[Show abstract][Hide abstract] ABSTRACT: Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared to heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with short and long access to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from long access self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid dependent subjects.Neuropsychopharmacology accepted article preview online, 18 December 2012; doi:10.1038/npp.2012.261.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist-induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction.
Science translational medicine 08/2012; 4(146):146ra110. · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.
Journal of Neuroscience 05/2012; 32(22):7563-71. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.
[Show abstract][Hide abstract] ABSTRACT: Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
[Show abstract][Hide abstract] ABSTRACT: Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten.
Journal of Medicinal Chemistry 06/2011; 54(14):5195-204. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During the transition to alcohol and drug addiction, neuromodulator systems in the extended amygdala are recruited to mediate aspects of withdrawal and relapse via convergence on inhibitory gamma-aminobutyric acid (GABA) neurons in central amygdala (CeA).
This study investigated the role of neuropeptide Y (NPY) in excessive alcohol drinking by making rats dependent on alcohol via alcohol vapor inhalation. This study also utilized intracellular and whole-cell recording techniques to determine the effects of NPY on GABAergic inhibitory transmission in CeA, synaptic mechanisms involved in these NPY effects, and NPY interactions with alcohol in the CeA of alcohol-naive and alcohol-dependent rats.
Chronic NPY treatment blocked excessive operant alcohol-reinforced responding associated with alcohol dependence, as well as gradual increases in alcohol responding by intermittently tested nondependent control animals. Neuropeptide Y decreased baseline GABAergic transmission and reversed alcohol-induced enhancement of inhibitory transmission in CeA by suppressing GABA release via actions at presynaptic Y(2) receptors.
These results highlight NPY modulation of GABAergic signaling in central amygdala as a promising pharmacotherapeutic target for the treatment of alcoholism. Gamma-aminobutyric acid neurons in the CeA likely constitute a major point of convergence for neuromodulator systems recruited during the transition to alcohol dependence.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of opioid abuse and dependence has been on the rise in just the past few years. Animal studies indicate that extended access to heroin produces escalation of intake over time, whereas stable intake is observed under limited-access conditions. Escalation of drug intake has been suggested to model the transition from controlled drug use to compulsive drug seeking and taking. Here, we directly compared the pattern of heroin intake in animals with varying periods of heroin access. Food intake was also monitored over the course of escalation. Rats were allowed to lever press on a fixed-ratio 1 schedule of reinforcement to receive intravenous infusions of heroin for 1, 6, 12, or 23h per day for 14 sessions. The results showed that heroin intake in the 12 and 23h groups markedly increased over time, whereas heroin intake in the 1h group was stable. The 6h group showed a significant but modest escalation of intake. Total heroin intake was similar in the 12 and 23h groups, but the rate of heroin self-administration was two-fold higher in the 12h group compared with the 23h group. Food intake decreased over sessions only in the 12h group. The 12 and 23h groups showed marked physical signs of naloxone-precipitated withdrawal. These findings suggest that 12h heroin access per day may be the optimal access time for producing escalation of heroin intake. The advantages of this model and the potential relevance for studying drug addiction are discussed.
Pharmacology Biochemistry and Behavior 03/2011; 98(4):570-4. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The anxiolytic effects of neuropeptide Y (NPY) are mediated in part by the central nucleus of the amygdala (CeA), a brain region involved in the regulation of alcohol-drinking behaviors. Centrally administered NPY suppresses alcohol drinking in subpopulations of rats vulnerable to the development of high alcohol-drinking behavior. The purpose of the current study was to determine the role of NPY in the CeA on elevated alcohol drinking produced by alcohol dependence. Adult male Wistar rats were trained to respond for 10% w/v alcohol in an operant situation with the use of a supersaccharin fading procedure. Following stabilization of responding, rats were divided into two groups matched for intake and given daily access to either alcohol-containing (9.2% v/v) liquid diet or an isocaloric control diet. Following extended access to the diet and reliable separation of operant responding between dependent and non-dependent rats during 6-h withdrawal tests, all rats were implanted bilaterally with cannulae aimed at the CeA. Rats were then infused with 4 NPY doses (0.0, 0.25, 0.5, 1.0 microg/0.5 microl aCSF) in a within-subjects Latin-square design during acute withdrawal and tested for operant alcohol responding 30 min later. Alcohol-dependent rats exhibited higher operant alcohol responding than non-dependent rats when infused with vehicle, but responding was similar in the two groups following infusion of all doses of NPY. These results indicate that NPY abolishes dependence-induced elevations in alcohol drinking and implicate the recruitment of limbic NPY systems in the motivational drive to consume alcohol following the transition to dependence.
Pharmacology Biochemistry and Behavior 10/2008; 90(3):475-80. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The immediate early gene, activity-regulated cytoskeleton-associated protein (Arc), has been implicated in synaptic plasticity. However, the role of Arc in alcoholism is unknown. Here, we report that the anxiolytic effects of acute ethanol were associated with increased brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (trkB) expression, increased phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), Elk-1, and cAMP responsive element-binding protein (CREB), increased Arc expression, and increased dendritic spine density (DSD) in both the central amygdala (CeA) and medial amygdala (MeA) but not in the basolateral amygdala (BLA) of rats. Conversely, the anxiogenic effects of withdrawal after long-term ethanol exposure were associated with decreased BDNF and trkB expression, decreased phosphorylation of Erk1/2, Elk-1, and CREB, decreased Arc expression, and decreased DSD in both the CeA and MeA but not in the BLA of rats. We also showed that BDNF infusion into the CeA normalized phosphorylation of Erk1/2, Elk-1, and CREB, and normalized Arc expression, thereby protecting against the onset of ethanol withdrawal-related anxiety. We further demonstrated that arresting Arc expression in the CeA decreased DSD, thereby increasing anxiety-like and alcohol-drinking behaviors in control rats. These results revealed that BDNF-Arc signaling and the associated DSD in the CeA, and possibly in the MeA, may be involved in the molecular processes of alcohol dependence and comorbidity of anxiety and alcohol-drinking behaviors.
Journal of Neuroscience 04/2008; 28(10):2589-600. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family of neurotrophins and plays a vital role in synaptic plasticity. This study investigated the involvement of the amygdaloid BDNF system in molecular mechanisms underlying anxiety and alcohol-drinking behaviors. Male Sprague Dawley rats were cannulated targeting central amygdala (CeA), medial amygdala (MeA), or basolateral amygdala (BLA), and BDNF expression was manipulated using an antisense oligodeoxynucleotide (ODN) strategy. Anxiety-like and alcohol-drinking behaviors were measured after infusion of BDNF sense and antisense ODNs with or without BDNF coinfusion, using the elevated plus-maze test and two-bottle free-choice paradigm, respectively. Here we report that BDNF antisense ODN infusions into the CeA and MeA, but not BLA, provoked anxiety-like behaviors in rats, which were rescued by BDNF coinfusion. The levels of BDNF, p-ERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2), and p-CREB (phosphorylated cAMP responsive-element binding protein) were decreased by BDNF antisense, but not by sense, ODN infusions, which were restored to normal after BDNF coinfusions. Furthermore, BDNF antisense ODN infusions into the CeA or MeA, but not into BLA, increased alcohol intake, which was attenuated by BDNF coinfusions. These novel results suggest that decreased BDNF levels in the CeA and MeA, but not in the BLA, are crucial in regulating alcohol-drinking and anxiety-like behaviors in rats.
Journal of Neuroscience 09/2006; 26(32):8320-31. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The nucleus accumbens (NAc) brain structures have been implicated in the reward and reinforcing properties of ethanol. The present study investigated the role of nucleus accumbal cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling in alcohol drinking and anxiety-like behaviors of rats. It was found that infusion of PKA inhibitor (Rp-cAMP) into the NAc shell significantly increased the alcohol but not the sucrose intake, without modulating the anxiety-like behaviors, as measured by elevated plus maze test in rats. PKA inhibitor infusion into the NAc shell significantly decreased the protein levels of alpha-catalytic subunit of PKA (PKA-Calpha) and phosphorylated cAMP response element-binding protein (p-CREB) as well as decreased the protein levels of neuropeptide Y (NPY) in the shell but not in the NAc core of rats. On the other hand, infusion of PKA activator (Sp-cAMP) or NPY alone into the NAc shell did not produce any changes in alcohol intake; however, when these agents were coinfused with PKA inhibitor, they significantly attenuated the increases in alcohol preference induced by pharmacological inhibition of PKA. Interestingly, PKA activator coinfusion with PKA inhibitor into the NAc shell significantly normalized the PKA inhibitor-induced decreases in the protein levels of PKA-Calpha and p-CREB as well as of NPY in the NAc shell of rats. Taken together, these results provide the first evidence that decreased PKA function in the NAc shell is involved in alcohol drinking but not in anxiety-like behaviors of rats. Furthermore, decreased function of PKA may regulate alcohol drinking behaviors via CREB-mediated decreased expression of NPY in the NAc shell of rats.
[Show abstract][Hide abstract] ABSTRACT: An increasing body of evidence suggests that genetic factors play a role in alcohol drinking behaviors. C57BL/6J (C57) mice innately consume larger amounts of alcohol compared to that consumed by DBA/2J (DBA) mice. Furthermore, alterations in cAMP-responsive element binding (CREB) protein function in the brain have been implicated in alcohol drinking behaviors. The present investigation examined innate expression and phosphorylation of CREB in various brain structures of C57 and DBA mice. It was found that CREB expression and phosphorylation was lower, specifically in the shell structure of the nucleus accumbens, in C57 mice compared to that in DBA mice. CREB expression and phosphorylation were similar in other brain regions such as the nucleus accumbens core and the cortical, amygdaloid, hippocampal, and striatal structures of C57 and DBA mice. The expression of a cAMP-inducible gene, neuropeptide Y (NPY), was also investigated in the nucleus accumbens region of C57 and DBA mice. It was found that in C57 mice, NPY protein levels were lower in the shell but not in the core structure of the nucleus accumbens compared to that in DBA mice. It was also found that C57 mice are not innately anxious, but they consume larger amounts of alcohol than do DBA mice. Because the shell structure of the nucleus accumbens has been implicated in reward mechanisms of alcohol, it is possible that lower CREB function in this brain structure may be in part associated with the excessive alcohol drinking behavior of C57 mice.
Journal of Neuroscience Research 01/2004; 74(6):967-75. · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To define the molecular basis of alcohol drinking behaviors, the effects of voluntary ethanol intake on the expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and on the expression and phosphorylation of cAMP responsive element binding protein (CREB) [corrected] in the nucleus accumbens (NAc), central amygdala, and frontal cortex of rats were investigated. Voluntary ethanol intake significantly decreased the expression of CaM kinase IV and CREB phosphorylation but not of CREB protein levels [corrected], specifically in the shell of NAc. These changes were not observed in the core of NAc, central amygdala and frontal cortex. Mianserin treatment significantly attenuated ethanol intake and antagonized the voluntary ethanol-induced reduction in expression of CaM kinase IV and CREB phosphorylation in the shell of NAc. This is the first evidence to suggest that decreased CaM kinase IV-dependent CREB phosphorylation in the shell region of NAc may play a role in the reward mechanisms of alcohol drinking.