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Effects of acamprosate on memory in healthy young subjects
Abstract
Several studies have shown acamprosate (calciumacetylhomotaurinate) to increase abstinence rates in weaned alcoholics. Chronic alcoholics often suffer from cognitive deficits. Since acamprosate appears to interact with N-methyl-D-aspartate (NMDA) receptors, a subclass of glutamate receptors playing an important role in learning and memory processes, this study was performed in order to investigate different cognitive functions during administration of acamprosate.
A randomized, double-blind, cross-over, placebo-controlled design, involving 12 healthy male volunteers was used. Acamprosate 2 g daily per os or placebo were administered for 7 days respectively, with a wash-out interval of 21 days between phases. Mood and different memory functions (i.e., working memory, delayed recall, recognition tasks) were assessed.
It was shown that a dose of acamprosate 2 g/day for 7 days may produce an impairment in delayed free recall. Recognition tasks, short term working memory and mood were not altered.
The present study supports the hypothesis that acamprosate impairs memory functions. This is in keeping with the concept of acamprosate acting as NMDA receptor antagonist. The limitations of the study are discussed.
... The objectives of this study are to determine if there is a pharmacokinetic (PK) or pharmacodynamic (PD) drug interaction between acamprosate and naltrexone in normal, healthy adult subjects. Chronic heavy alcohol intake and some pharmacological agents selective for either opioid or NMDA receptors have been associated with changes in memory and cognition (Chaves et al. 1988;Cohen et al. 1983;Kathmann et al. 1996;Malenka 1991;O'Mahony and Doherty 1996;Parsons and Farr 1981;Schneider et al. 1999;Willetts et al. 1990). Therefore, evaluation of a pharmacodynamic drug interaction will focus on tests of cognitive functioning. ...
... Rather, the different pharmacodynamic profiles of acamprosate and naltrexone found on cognitive testing support the view that these drugs operate via different neural pathways and mechanisms. From a clinical perspective, these changes in performance from baseline were detected in a statistically powerful within subjects design, but the magnitude of the differences are small, i.e., 10-30 milliseconds in mean performance speed, or recall of approximately one word, over an entire task sequence as per prior reports (Schneider et al. 1999). ...
Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-beta-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-beta-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.
... The role that modulation of glutamatergic signalling through acamprosate may have in relation to longer-term cognitive processes has also been investigated. Human studies have failed to demonstrate significant improvements or detriment on working memory in healthy controls (Schneider et al., 1999) and, memory and attention measures in patients with schizophrenia and co-morbid alcohol dependence (Ralevski et al., 2011). Whereas pre-clinical evidence suggests that both ethanol consuming rats and ethanol naïve rats experience an improvement in both spatial learning in Morris Water Maze paradigms, and short-term memory tasks using social recognition tests Szulc et al., 2002). ...
There is an increasing awareness of the link between chronic alcohol consumption and the development of cognitive, behavioural and functional deficits. Currently, preventative strategies are limited and require engagement in dedicated long-term rehabilitation and sobriety services, the availability of which is low. The acute alcohol withdrawal syndrome is an episode of neurochemical imbalance leading to autonomic dysregulation, increased seizure risk and cognitive disorientation. In addition to harm from symptoms of alcohol withdrawal (e.g. seizures), the underpinning neurochemical changes may also lead to cytotoxicity through various cellular mechanisms, which long-term, may translate to some of the cognitive impairments observed in Alcohol-Related Brain Damage (ARBD). Here we review some of the pharmacological and neurochemical mechanisms underpinning alcohol withdrawal. We discuss the cellular and pharmacological basis of various potential neuroprotective strategies that warrant further exploration in clinical populations with a view to preventing the development of ARBD. Such strategies, when integrated into the clinical management of acute alcohol withdrawal, may impact large populations of individuals, who currently face limited dedicated service delivery and healthcare resource.
... The drugs proposed mechanism of action at NMDA receptors suggests acamprosate would have negative effects on learning and memory, indeed previous cognitive work in healthy participants indicates an acamprosate-induced impairment in delayed free recall. However, working memory was unaffected by acamprosate in the same participants (101). Similarly, there was no significant effect of acamprosate on working memory performance of rats in a three-panel runway task. ...
Substance use disorders are chronic, relapsing, and harmful conditions characterized by executive dysfunction. While there are currently no approved pharmacotherapy options for stimulant and cannabis use disorders, there are several evidence-based options available to help reduce symptoms during detoxification and aid long-term cessation for those with tobacco, alcohol and opioid use disorders. While these medication options have shown clinical efficacy, less is known regarding their potential to enhance executive function. This narrative review aims to provide a brief overview of research that has investigated whether commonly used pharmacotherapies for these substance use disorders (nicotine, bupropion, varenicline, disulfiram, acamprosate, nalmefene, naltrexone, methadone, buprenorphine, and lofexidine) effect three core executive function components (working memory, inhibitory control and cognitive flexibility). While pharmacotherapy-induced enhancement of executive function may improve cessation outcomes in dependent populations, there are limited and inconsistent findings regarding the effects of these medications on executive function. We discuss possible reasons for the mixed findings and suggest some future avenues of work that may enhance the understanding of addiction pharmacotherapy and cognitive training interventions and lead to improved patient outcomes.
... None of these medications are thought to reduce drinking by enhancing cognitive functioning. Indeed, neither naltrexone (Hatsukami, Mitchell, Morley, Morgan, & Levine, 1986) nor disulfiram (Peeke et al., 1979) have an effect on cognitive performance, and acamprosate may even hinder aspects of memory functioning (Schneider et al., 1999). This cognitive enhancement strategy for treating substance use disorder is important given that recent theoretical models of substance use disorder emphasize impaired cognitive control as a predisposing and maintaining factor (Goldstein & Volkow, 2011;Lyvers, 2000). ...
Varenicline reduces drinking in people with alcohol use disorder, but little is known about the mechanisms underlying this effect. Varenicline targets α4β2 and α7 nicotinic acetylcholine receptors, which are associated with several cognitive functions such as working memory. Varenicline may improve drinking outcomes by enhancing cognitive functioning. The current manuscript reports on cognitive outcomes from a placebo-controlled, double-blind human laboratory experiment examining the effects of varenicline on drinking behavior (Verplaetse et al., 2016a). Participants were 55 adult heavy drinkers who met criteria for an alcohol use disorder. They were randomized to receive varenicline (1 mg/day, 2 mg/day) or placebo. They completed a baseline assessment of cognitive functioning (i.e., digits backward task, continuous performance task) before starting medication. After a medication titration period, they attended a laboratory session (post medication Day 8) where they completed the cognitive assessment battery and an alcohol-primed ad libitum drinking task. Blood was collected to measure plasma varenicline levels. Varenicline produced dose-dependent improvements in working memory. Although there was no significant effect of oral varenicline dose on response time on the continuous performance task, participants with higher levels of plasma varenicline showed greater improvement of reaction time (RT). Among participants receiving 2 mg/day varenicline, larger improvements in working memory were associated less drinking, although mediation analyses did not find a significant indirect effect. These findings suggest that varenicline can improve working memory above baseline levels in heavy drinkers. Varenicline may reduce rates of alcohol use by improving working memory.
... Compared to the large number of studies that have examined the effect of acamprosate on alcohol drinking, data on the effects of acamprosate on cognitive function are relatively scarce. Studies involving healthy human subjects or alcoholics have reported both moderate improvements and impairments on cognitive or psychomotor tasks (Schneider et al., 1998(Schneider et al., , 1999Soyka et al., 1998). A study using acute application of acamprosate in drug-na€ ıve rats found no effect on short-term memory (Mikolajczak et al., 2002). ...
... Although the mechanisms underlying the behavioral effects of acamprosate remain unclear, NMDA receptors are an important substrate underlying learning (for review, Sweatt, 1999), and the effects of acamprosate on glutamatergic processes may produce learning deficits. Indeed, chronic acamprosate treatment impairs delayed recall in non-alcoholic subjects (Schneider et al., 1999), although acamprosate has no effect on working memory (Kozaryn et al., 2001) or short-term memory (Mikolajczak et al., 2002) in rats. Although studies are needed to directly compare the effects of alcohol cessation aids on learning, if naltrexone and acamprosate fail to ameliorate ethanol-induced cognitive deficits and varenicline can ameliorate these deficits, varenicline may be a more complete therapeutic agent for treating alcohol abuse and addiction. ...
Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an alpha4beta2 nicotinic receptor partial agonist and alpha7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL/6 mice. Conditioning consisted of two auditory conditioned stimulus (CS; 30s, 85dB white noise)-foot shock unconditioned stimulus (US; 2s, 0.57mA) pairings. For all studies, saline or ethanol (1.0, 1.5, 2.0g/kg i.p.) was administered 15min before training, and saline or varenicline (0.05, 0.1, 0.2mg/kg i.p.) was administered 60min before either training or testing. For blood alcohol analysis, saline or varenicline (0.1mg/kg) was administered 60min before collection, and saline or ethanol (1.0, 1.5, 2.0g/kg) was administered 15min before collection. Varenicline dose-dependently ameliorated ethanol-induced conditioning deficits for all three doses of ethanol when administered before training but not when administered 24h later, before testing. In addition, varenicline did not alter blood alcohol concentration. The smoking cessation aid varenicline may have therapeutic uses for treating ethanol-associated disruptions in cognitive processes.
Ethanol has multiple specific targets in the brain that combine to yield a complexly nuanced psychoactive agent (1). However, the study of glutamatergic targets of ethanol have been a recent development (2). The recency of these clinical studies may be surprising. Glutamate is the most prevalent excitatory neurotransmitter in the cerebral cortex and it mediates most output of the cortex and limbic system (3). Also, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is among the highest-affinity targets of ethanol inthe brain (4). This chapter will provide an introduction to studies indicating that NMDA receptor blockade contributes to the behavioral effects of ethanol in humans. In doing so, it will provide clinical insights into the neurobiology of the rewarding and dysphoric effects associated with the blockade of NMDA receptors by ethanol. This chapter will then describe evidence of glutamatergic dysregulation in ethanol-dependent patients. In doing so, it will emphasize the hypothesis that ethanol tolerance may be associated with alterations in the reward valence of the NMDA antagonist component of ethanol action. It will also describe evidence that the familial vulnerability to alcoholism may be associated with alterations in NMDA receptor function that promote its use.
The terms “dual diagnosis” and “co-occurring” are used to refer to patients with both psychiatric and substance use disorders, but recent research has broadened the concept to identify patients with the presence of any two or more medical conditions as well as numerous related psychosocial conditions that derive, to varying degrees, from the medical diagnoses. Traditionally, medical care for the dually diagnosed patient has focused treatment on the individual diseases and has had unintended consequences in patients with dual diagnoses, namely, the potential for high treatment burden (e.g., polypharmacy, frequent appointments, multiple procedures) or worsening of one disease by treatment of another. Within the mental health care system, this siloing (i.e., operating in isolation) of healthcare delivery approach has led to fragmented and stymied mental health care delivery. This chapter reviews the evolution of treatment for the dually diagnosed individual and veteran from the sequential approach to parallel and finally integrated approach that affords the most benefits with the least harm.
Introduction:
Alcohol, tobacco, and illegal drug usage is pervasive throughout the world, and abuse of these substances is a major contributor to the global disease burden. Many pharmacotherapies have been developed over the last 50years to target addictive disorders. While the efficacy of these pharmacotherapies is largely recognized, their cognitive impact is less known. However, all substance abuse disorders are known to promote cognitive disorders like executive dysfunction and memory impairment. These impairments are critical for the maintenance of addictive behaviors and impede cognitive behavioral therapies that are regularly administered in association with pharmacotherapies. It is also unknown if addictolytic medications have an impact on preexisting cognitive disorders, and if this impact is modulated by the indication of prescription, i.e. abstinence, reduction or substitution, or by the specific action of the medication.
Method:
We reviewed the cognitive effects of labeled medications for tobacco addiction (varenicline, bupropion, nicotine patch and nicotine gums), alcohol addiction (naltrexone, nalmefene, baclofen, disulfiram, sodium oxybate, acamprosate), and opioid addiction (methadone, buprenorphine) in human studies. Studies were selected following MOOSE guidelines for systematic reviews of observational studies, using the keywords [Cognition] and [Cognitive disorders] and [treatment] for each medication.
Results:
971 articles were screened and 77 studies met the inclusion criteria and were reported in this review (for alcohol abuse, n=21, for tobacco n=22, for opioid n=34. However, very few comparative clinical trials have explored the chronic effects of addictolytic medications on cognition in addictive behaviors, and there are no clinical trials on the cognitive impact of nalmefene in patients suffering from alcohol use disorders.
Discussion:
Although some medications seem to enhance cognition in patients suffering from cognitive disorders, others could promote cognitive impairments, and our work highlights a lack of literature on this subject. In conclusion, more comparative clinical trials are needed to better understand the cognitive impact of addictolytic medications.
Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late Phase III trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly one-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X.
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In thirteen of sixteen placebo-controlled trials in Europe, acamprosate increased abstinence in detoxified alcohol-dependent patients. It is approved in most EU countries. Its action at N-methyl-D-aspartate (NMDA) receptors appears to account for many of its effects. The number needed to treat in the fifteen trials suitable for meta-analysis has been calculated at 8.15. Trials of naltrexone in Europe have shown less clear evidence of efficacy than trials of acamprosate, whether abstinence or relapse to heavy drinking is used as the outcome criterion. With reduction in heavy drinking days as the criterion, naltrexone compared favorably to acamprosate in an open study in moderate alcohol dependence; one double-blind study has pointed to an advantage of the combination of naltrexone with acamprosate over either drug. To date, there are no trials published of nalmefene in European clinics. While many centers routinely offer a trial of acamprosate to newly detoxified patients aiming for abstinence, naltrexone usage varies. Some centers suggest naltrexone not only for patients aiming for abstinence but also for patients for whom continued drinking is a therapeutic possibility or a clinical inevitability.
Taurine is a semi-essential amino acid widely distributed in the body and we take in it from a wide range of nutritive-tonic drinks to improve health. To date, we have elucidated that oral supplementation of taurine does not affect learning and memory in the rat. However, there are few studies concerning the direct effects of taurine in the brain at the behavior level. In this study, we intracerebroventricularly administered taurine to rats and aimed to elucidate the acute effects on learning and memory using the Morris water maze method.
Escape latency, swim distance, and distance to zone, which is the integral of the distance between the rats and the platform for every 0.16 seconds, were adopted as parameters of the ability of learning and memory. We also tried to evaluate the effect of intraperitoneal taurine administration.
Escape latency, swim distance, and distance to zone were significantly longer in the intracerebroventricularly taurine-administered rats than in the saline-administered rats. Mean swimming velocity was comparable between these two groups, although the physical performance was improved by taurine administration. Probe trials showed that the manner of the rats in finding the platform was comparable. In contrast, no significant differences were found between the intraperitoneally taurine-administered rats and the saline-administered rats.
These results indicate that taurine administered directly into the brain ventricle suppresses and delays the ability of learning and memory in rats. In contrast, it is implied that taurine administered peripherally was not involved in learning and memory.
Problems with memory and attention are common to both schizophrenia and alcohol dependence. The objectives of this study were to examine the effect of acamprosate treatment on cognition and to assess whether the changes in drinking patterns or psychotic symptoms were related to changes in cognitive functioning. Outpatients with schizophrenia spectrum disorders and alcohol dependence (n = 23) were randomized (double-blind) to either acamprosate or placebo treatment for 12 weeks. Assessments (baseline and week 12) included alcohol use, symptoms of psychosis, memory, and attention. The results showed that acamprosate had no effect on cognitive functioning and that there was no relationship between change in alcohol consumption or psychotic symptoms and change in cognitive functioning in this sample of patients. The finding that acamprosate had no negative effects on cognition is clinically relevant and reinforces previous reports that acamprosate can be used safely for alcohol reduction in this group of patients.
Alcoholism is one of the most prevalent substance dependence disorders in the world. Advances in research in the neurobiological mechanisms underlying alcohol dependence have identified specific neurotransmitter targets for the development of pharmacological treatments. Acamprosate, marketed under the brand name Campral, is an orally administered drug available by prescription in the U.S. and throughout much of the world for treating alcohol dependence. Its safety and efficacy have been demonstrated in numerous clinical trials worldwide. Here we provide an overview of acamprosate in the context of the neurobiological underpinnings of alcohol dependence. We propose that unlike previously available pharmacotherapies, acamprosate represents a prototypical neuromodulatory approach in the treatment of alcohol dependence. A neuromodulatory approach seeks to restore the disrupted changes in neurobiology resulting from chronic alcohol intake. We believe that a neuromodulatory approach will provide a heuristic framework for developing more effective pharmacotherapies for alcohol dependence.
Acamprosate, marketed under the brand name Campral, (Forest Pharmaceuticals, Inc., Saint Louis, MO, USA; Merck Sante s.a.s., Lyon, France) is an orally administered drug approved in the US and throughout much of the world for treating alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide and as with all pharmacotherapies for alcoholism, it is used in conjunction with psychosocial interventions.
This article reviews the mechanism of action, clinical efficacy and safety of acamprosate in Phase I, II and III randomized controlled trials involving healthy and alcohol-dependent populations using published reports from 1984 to 2009.
This review provides an update of the mechanism of action and the safety and efficacy profile of acamprosate.
Acamprosate appears to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Acamprosate's excellent safety profile along with several pharmacokinetic and pharmacodynamic characteristics make it well suited for treating a broad population of alcohol-dependent patients.
The aim of this study was to evaluate the effect of treatment with single (1x) and multiple (10x) doses of the anti-craving compound acamprosate (AC, calcium acetyl homotaurinate) on working memory in rats, using in a three-panel runway test. We measured tasks after the animals were treated with AC (500 mg/kg/d, i.p.); scopolamine (SC, 0.5 mg/kg/d, i.p.), a cholinergic muscarinic receptor antagonist; or both drugs concomitantly (ACSC), either for 1 day (1x) or daily for 10 consecutive days (10x). Neither 1x not 10x AC alone had a significant effect on working memory task performance, whereas treatment with SC alone had a significantly negative effect on the ability of the rats to complete the tasks. Rats receiving ACSC performed better than those receiving SC alone, making fewer errors and displaying shorter latency, similar to the performance of the control group. These observations support the hypothesis of an indirect involvement of AC in the cholinergic system.
It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures.
Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 microM) alone or on neurotoxic challenges induced by either 50 microM NMDA or 100 microM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge.
Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced "basal" propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK-801; 30 microM) and, to a lesser extent, with ifenprodil (50 microM). Acamprosate did not significantly potentiate or inhibit NMDA-induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine-induced neurotoxicity.
No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA-induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine-mediated effects.
The aim of this study was to evaluate the effect of multiple acamprosate (500.0 mg/kg, p.o.) administration on short-term memory, using the social recognition test in rats. Ifenprodil (1.0 mg/kg, i.p.), arcaine (5.0 mg/kg, i.p.) and spermidine (20.0 mg/kg, i.p.) were chosen as polyamine ligands and their action or interaction with acamprosate was also studied. The doses used did not show any sedative activity, which was assessed by measuring locomotor activity and the hypnotic effect of ethanol. The findings suggest that acute acamprosate treatment did not impair short-term memory. Multiple acamprosate and a single spermidine or arcaine administration led to better performance in the memory test, whereas no significant difference was observed in ifenprodil-treated rats. Co-administration of a single arcaine or spermidine dose with multiple acamprosate produced worse results. This means that the effect of repeated acamprosate administration can be changed by the co-administration of other polyamine ligands, so that care should be taken in interpreting.
To review the literature related to the treatment of alcohol dependence with acamprosate, a synthetic compound structurally similar to the naturally occurring amino acid, homotaurine.
Primary literature and review articles were identified by MEDLINE search (1966-June 2003). Abstracts from recent meetings were also reviewed.
Acamprosate has been marketed in 24 countries. Although the precise mechanism of acamprosate in the treatment of alcohol-dependent patients is unclear, it may restore the balance between inhibitory and excitatory neurotransmission in the central nervous system. European trials have shown consistent increases in abstinence rates compared with placebo when acamprosate use was paired with appropriate psychosocial and behavioral therapies. Decreased direct and indirect healthcare costs associated with acamprosate treatment have also been reported.
Acamprosate is a promising medication for the treatment of alcohol dependence in the US.
Acamprosate has been commercially available in the USA since 2004 to treat alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide, which overall have shown significant improvements in abstinence compared with placebo. As with all alcoholism pharmacotherapies, acamprosate is used in conjunction with psychosocial interventions. One frequently described mechanism stipulates that acamprosate supports abstinence by normalizing the often protracted dysregulation of NMDA-mediated glutamatergic neurotransmission that follows chronic heavy alcohol use and withdrawal. This article reviews the clinical safety and efficacy of acamprosate, as well as results from recent pharmacoeconomic and human laboratory studies. These data elucidate the economic benefits of acamprosate, as well as its effects on cognition and alcohol-related sleep disturbances.
Long-term potentiation (LTP) has for a long time captured the imagination of neuroscientists as a model with which to probe the cellular mechanisms of learning and memory in the mammalian brain. In this article we describe the recent evidence that has revealed the pivotal role of NMDA receptors in the induction of LTP, and discuss the possible mechanisms involved in the maintenance of the potentiated state.
Research studies focusing on the psychometric properties of the Beck Depression Inventory (BDI) with psychiatric and nonpsychiatric samples were reviewed for the years 1961 through June, 1986. A meta-analysis of the BDI's internal consistency estimates yielded a mean coefficient alpha of 0.86 for psychiatric patients and 0.81 for nonpsychiatric subjects. The concurrent validitus of the BDI with respect to clinical ratings and the Hamilton Psychiatric Rating Scale for Depression (HRSD) were also high. The mean correlations of the BDI samples with clinical ratings and the HRSD were 0. 72 and 0.73, respectively, for psychiatric patients. With nonpsychiatric subjects, the mean correlations of the BDI with clinical ratings and the HRSD were 0.60 and 0.74, respectively. Recent evidence indicates that the BDI discriminates subtypes of depression and differentiates depression from anxiety.
Male Sprague-Dawley rats were pulmonary alcoholised for 30 days. Six were treated with acamprosate (400 mg/kg/day, PO) during alcoholisation. The control nonalcoholised group also received acamprosate (400 mg/kg/day, PO) during the 30 days. At the end of the experiment, brains areas (cortex, hippocampus, thalamus, striatum, and olfactory bulbs) were dissected for the study of synaptosomal 3H-GABA uptake. In another experiment, GABA levels were determined in the same areas using HPLC with electrochemical detection. Blood ethanol levels were also measured during alcoholisation. Acamprosate treatment did not modify blood ethanol levels. In cortex and olfactory bulbs, alcoholisation increased 3H-GABA uptake (Vmax) with an increase in the affinity (Km). 3H-GABA uptake was not affected by alcoholisation in other brain areas. In hippocampus and thalamus, acamprosate treatment enhanced 3H-GABA uptake (Vmax) only in alcoholised rats. Moreover, in thalamus, alcoholisation enhanced GABA levels. The effect of alcohol and acamprosate on GABA presynaptic events is discussed and it is concluded that the action of ethanol and acamprosate on GABA transport could be, in part, responsible for the modulation by acamprosate treatment of ethanol behaviour.
Recent studies have shown that several compounds known to act as competitive or non-competitive antagonists of NMDA receptors can disrupt learning in rodents. The present study was carried out to investigate the effects of a range of NMDA antagonists, acting at several sites in the NMDA receptor complex, on the acquisition of learned fear in mice. Dose-related disruptions of learning were produced by the non-competitive antagonists phencyclidine, dizocilpine, dextromethorphan and (+) and (-)N-allylnormetazocine. The (+) enantiomer of N-allylnormetazocine was approximately twice as potent as the (-) enantiomer. The competitive NMDA receptor antagonist, CGS 19755, also blocked the acquisition of learned fear as did the non-specific glutamate antagonist riluzole. In contrast, the anti-ischaemic drugs ifenprodil and SL 82.0715, which probably act as NMDA antagonists through an effect on the polyamine site, had no effect on learning up to doses which substantially reduced locomotion. The sigma receptor ligand DTG was also inactive. These results confirm that both competitive and non-competitive NMDA antagonists disrupt learning but indicate that the extent to which such an effect is observed may depend on the site at which the compounds act within the receptor complex. Activity at sigma receptors is unrelated to the effect on learning.
There is considerable interest in the development of NMDA antagonists as potential therapeutic agents in the treatment of convulsant, neurodegenerative and anxiety disorders. Because the clinical use of phencyclidine (PCP) has been precluded by its psychotomimetic effects and abuse potential, there has been concern that other NMDA antagonists including those acting competitively might produce similar untoward effects. However, the studies in animals, reviewed here by Joyce Willetts, Robert Balster and David Leander, suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences. These differences have implications for the development of NMDA antagonists with less likelihood for producing PCP-like side-effects.
2-Amino-5-phosphonovalerate (APV, icv) phencyclidine (PCP, ip) and scopolamine (sc) dose-dependently disrupted short term working memory in radial maze. These drugs injected before, but not after training attenuated retention of long term memory in passive avoidance task. A relation of PCP action to its antagonism at NMDA receptors may be suggested.
In a previous study, it was shown that in rats Ca-acetyl homotaurinate suppresses or eliminates the high oral intake of ethanol induced by earlier chronic ethanol administration, and to a lesser degree the spontaneous ethanol intake of ethanol-naive rats. The present study examines the effect of the drug on the chronic and acute toxicity of ethanol as a possible mechanism in its alteration of the reinforcing properties of ethanol intake. In the first experiment, it was demonstrated that chronic administration of the drug (45 mg/kg per day) for 15 days, alone or combined with chronic intragastric administration of high doses of ethanol, did not significantly alter subsequent ethanol intake. In two other experiments, it was shown that the drug did not interfere with acute ethanol toxicity as tested by ethanol-induced hypothermia, motor impairment and taste aversion in ethanol-naive rats. It is concluded that the acute activity of Ca-AOTA on CNS mechanisms presumably involved in the state of tolerance-dependence, other than those concerned in ethanol-induced hypothermia, motor impairment and taste aversion, may explain its action on the reinforcing property of ethanol intake.
Inpatient alcoholics (N = 54 men), nonhospitalized members of an Alcoholics Anonymous group (N = 15 men) and nonalcoholic inpatients (N = 10 men) were shown a 55-min film on alcoholism and were subsequently given memory tests for recall and recognition of information from the film. The performance of the inpatient alcoholics was impaired relative to that of the controls. Alcoholics who were tested earlier in treatment performed worse than those tested 3 or more weeks after their last drink. These results suggest that treatment-relevant information may not be well remembered by alcholics until they have been in treatment for at least 2-3 weeks.
Acamprosate (calciumacetylhomotaurinate) is used therapeutically against relapse in weaned alcoholics. In the present study, the mechanism of action was investigated by making intracellular in vitro and extracellular in vivo recordings from rat neocortical neurons. Acamprosate (0.1-1 mM) added to the perfusion fluid in vitro reduced excitatory and inhibitory postsynaptic potentials and the depolarizing responses evoked by iontophoretic application of the excitatory amino acids, L-glutamate, L-aspartate, L-homocysteate and N-methyl-D-aspartate, but did not alter the responses to gamma-aminobutyric acid. Acamprosate decreased electrical excitability without apparently changing membrane potential, input resistance, afterhyperpolarization, or threshold and amplitude of the action potential. In vivo iontophoretic application of acamprosate reduced the extracellularly recorded unit activity elicited by iontophoretically applied L-glutamate, whereas spontaneous discharges remained unaffected. These data suggest that acamprosate reduces the postsynaptic efficacy of excitatory amino acid neurotransmitters and lowers neuronal excitability in the neocortex of the rat.
Two samples of adequately detoxified hospital-treated alcohol abusers were neuropsychologically assessed for alcohol-related cognitive impairment. Both groups manifested the commonly found impairments on the Wechsler Adult Intelligence Scale (N = 50) and the Revised Wechsler Adult Intelligence Scale (N = 44). In addition, an almost identical pattern of substantial impairment was found when both groups were examined by Russell's (1975, 1988) version of the logical memory and visual reproduction subtests of the Wechsler Memory Scale. A clear pattern of memory impairment for both verbal and non-verbal memory was found.