Relapse-like Behavior Research Articles

Phosphodiesterase 10A Regulates Alcohol and Saccharin Self-Administration in Rats

A history of stress produces increases in rodent relapse-like alcohol self-administration behavior and regional brain gene expression of phosphodiesterase 10A (PDE10A), a dual-specificity cyclic adenosine monophosphate/cyclic guanosine monophosphate-inhibiting enzyme. Here, we tested the hypothesis that administration of TP-10, a specific PDE10A inhibitor, would reduce alcohol self-administration in conditions predisposing to elevated self-administration. TP-10 administration dose-dependently (0.562, 1.0 mg/kg; subcutaneously) reduced relapse-like alcohol self-administration regardless of stress history enhancement of relapse-like behavior. TP-10 also reduced alcohol self-administration in genetically alcohol-preferring rats, as well as in alcohol-non-dependent and -dependent rats. Effective systemic TP-10 doses did not alter alcohol pharmacokinetics, significantly reduce motor activity or intrabout operant response speed, or promote a conditioned place aversion. TP-10 also reduced saccharin self-administration, suggesting a general role for PDE10A in the self-administration of reinforcing substances. PDE10A inhibition in the dorsolateral striatum, but not the nucleus accumbens, reduced alcohol self-administration. Taken together, the results implicate dorsolateral striatum PDE10A in facilitating alcohol intake and support further investigation of PDE10A systems in the pathophysiology and potential treatment of substance use disorders.

Relaxin-3/RXFP3 system regulates alcohol-seeking

Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased self-administration of alcohol in a dose-related manner and attenuated cue- and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of reward-seeking.

Social partners prevent alcohol relapse behavior in prairie voles

There is robust evidence for a protective role of interpersonal factors such as social support on alcohol relapse, but research on the mechanisms that social factors may be acting on to effectively protect individuals against relapse is lacking. Prairie voles are highly social, monogamous rodents that freely self-administer ethanol in high amounts, and are a useful model for understanding social influences on alcohol drinking. Here we investigated whether prairie voles can be used to model social influences on relapse using the alcohol deprivation effect, in which animals show a transient increase in ethanol drinking following deprivation. In Experiment I, subjects were housed alone during four weeks of 24-h access to 10% ethanol in a two-bottle choice test. Ethanol was then removed from the cage for 72 h. Animals remained in isolation or were then housed with a familiar same-sex social partner, and ethanol access was resumed. Animals that remained isolated showed an increase in ethanol intake relative to pre-deprivation baseline, indicative of relapse-like behavior. However, animals that were socially housed did not show an increase in ethanol intake, and this was independent of whether the social partner also had access to ethanol. Experiment II replicated the alcohol deprivation effect in a separate cohort of isolated animals. These findings demonstrate that prairie voles display an alcohol deprivation effect and suggest a 'social buffering' effect of relapse-like behavior in the prairie vole. This behavioral paradigm provides a novel approach for investigating the behavioral and neurobiological underpinnings of social influences on alcohol relapse.

S06 * ARE METABOTROPIC GLUTAMATE RECEPTORS PROMISING TARGETS FOR ALCOHOL ADDICTION?

S06 * ARE METABOTROPIC GLUTAMATE RECEPTORS PROMISING TARGETS FOR ALCOHOL ADDICTION?

The Selective Dopamine β-Hydroxylase Inhibitor Nepicastat Attenuates Multiple Aspects of Cocaine-Seeking Behavior

Although norepinephrine (NE) does not typically modulate cocaine self-administration under traditional schedules of reinforcement, it is required for different inducers of the reinstatement of cocaine-seeking behavior via activation of multiple adrenergic receptor subtypes. We predicted that blockade of NE synthesis would attenuate all known modalities of reinstatement and showed previously that the selective dopamine β-hydroxylase inhibitor, nepicastat, had no effect on either maintenance of operant cocaine self-administration maintained on a fixed-ratio 1 schedule or reinstatement of food seeking but did abolish cocaine-primed reinstatement. In the present series of studies, we first evaluated the dose-dependent effect of nepicastat (5, 50, or 100 mg/kg) on novelty-induced locomotor activity and found that it blunted exploration only at the highest dose. Next, we assessed the ability of nepicastat (50 mg/kg) to reduce breakpoint responding for cocaine on a progressive ratio schedule and reinstatement induced by drug-associated cues and stress. We found that nepicastat significantly lowered the breakpoint for cocaine, but not for regular chow or sucrose, and attenuated cue-, footshock-, and yohimbine-induced reinstatement. Combined, these results indicate that nepicastat can reduce the reinforcing properties of cocaine under a stringent schedule and can attenuate relapse-like behavior produced by cocaine, formerly cocaine-paired cues, and physiological and pharmacological stressors. Thus, nepicastat is one of those rare compounds that can reduce reinforced cocaine seeking as well as all three reinstatement modalities, while sparing exploratory behavior and natural reward seeking, making it a promising pharmacotherapy for cocaine addiction.

Hippocampal neurogenesis protects against cocaine-primed relapse.

Accumulating evidence demonstrates a functional role for the hippocampus in mediating relapse to cocaine-seeking behavior and extinction-induced inhibition of cocaine seeking, and dentate gyrus neurogenesis in the hippocampus may have a role. Here, we tested the hypothesis that disruption of normal hippocampal activity during extinction alters relapse to cocaine-seeking behavior as a function of dentate gyrus neurogenesis. Adult rats were trained to self-administer cocaine on a fixed-ratio schedule, followed by extinction and cocaine-primed reinstatement testing. Some rats received low-frequency stimulation (LFS; 2 Hz for 25 minutes) after each extinction session in the dorsal or ventral hippocampal formation. All rats received an injection of the mitotic marker 5-bromo-2'-deoxyuridine (BrdU) to label developing dentate gyrus neurons during self-administration, as well as before or after extinction and LFS. We found that LFS during extinction did not alter extinction behavior but enhanced cocaine-primed reinstatement. Cocaine self-administration reduced levels of 24-day-old BrdU cells and dentate gyrus neurogenesis, which was normalized by extinction. LFS during extinction prevented extinction-induced normalization of dentate gyrus neurogenesis and potentiated cocaine-induced reinstatement of drug seeking. LFS inhibition of extinction-induced neurogenesis was not due to enhanced cell death, revealed by quantification of activated caspase3-labeled cells. These data suggest that LFS during extinction disrupts hippocampal networking by disrupting neurogenesis and also strengthens relapse-like behaviors. Thus, newly born dentate gyrus neurons during withdrawal and extinction learning facilitate hippocampal networking that mediates extinction-induced inhibition of cocaine seeking and may play a key role in preventing relapse.

Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice

Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse-like behaviour can be investigated using animal models of drug seeking. As yet there have been no comprehensive brain mapping studies that have specifically examined the neuroanatomical substrates of cue-induced opiate seeking following abstinence in a mouse operant paradigm. The aim of this study was to compare the brain regions involved in sucrose vs. morphine seeking following protracted abstinence in mice. Male CD1 mice were trained to respond for either sucrose (10% w/v) or intravenous morphine (0.1 mg kg(-1) per infusion) in an operant paradigm in the presence of a discrete cue. Once stable responding was established, mice were subjected to abstinence in their home cages for 3 weeks and then perfused for tissue collection, or returned to the operant chambers to assess cue-induced reward seeking before being perfused for tissue collection. Brain tissue was processed for Fos immunohistochemistry and Fos expression was quantified in a range of brain nuclei. We identified unique patterns of neuronal activation for sucrose and morphine seeking mice as well as some overlap. Structures activated in both ‘relapse' groups included the anterior cingulate and orbitofrontal cortex, nucleus accumbens shell, bed nucleus of the stria terminalis, substantia nigra pars compacta, ventral tegmental area, hippocampus, periaqueductal grey, locus coeruleus and lateral habenula. Structures that were more activated in morphine seeking mice included the nucleus accumbens core, basolateral amygdala, substantia nigra pars reticulata, and the central nucleus of the amygdala. The dorsal raphe was the only structure examined that was specifically activated in sucrose seeking mice. Overall our findings support a cortico-striatal limbic circuit driving opiate seeking, and we have identified some additional circuitry potentially relevant to reward seeking following abstinence.

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking

Orexinergic signalling is critical to drug relapse-like behaviour; however, the CNS sites(s) of action remain unknown. Two candidate brain regions are the paraventricular thalamus (PVT) and ventral tegmental area (VTA). We assessed the effect of intra-PVT or -VTA administration of the orexin-1 receptor (OrxR1) antagonist SB-334867 on discriminative cue-induced cocaine-seeking. Animals received either PVT- or VTA-directed SB-334867 (0, 3 or 6 μg; 0, 1 or 3 μg, respectively) prior to reinstatement testing elicited by presenting cocaine-paired stimuli (S+). The effect of VTA-directed injections of SB-334867 (0 or 3 μg) on locomotor activity was also assessed. Intra-VTA, but not -PVT, SB-334867 dose-dependently attenuated S+-induced reinstatement (3 μg dose, p<0.01). Intra-VTA SB-334867 had no effect on locomotor activity. We conclude that OrxR1 signalling within the VTA, but not the PVT, mediates cue-induced cocaine-seeking behaviour. We hypothesize that blockade of VTA OrxR1 signalling may reduce nucleus accumbens dopamine in response to drug cue presentation.

Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429.

Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined. Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats. L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding. At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution. To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.

Per1Brdm1 mice self-administer cocaine and reinstate cocaine-seeking behaviour following extinction

A clear interrelationship between biological rhythms and addiction has emerged from recent preclinical and clinical studies. In particular, the manipulation of the so-called 'clock genes' interferes with the manifestation of drug-related responses. For instance, Period 1 (Per1(Brdm1)) mutant mice do not display behavioural sensitization in response to repeated cocaine administration and do not express cocaine conditioned place preference, in contrast to control littermates. To assess the involvement of the mPer1 gene in a robust model of cocaine reinforcement and relapse-like behaviour, we tested Per1(Brdm1) mutant mice and their littermates for self-administration of several doses (0.06-0.75 mg/kg/infusion) of cocaine, and for reinstatement of an extinguished cocaine-seeking response. Per1(Brdm1) mutant mice did not differ from control littermates in their propensity to self-administer cocaine or to reinstate an extinguished cocaine-seeking behaviour in response to drug-associated cues or cocaine priming. In contrast to our earlier data on Per1(Brdm1) mutant mice in cocaine sensitization and conditioned place preference, this finding does not suggest a relationship between the circadian clock gene mPer1 in cocaine self-administration and reinstatement of cocaine-seeking behaviour. This study adds one further example to the notion that various behavioural tests usually used in addiction research rely on different neurobiological substrates.

Activation of Nuclear PPARγ Receptors by the Antidiabetic Agent Pioglitazone Suppresses Alcohol Drinking and Relapse to Alcohol Seeking

Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARγ) receptors, which in the brain are expressed both in neurons and in glia. We evaluated the effect of PPARγ activation by TZDs on alcohol drinking, relapse-like behavior, and withdrawal in the rat. We also tested the effect of TZDs on alcohol and saccharin self-administration. We showed that activation of PPARγ receptors by pioglitazone (0, 10, and 30 mg/kg) and rosiglitazone (0, 10 and 30 mg/kg) given orally selectively reduced alcohol drinking. The effect was blocked by pretreatment with the selective PPARγ antagonist GW9662 (5 μg/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARγ receptors in the central nervous system. Pioglitazone abolished reinstatement of alcohol seeking, a relapse-like behavior, induced by yohimbine, a pharmacologic stressor, but did not affect cue-induced relapse. In the self-administration experiments, pioglitazone reduced lever pressing for alcohol but not for saccharin. Finally, pioglitazone prevented the expression of somatic signs of alcohol withdrawal. These findings provide new information about the role of brain PPARγ receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions.

The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood–brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 ( N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats

A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents. The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats. The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats. Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens. These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.

Alcohol‐seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate‐oxidase‐coated biosensors

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.

Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use–dependent inhibitor of dopamine synthesis

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

Pre-Clinical Evidence that Corticotropin-Releasing Factor (CRF) Receptor Antagonists are Promising Targets for Pharmacological Treatment of Alcoholism

Alcoholism is a chronic disorder characterized by cycling periods of excessive ethanol consumption, withdrawal, abstinence and relapse, which is associated with progressive changes in central corticotropin-releasing factor (CRF) receptor signaling. CRF and urocortin peptides act by binding to the CRF type 1 (CRF1R) or the CRF type 2 (CRF2R) receptors, both of which have been implicated in the regulation of neurobiological responses to ethanol. The current review provides a comprehensive overview of preclinical evidence from studies involving rodents that when viewed together, suggest a promising role for CRFR antagonists in the treatment of alcohol abuse disorders. CRFR antagonists protect against excessive ethanol intake resulting from ethanol dependence without influencing ethanol intake in non-dependent animals. Similarly, CRFR antagonists block excessive binge-like ethanol drinking in non-dependent mice but do not alter ethanol intake in mice drinking moderate amounts of ethanol. CRFR antagonists also protect against increased ethanol intake and relapse-like behaviors precipitated by exposure to a stressful event. Additionally, CRFR antagonists attenuate the negative emotional responses associated with ethanol withdrawal. The protective effects of CRFR antagonists are modulated by CRF1R. Finally, recent evidence has emerged suggesting that CRF2R agonists may also be useful for treating alcohol abuse disorders.

Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking

Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine. NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment. The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively. These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

Metabotropic Glutamate Receptor Ligands as Potential Therapeutics for Addiction

There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials.

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK 1/2 phosphorylation in specific limbic brain regions: Blockade by the mGluR5 antagonist MPEP

Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK 1/2) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK 1/2 activation in reward-related limbic brain regions. Selectively-bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10 mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10 mg/kg) conditions for analysis of p-ERK 1/2, total ERK 1/2, and p-ERK 5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a three to five-fold increase in p-ERK 1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK 1/2 IR. p-ERK 1/2 IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK 5 were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK 1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK 1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.