoric and dysphoric consequences of ethanol intoxication. Adaptations within glutamatergic systems appear to contribute to ethanol tolerance and dependence and to both acute and protracted features of ethanol withdrawal. Perhaps because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic systems appear to contribute to the vulnerability to alcoholism, and novel glutamatergic agents may play a role in the treatment of ethanol abuse and dependence.
Anticonvulsant drugs have been used in the treatment of alcohol addiction with relatively good results. The purpose of the present study was to evaluate tolerance and safety of topiramate in patients presenting alcohol dependence.
We studied 24 patients that fulfilled alcohol-dependence criteria (DSM-IV) and presented other psychiatric disorders for which the use of topiramate was indicated. During the 12 weeks of the study, the patients received topiramate (262 mg/day) plus the psychoactive drugs they were taking for the other disorders. Carbohydrate-deficient transferrin (CDT) values and measures of craving and alcohol use were taken every 2 weeks.
Baseline rating of amount and frequency of craving and alcohol use decreased significantly by week 2, and CDT values decreased from week 6. Topiramate was well tolerated, and there were only three dropouts due to adverse events.
Topiramate is safe and well tolerated, and may be beneficial in the treatment of alcohol dependence. A placebo-controlled study would be of interest.
We have studied the effects of acute and chronic treatment with the anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5-hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus of freely moving rats using in vivo microdialysis.
Acute LTG (10 and 20 mg kg−1) decreased extracellular 5-HT, but had no effect on its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Dialysate DA was also decreased by LTG as were its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). When transmitter release was stimulated by either 50 μM veratridine or 100 mM K+, marked increases in the release of both transmitters occurred, but LTG was entirely without effect on this.
In chronic experiments, rats were dialysed after 2, 4, 7, 14 and 21 days of LTG treatment (5 mg kg−1, twice daily). During this period a progressively different response to the drug was seen. After 2 days, basal extracellular 5-HT was significantly greater in treated rats than control rats. This effect persisted up to 14 days, but by 21 days 5-HT levels had returned to control values. 5-HIAA levels were unaltered and there was no effect of LTG on veratridine or K+ stimulated 5-HT release.
Similarly, DA concentrations significantly increased after 2–7 days of LTG treatment, but returned and remained at basal values thereafter. During the treatment period LTG had no effect on extracellular DOPAC, but HVA followed a similar pattern to its parent transmitter. As with 5-HT, at no time point did LTG have any effect on stimulated DA release.
These neurochemical findings observed in these experiments are considered in relation to the use of LTG in bipolar disorder.
British Journal of Pharmacology (2004) 142, 136–142. doi:10.1038/sj.bjp.0705737
Glutamatergic neurotransmission has been implicated in drug-environment conditioning, but little is known about the role of glutamate in alcohol seeking maintained by alcohol-associated cues. Therefore, we examined the effects of ionotropic glutamate receptor antagonists on cue-induced ethanol-seeking behavior in the extinction/reinstatement model.
Rats were trained to orally self-administer ethanol (10% w/v) and a nonrewarding (80 microM) quinine solution on randomly alternating days. Ethanol and quinine availability were signaled by olfactory discriminative stimuli (S+/S-). In addition, ethanol delivery was accompanied by a light stimulus (CS+) and quinine delivery by an auditory stimulus (CS-). Thereafter, rats were subjected to extinction training during which responding had no programmed consequences. Reinstatement of responding was tested under three conditions: in the presence of the S-/CS-, S+/CS+, and S+/CS+ together with a small (0.2 ml) response-contingent oral ethanol dose at the beginning of the reinstatement session (S+/CS+/priming). We examined the effects of the noncompetitive NMDA receptor antagonist MK-801 (0, 0.05, 0.15 mg/kg intraperitoneally), the competitive NMDA antagonist CGP39551 (0, 5, 10 mg/kg intraperitoneally), the NMDA/glycine receptor antagonist L-701,324 (0, 2, 4 mg/kg intraperitoneally), the AMPA/kainate receptor antagonist CNQX (0, 0.5, 1.5 mg/kg intraperitoneally), and the opioid receptor antagonist naltrexone (0, 0.3, 1 mg/kg subcutaneously) on ethanol seeking under the S+/CS+/priming condition.
Presentation of the S+/CS+ stimulus condition reinstated extinguished responding, whereas presentation of the S-/CS- condition did not. Response-contingent ethanol priming enhanced reinstatement further. Under these reinstatement conditions, L-701,324, CNQX, and naltrexone inhibited ethanol-seeking behavior significantly. In contrast, MK-801 and CGP39551 failed to affect reinstated responding.
These results show that glutamate antagonism suppresses ethanol-seeking behavior induced by ethanol-paired stimuli. Furthermore, the data suggest that ionotropic glutamate receptors may have differential roles in mediation of this behavior.
The development of treatments for alcohol dependence has been significantly complicated by the multiple actions of ethanol at the neurotransmitter level, heterogeneity among patients with alcohol dependence, the complexity of defining and measuring the phenomenon of craving, and the challenge of quantifying alcohol intake in patients. Increasingly, anticonvulsant medications are showing promise for the safe and effective amelioration of alcohol withdrawal symptoms. Furthermore, there is evidence that anticonvulsant medications are promising treatments for reducing drinking and preventing relapse among alcohol-dependent individuals. In recent years, many medications have been evaluated for the treatment of alcohol dependence, including those that interact with dopaminergic, serotonergic, opioid or glutamate and/or GABA systems. So far, naltrexone, acamprosate and, more recently, the anticonvulsant, topiramate, have shown some efficacy for the treatment of heterogeneous populations of individuals with alcohol dependence. Both ondansetron and sertraline appear to have some efficacy in treating different subgroups of alcoholic.
Topiramate, a fructopyranose derivative, was superior to placebo at improving the drinking outcomes of alcohol-dependent individuals.
To determine whether topiramate, compared with placebo, improves psychosocial functioning in alcohol-dependent individuals and to discover how this improvement is related to heavy drinking behavior.
Double-blind, randomized, controlled, 12-week clinical trial comparing topiramate vs placebo for treating alcohol dependence (1998-2001).
One hundred fifty alcohol-dependent individuals, diagnosed using the DSM-IV.
Seventy-five participants received topiramate (escalating dose of 25 mg/d to 300 mg/d), and 75 had placebo and weekly standardized medication compliance management.
Three elements of psychosocial functioning were measured: clinical ratings of overall well-being and alcohol-dependence severity, quality of life, and harmful drinking consequences. Overall well-being and dependence severity and quality of life were analyzed as binary responses with a generalized estimating equation approach; harmful drinking consequences were analyzed as a continuous response using a mixed-effects, repeated-measures model.
Averaged over the course of double-blind treatment, topiramate, compared with placebo, improved the odds of overall well-being (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.16-2.60; P =.01); reported abstinence and not seeking alcohol (OR = 2.63; 95% CI, 1.52-4.53; P =.001); overall life satisfaction (OR = 2.28; 95% CI, 1.21-4.29; P =.01); and reduced harmful drinking consequences (OR = -0.07; 95% CI, -0.12 to -0.02, P =.01). There was a significant shift from higher to lower drinking quartiles on percentage of heavy drinking days, which was associated with improvements on all measures of psychosocial functioning.
As an adjunct to medication compliance enhancement treatment, topiramate (up to 300 mg/d) was superior to placebo at not only improving drinking outcomes but increasing overall well-being and quality of life and lessening dependence severity and its harmful consequences.
The antiepileptic drug lamotrigine (LTG) is a relatively novel anticonvulsant frequently used in polytherapy and increasingly in monotherapy. LTG is believed to act by reducing excitatory glutamate (GLU) release due to an inhibition of Na(+) channels. In the present study, we have investigated the effects of acute and chronic (up to 21 days) treatment with LTG on basal and either veratridine- or KCl-stimulated release of aspartate (ASP), GLU, taurine (TAU) and GABA in the hippocampus of freely moving rats using microdialysis. Additionally, we have measured LTG concentrations in the plasma, whole brain and extracellular fluid of rats at the same time points. LTG significantly reduced basal ASP and GLU but only at the highest dose used (20 mg/kg) and was entirely without effect on basal TAU or GABA. When either veratridine or 100 mM KCl were added to the infusion medium amino acid release was evoked although the extent of this varied from one amino acid to another. LTG (10 mg/kg) reduced veratridine-evoked release of all four amino acids studied, although this was most marked in the case of GLU. LTG had no effect on KCl-stimulated amino acid release. When given for up to 21 days (2 x 5 mg/kg/day), LTG had no effect on basal amino acid levels. In contrast, LTG demonstrated over the time period studied an increasingly inhibitory effect on veratridine-evoked amino acid release. This effect of the drug was proportionally much greater in the case of GLU than for the other three amino acids studied. Measurement of plasma, whole brain tissue and extracellular LTG showed that in each of these compartments, it had reached an apparent steady state within 4 days of commencement of treatment and appeared to mirror the neurochemical changes measured. Our estimate of plasma LTG indicates that during chronic study, this was well within the therapeutic range, suggesting that the current neurochemical observations are clinically relevant.
Prime diagnostic criteria for drug addiction include uncontrollable urges to obtain drugs and reduced behavioral responding for natural rewards. Cellular adaptations in the glutamate projection from the prefrontal cortex (PFC) to the nucleus accumbens have been discovered in rats withdrawn from cocaine that may underlie these cardinal features of addiction. A hypothesis is articulated that altered G protein signaling in the PFC focuses behavior on drug-associated stimuli, while dysregulated PFC-accumbens synaptic glutamate transmission underlies the unmanageable motivation to seek drugs.
Modulators of glutamate receptors especially of the N-methyl-D-aspartate receptors (NMDARs) have recently been suggested as putative pharmacotherapeutic agents in the treatment of alcohol relapse. However, at present it is not clear, which binding and modulatory sites of the NMDAR are involved in relapse behavior. We, therefore, performed a pharmacological mapping study in long-term alcohol drinking rats using the alcohol deprivation effect (ADE) as a model for relapse behavior. In a comprehensive fashion, we studied dose-response curves, employing the following selective pharmacological agents: the NMDAR competitive antagonist CGP37849, the glycine binding site antagonist L-701.324, the NR2B subunit selective antagonist ifenprodil, which acts at the polyamine binding site, the NMDAR channel blocker neramexane, and ethanol, which acts as a functional antagonist at the NMDAR. Our data show that the animals' alcohol consumption inversely correlates with the dose of ethanol administered intraperitoneally. This indicates that under the present experimental conditions alcohol intake during an ADE is an entirely pharmacologically driven behavior that is not under the control of other factors such as taste or novelty of alcohol re-exposure. The effects of the administration of the aforementioned compounds were comparable to those of ethanol, suggesting a similar pharmacological impact on relapse behavior. Repeated administration of both competitive and uncompetitive NMDAR antagonist dose-dependently suppressed alcohol consumption during ADE. In addition, ifenprodil and L-701.324 dose-dependently reduced the expression of an ADE as well. In summary, the results suggest that an inhibition of NMDAR function in general, rather than a particular interference with a specific binding site of this receptor, is sufficient for the reduction of relapse behavior.
Comorbid alcohol dependence is common in patients with schizophrenia and is associated with a variety of serious adverse consequences. Although case reports exist concerning the positive impact of lamotrigine addition on clozapine treatment in resistant schizophrenia, a review of the literature fails to document any evidence regarding a combination of the two in the treatment of patients with schizophrenia and comorbid alcohol dependence. In the present study, we present three cases in which patients with resistant schizophrenia and comorbid alcohol use disorder were given lamotrigine to augment clozapine. Our findings suggest that clozapine plus lamotrigine may be helpful in reducing alcohol consumption and craving among patients with schizophrenia and comorbid alcohol dependence.
The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect-time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, k(abs) = 8.50 h(-1), k(el) = 0.025 h(-1), k(e0) = 3.75 h(-1), Emax = 100.0% (fixed), EC50 = 3.44 mg/L and gamma = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs.
Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics.
Gabapentin was compared with phenobarbital for the treatment of alcohol withdrawal in a randomized, open-label, controlled trial in 27 inpatients. There were no significant differences in the proportion of treatment completers between treatment groups or the proportion of patients in each group requiring rescue medication for breakthrough signs and symptoms of alcohol withdrawal. There were no significant treatment differences in withdrawal symptoms or psychological distress, nor were there serious adverse events. These findings suggest that gabapentin may be as effective as phenobarbital in the treatment of alcohol withdrawal. Given gabapentin's favorable pharmacokinetic profile, further study of its effectiveness in treating alcohol withdrawal is warranted.
Bipolar disorder is significantly associated with alcohol use disorders. Anticonvulsant drugs are used in the treatment of bipolar disorder and they have also been used to treat alcohol dependence. The purpose of the present study was to evaluate tolerance and safety of lamotrigine in a dual-diagnosis population presenting bipolar disorder and alcohol dependence. Open-label lamotrigine was examined in 28 outpatients with DSM-IV bipolar disorder and alcohol dependence. Lamotrigine was added to existing medication regimens.
Lamotrigine was started at a dose of 25 mg/day and titrated to a maximum dose of 300 mg/day. Subjects received a baseline evaluation which included a Structured Clinical Interview for DSM-IV (SCID) and weekly assessments for 12 weeks with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), Severity of Alcohol Dependence Scale (SADS), a Visual Analogue Scale for Craving severity (VASC), and alcohol consumption. The concentration of carbohydrate-deficient transferrin (CDT) was used as an indirect measure of alcohol consumption. The sample consisted of 18 men and 10 women diagnosed with alcohol dependence and bipolar disorder I (n = 21) or bipolar disorder II (n = 7), with a mean age of 36.5 +/- 7.7 years.
Significant improvement was observed in HAM-D, YMRS, and BPRS scores (p < 0.01). Craving and CDT also significantly decreased (p < 0.001). Lamotrigine was well tolerated with no dropout subjects due to adverse events.
Lamotrigine is safe and well tolerated in this sample and associated with improvement in mood, alcohol craving and alcohol consumption. A placebo-controlled study would be of interest.
Some psychoactive drugs are abused because of their ability to act as reinforcers. As a consequence behavioural patterns (such as drug-seeking/drug-taking behaviours) are promoted that ensure further drug consumption. After prolonged drug self-administration, some individuals lose control over their behaviour so that these drug-seeking/taking behaviours become compulsive, pervading almost all life activities and precipitating the loss of social compatibility. Thus, the syndrome of addictive behaviour is qualitatively different from controlled drug consumption. Drug-induced reinforcement can be assessed directly in laboratory animals by either operant or non-operant self-administration methods, by classical conditioning-based paradigms such as conditioned place preference or sign tracking, by facilitation of intracranial electric self-stimulation, or, alternatively by drug-induced memory enhancement. In contrast, addiction cannot be modelled in animals, at least as a whole, within the constraints of the laboratory. However, various procedures have been proposed as possible rodent analogues of addiction's major elements including compulsive drug seeking, relapse, loss of control/impulsivity, and continued drug consumption despite negative consequences. This review provides an extensive overview and a critical evaluation of the methods currently used for studying drug-induced reinforcement as well as specific features of addictive behaviour. In addition, comic strips that illustrate behavioural methods used in the drug abuse field are provided given for free download under http://www.zi-mannheim/psychopharmacology.de.
The Fawn-Hooded rat (FH/Wjd) is an inbred alcohol-preferring rat strain, unlike most of the other strains that were selectively bred for high alcohol intake and preference. It was chosen for study some 16 years ago because of a reported mutation that disrupted platelet serotonin function. Although the FH/Wjd rat has high alcohol intake (>5 g/kg/day) and preference (>65%), interbreeding with an alcohol-non-preferring inbred strain suggested that these measures are unrelated to the serotonin abnormality. Similarly, the exaggerated immobility of the FH/Wjd rats in the forced swim test did not correlate with the high alcohol intake. Many compounds have been tested in the FH/Wjd rats after both acute and chronic treatment and a substantial number of them have proved effective. However, as the case with opiate antagonists, tolerance to the effects of the drug can develop. An up-regulation of opioid receptors accompanied the chronic treatment and this mechanism may account for the development of tolerance. Tolerance to opiate antagonists has also been demonstrated in two of the selectively bred alcohol-preferring rat lines, but it is unknown whether this process may contribute to the relapses seen in individuals being treated with naltrexone. Other drugs that reliably decrease alcohol intake in the FH/Wjd rats include the 5-hydroxytryptamine-2A receptor antagonist, amperozide, the mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and herbal derivatives such as ibogaine, St. John's wort and kudzu extract. Thus, studies in the FH/Wjd rat have led to the discovery of a wide variety of targets for the development of novel agents to treat alcoholism. The fact that several of these drugs were shown to reduce alcohol intake in some of the selectively bred alcohol-preferring rat lines and/or alcohol-preferring vervet monkeys increases our confidence that they are good candidates for further development.
Introduction:
There has been increasing interest in the use of anticonvulsant agents in the treatment of alcoholism. Anticonvulsant agents have mostly been evaluated as an alternative to benzodiazepines in the treatment of alcohol withdrawal. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol (i.e., interactions that could increase psychomotor deficits, cognitive impairment, and increase intoxication). This is particularly important in the treatment of alcohol withdrawal and relapse prevention in outpatients. Unfortunately, these untoward clinical interactions between anticonvulsants and alcohol in alcoholic patients have not been thoroughly assessed. The current clinical laboratory study was conducted to evaluate the safety and tolerability of the anticonvulsant gabapentin in alcoholic subjects. In addition, the ability of gabapentin to reduce alcohol craving and consumption was evaluated.
Methods:
Thirty-five non-treatment-seeking alcoholic subjects were enrolled in a subacute human laboratory study and received double-blind treatment with up to 1,200 mg of gabapentin (n=18) or placebo (n=17) for 8 days. The safety and tolerability of gabapentin were monitored in the natural environment during the first 5 days of medication treatment and during a free-choice limited access consumption paradigm following an initial drink of alcohol in a bar-lab setting on Day 7.
Results:
There was no overall effect of gabapentin on drinking or craving; however, it was tolerated (e.g., mood and sedation) as well as placebo over 5 days of natural drinking. During the bar-lab drinking session, there were no differences in subjective high or intoxication between subjects treated with gabapentin or placebo.
Discussion:
This study provides initial evidence that the anticonvulsant gabapentin is safe if used in conjunction with alcohol consumption in alcoholic individuals. Further study is needed with this and other lab models to determine the utility and safety of gabapentin in the treatment of alcoholism.
Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-D-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate.
This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately.
All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam.
This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.