Lateral hypothalamic GABAergic neurons encode alcohol memories.

In alcohol use disorder, the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse but also encoding and expression of alcohol memories. GABAergic neurons in the lateral hypothalamus (LH-GABA) have been shown to be critical for food-cue memories and motivation; however, the extent to which this role extends to alcohol-cue memories and motivations remains unexplored. In this study, we aimed to describe how alcohol-related memories are encoded and expressed in LH GABAergic neurons. Our first step was to monitor LH-GABA calcium transients during acquisition, extinction, and reinstatement of an alcohol-cue memory using fiber photometry. We trained the rats on a Pavlovian conditioning task, where one conditioned stimulus (CS+) predicted alcohol (20% EtOH) and another conditioned stimulus (CS-) had no outcome. We then extinguished this association through non-reinforced presentations of the CS+ and CS- and finally, in two different groups, we measured relapse under non-primed and alcohol-primed induced reinstatement. Our results show that initially both cues caused increased LH-GABA activity, and after learning only the alcohol cue increased LH-GABA activity. After extinction, this activity decreases, and we found no differences in LH-GABA activity during reinstatement in either group. Next, we inhibited LH-GABA neurons with optogenetics to show that activity of these neurons is necessary for the formation of an alcohol-cue association. These findings suggest that LH-GABA might be involved in attentional processes modulated by learning.

Rats choose alcohol over social reward in an operant choice procedure.

The interaction between social factors and alcohol addiction is complex, with potential for both positive and negative contributions to drug use and abstinence. Positive social connections are an important component in successful abstinence, and yet the social context of alcohol use can also lead to relapse. Recently it was shown that rats overwhelmingly choose social reward over methamphetamine, cocaine, and heroin in a discrete choice procedure, and that prolonged choice for social reward attenuates incubation of drug craving. The extent to which this effect generalises to rats trained to self-administer alcohol is not known. In this study we aimed to test the effect of social reward on choice for alcohol in male and female rats. We first validated social reward self-administration in both male and female Long-Evans rats, and found that 60 s access to a social partner of the same sex can serve as an operant reinforcer. Next we trained rats to self-administer both social reward and alcohol (20% ethanol in water), and then used discrete choice trial based tests to determine whether there is a choice preference for alcohol or social reward. Our main finding is that both male and female rats showed persistent choice for alcohol over social reward, with only minor differences between the sexes. We also show that choice for alcohol could be reduced via increased response requirement for alcohol, pre-choice alcohol exposure, and also decreasing the alcohol percentage. This study shows that preference for social rewards over drugs may not generalise to rats self-administering alcohol, and we describe several conditions where choice for social reward can be developed. This study highlights the important contribution of social factors to alcohol abuse, and future studies can investigate the neurobiology underlying a shift in preference from alcohol to social rewards.

Role of anterior insula cortex in context-induced relapse of nicotine-seeking.

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.

Alcohol Seeking Under Risk of Punishment Is Associated With Activation of Cortical and Subcortical Brain Regions.

In humans, stimuli associated with alcohol availability can provoke relapse during abstinence. In this study, we investigated the role of discriminative stimuli (DS) in the control of alcohol seeking in two types of behavioral tests. The first test examined the ability of an alcohol-associated DS to promote alcohol seeking (relapse) after punishment-imposed abstinence in the presence of a different DS. Following this, we tested whether the differentially associated DS can promote and suppress alcohol self-administration in a within-session discrimination task. During the within-session discrimination task, we also tested the rate of alcohol self-administration when two DS are presented in a compound. We first trained Long-Evans male rats (n = 24) to self-administer alcohol in the presence of one DS (reward-associated discriminative stimulus, rewDS) and then punished that behavior in the presence of a different DS (punishment-associated discriminative stimulus, punDS). On the test, we found that rats tested with the rewDS showed higher alcohol seeking than rats tested with the punDS. This result shows that a single Cue DS can promote alcohol seeking in a manner comparable to contexts. Subsequently, we trained 16 of these rats in a within-session trial-based discrimination task, comprised of intervening 2-min trials of rewDS, punDS, or conflict with rewDS and punDS in compound and a reduced probability of punishment. We found that alcohol self-administration is bi-directionally regulated by the rewDS and punDS. In conflict trials, alcohol self-administration was at a rate that was intermediate between the rewDS and punDS trials. In a final test, rats were presented with one of the three trial conditions and perfused for Fos immunohistochemistry. We found Fos expression was higher in the rats tested in the conflict condition in three interconnected sub-cortical brain regions. This study demonstrated the important role that alcohol-associated DS plays an important role in promoting relapse to alcohol seeking after punishment-imposed abstinence. We also implemented a within-session discrimination task that allows for the study of alcohol seeking under motivational conflict, which may be relevant for alcohol use despite negative consequences. The results from the Fos data suggest that higher alcohol seeking in approach-avoidance motivational conflict is associated with activation of sub-cortical regions but not cortical regions.

From stress to depression: development of extracellular matrix-dependent cognitive impairment following social stress.

Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. We profiled the development of an enduring depressive-like state by assessing affective behavior and hippocampal function during the 2 months following social-defeat stress. We measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during the sustained depressive-like state. Affective disturbance and cognitive impairments develop disparately after social stress, with gradual appearance of affective deficits. In contrast, spatial memory was impaired both early after stress and during the late-emerging chronic depressive-like state, while intact in-between. Similarly, we observed a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Together our data (1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, (2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and (3) support a role of the ECM in mediating long-lasting effects on memory. From a translational point of view, it is important to prioritize on temporal phenotypic aspects in animal models to elucidate the underlying mechanisms of depression.

The role of impulsivity as predisposing behavioural trait in different aspects of alcohol self-administration in rats.

BACKGROUND: Therapeutic interventions to promote abstinence and prevent relapse in alcohol use disorder (AUD) are limitedly available. Therefore, targeting risk factors in the onset and maintenance of AUD could pose an interesting alternative treatment strategy. In this regard, over the last decade trait impulsivity has received considerable attention as such a risk factor predisposing substance dependence both in clinical populations and preclinical rodent studies. This study investigated whether different forms of impulsivity (action versus choice) predict distinct stages of instrumental alcohol self-administration, extinction and cue-induced relapse. METHODS: Two cohorts of n = 48 rats each were trained in an operant tasks for either impulsive action or impulsive choice. Subsequently, high and low impulsive rats were then tested in an alcohol self-administration and relapse model and following this retested in the impulsivity tasks to evaluate possible changes in impulsivity levels. RESULTS: The current data show that neither impulsive action, nor impulsive choice predict the extent to which rats consume alcohol and the extent to which rats are motivated to self-administer alcohol. Moreover, extinction of responding for alcohol and cue-induced relapse was not predicted by impulsivity. Interestingly, rats and most prominently low impulsive rats became more impulsive after the alcohol self-administration procedure. Although due to employed experimental design it is not clear whether this resulted from alcohol consumption or alcohol abstinence. CONCLUSION: Together, these findings lend further support for the notion of a unidirectional relationship between self-administration of the depressant drug alcohol and impulsivity.

Stress vulnerability promotes an alcohol-prone phenotype in a preclinical model of sustained depression.

Major depression and alcohol-related disorders frequently co-occur. Depression severity weighs on the magnitude and persistence of comorbid alcohol use disorder (AUD), with severe implications for disease prognosis. Here, we investigated whether depression vulnerability drives propensity to AUD at the preclinical level. We used the social defeat-induced persistent stress (SDPS) model of chronic depression in combination with operant alcohol self-administration (SA). Male Wistar rats were subjected to social defeat (five episodes) and prolonged social isolation (~12 weeks) and subsequently classified as SDPS-prone or SDPS-resilient based on their affective and cognitive performance. Using an operant alcohol SA paradigm, acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking were examined in the two subpopulations. SDPS-prone animals showed increased alcohol SA, heightened motivation to acquire alcohol, persistent alcohol seeking despite alcohol unavailability, signs of extinction resistance, and increased cue-induced relapse; the latter could be blocked by the α2 adrenoreceptor agonist guanfacine. In SDPS-resilient rats, prior exposure to social defeat increased alcohol SA without affecting any other measures of alcohol seeking and alcohol taking. Our data revealed that depression proneness confers vulnerability to alcohol, emulating patterns of alcohol dependence seen in human addicts, and that depression resilience to a large extent protects from the development of AUD-like phenotypes. Furthermore, our data suggest that stress exposure alone, independently of depressive symptoms, alters alcohol intake in the long-term.

Dorsomedial prefrontal cortex neurons encode nicotine-cue associations.

The role of medial prefrontal cortex (mPFC) in regulating nicotine taking and seeking remains largely unexplored. In this study we took advantage of the high time-resolution of optogenetic intervention by decreasing (Arch3.0) or increasing (ChR2) the activity of neurons in the dorsal and ventral mPFC during 5-s nicotine cue presentations in order to evaluate their contribution to cued nicotine seeking and taking. Wistar rats were trained to self-administer intravenous nicotine in 1 h self-administration sessions twice a day for a minimum of 10 days. Subsequently, dmPFC or vmPFC neuronal activity was modulated during or following presentation of the 5-s nicotine cue, both under extinction and self-administration conditions. We also used in vivo electrophysiology to record the activity of dmPFC neurons during nicotine self-administration and extinction tests. We show that optogenetic inhibition of dmPFC neurons during, but not following, response-contingent presentations of the nicotine cue increased nicotine seeking. We found no effect on nicotine self-administration or on food seeking in an extinction test. We also show that this effect is specific to dmPFC, because optogenetic inhibition of vmPFC had no effect on nicotine seeking and taking. In vivo recordings revealed that dmPFC network neuronal activity was modulated more strongly following nicotine cue presentation in extinction, compared to following nicotine self-administration. Our results strongly suggest that a population of neurons within the dmPFC is involved in encoding the incentive value of nicotine-associated cues.

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.

Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking.

RATIONALE: A strong association has been demonstrated between various forms of impulsivity and addiction-like behavior in both humans and rats. OBJECTIVES: In this study, we investigated how impulsive action, as measured in the 5-choice serial reaction time task (5-CSRTT), is affected during various stages of cocaine taking and seeking and by relapse-provoking stimuli in animals that were trained both in an intravenous cocaine self-administration paradigm and in the 5-CSRTT. METHODS: Rats were concurrently trained in the 5-CSRTT and cocaine self-administration protocol, and subsequently, the effects of cocaine (7.5 mg/kg) and the pharmacological stressor yohimbine (1.25 mg/kg) were tested in both paradigms. RESULTS: Cocaine self-administration (5 h/day) transiently altered impulsive action and increased errors of omission in the 5-CSRTT. Pharmacological challenges with cocaine and yohimbine induced increments in impulsive action and reinstated cocaine-seeking responses within the same animals. Further analyses revealed that the effects of cocaine and yohimbine on impulsive action did not correlate with their effects on reinstatement of cocaine seeking. CONCLUSIONS: These data suggest that although impulsive action and relapse can be pharmacologically modulated in the same direction within individuals, these effects appear not to be directly coupled.

Deep brain stimulation of the nucleus accumbens core but not shell reduces motivational components of heroin taking and seeking in rats.

BACKGROUND: Deep brain stimulation is explored as a new intervention for treatment-resistant substance use dependence. A candidate brain region is the nucleus accumbens, due to its involvement in reward and motivation. This study aimed to explore effects of NAcore and NAshell deep brain stimulation on aspects of heroin taking and seeking in a self-administration model for rats. METHODS: NAcore and NAshell deep brain stimulation was applied during 25 or 100 µg/kg/infusion heroin self-administration on an FR4 schedule of reinforcement and during cue- and heroin-induced reinstatement. In a separate group, effects of NAcore deep brain stimulation on heroin self-administration on a progressive ratio schedule and the first extinction session were examined. RESULTS: NAcore and NAshell deep brain stimulation did not alter heroin self-administration on an FR4 schedule. NAcore deep brain stimulation decreased cue - but not drug-induced reinstatement of heroin seeking, whereas NAshell deep brain stimulation did not affect reinstatement responding. In the second experiment, NAcore deep brain stimulation reduced responding during a progressive ratio schedule of heroin reinforcement. Finally, deep brain stimulation facilitated extinction from day 1 throughout the course of extinction learning. CONCLUSION: Taken together, the differential effects of NAcore and NAshell deep brain stimulation on heroin taking and seeking are in line with the distinct functional roles of these sub-regions therein. Conditioned cues have been shown to be very powerful stimuli for the persistence of addiction and relapse to drug use. Therefore, the present findings that NAcore deep brain stimulation decreases motivation for heroin taking and cue-conditioned behaviour and facilitates extinction learning are very promising, supporting the positive findings from clinical case studies.

Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects.

Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking.

BACKGROUND: Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. METHODS: Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA receptor agonist. RESULTS: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. CONCLUSIONS: These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence.

A sustained depressive state promotes a guanfacine reversible susceptibility to alcohol seeking in rats.

High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ≥9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.

On the Role of Cannabinoid CB1- and µ-Opioid Receptors in Motor Impulsivity.

Previous studies using a rat 5-choice serial reaction time task have established a critical role for dopamine D2 receptors in regulating increments in motor impulsivity induced by acute administration of the psychostimulant drugs amphetamine and nicotine. Here we investigated whether cannabinoid CB1 and/or µ-opioid receptors are involved in nicotine-induced impulsivity, given recent findings indicating that both receptor systems mediate amphetamine-induced motor impulsivity. Results showed that the cannabinoid CB1 receptor antagonist SR141716A, but not the opioid receptor antagonist naloxone, reduced nicotine-induced premature responding, indicating that nicotine-induced motor impulsivity is cannabinoid, but not opioid receptor-dependent. In contrast, SR141716A did not affect impulsivity following a challenge with the dopamine transporter inhibitor GBR 12909, a form of drug-induced impulsivity that was previously found to be dependent on µ-opioid receptor activation. Together, these data are consistent with the idea that the endogenous cannabinoid, dopamine, and opioid systems each play important, but distinct roles in regulating (drug-induced) motor impulsivity. The rather complex interplay between these neurotransmitter systems modulating impulsivity will be discussed in terms of the differential involvement of mesocortical and mesolimbic neurocircuitry.

Poor impulse control predicts inelastic demand for nicotine but not alcohol in rats.

Tobacco and alcohol dependence are characterized by continued use despite deleterious health, social and occupational consequences, implying that addicted individuals pay a high price for their use. In behavioral economic terms, such persistent consumption despite increased costs can be conceptualized as inelastic demand. Recent animal studies demonstrated that high-impulsive individuals are more willing to work for nicotine or cocaine infusions than their low-impulsive counterparts, indicating that this trait might be causally related to inelastic drug demand. By employing progressive ratio schedules of reinforcement combined with a behavioral economics approach of analysis, we determined whether trait impulsivity is associated with an insensitivity of nicotine or alcohol consumption to price increments. Rats were trained on a delayed discounting task, measuring impulsive choice. Hereafter, high- and low-impulsive rats were selected and trained to nose poke for intravenous nicotine or oral alcohol. Upon stable self-administration on a continuous reinforcement schedule, the price (i.e. response requirement) was increased. Demand curves, depicting the relationship between price and consumption, were produced using Hursh's exponential demand equation. Similar to human observations, nicotine and alcohol consumption in rats fitted this equation, thereby demonstrating the validity of our model. Moreover, high-impulsive rats displayed inelastic nicotine demand, as their nicotine consumption was less sensitive to price increments as compared with that in low-impulsive rats. Impulsive choice was not related to differences in alcohol demand elasticity. Our model seems well suited for studying nicotine and alcohol demand in rats and, as such, might contribute to our understanding of tobacco and alcohol dependence.

Varenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control.

RATIONALE: Treatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4ß2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats. OBJECTIVES: As preclinical data on alcohol taking and relapse are limited, we used a self-administration-reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 µg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour. RESULTS: Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT. CONCLUSIONS: Our data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction.

µ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice.

Acute challenges with psychostimulants such as amphetamine affect impulsive behavior in both animals and humans. With regard to amphetamine, it is important to unravel how this drug affects impulsivity since it is not only a widely abused recreational drug but also regularly prescribed to ameliorate maladaptive impulsivity. Therefore, we studied the effects of amphetamine in two rat models of impulsivity, the five-choice serial reaction time task and the delayed-reward task, providing measures of inhibitory control and impulsive choice, respectively. We focused on the role of opioid receptor activation in amphetamine-induced impulsivity as there is ample evidence indicating an important role for endogenous opioids in several behavioral and neurochemical effects of amphetamine. Results showed that amphetamine-induced inhibitory control deficits were dose-dependently attenuated by the preferential µ-opioid receptor antagonist naloxone, but not by the selective δ-opioid receptor antagonist naltrindole or κ-opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). In contrast, naloxone did not affect amphetamine-induced improvements in impulsive decision making. Naloxone also completely prevented inhibitory control deficits induced by GBR 12909 [1-(2-[bis(4-fluorophenyl)methoxy] ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a selective dopamine transporter inhibitor. Intracranial infusions of naloxone, the selective µ-opioid receptor antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)), morphine, and the selective µ-opioid receptor agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin acetate salt) revealed that µ-opioid receptor activation in the shell rather than the core subregion of the nucleus accumbens (NAc) modulates inhibitory control and subserves the effect of amphetamine thereon. Together, these results indicate an important role for NAc shell µ-opioid receptors in the regulation of inhibitory control, probably via an interaction between these receptors and the mesolimbic dopamine system.

Disruption of Long-Term Alcohol-Related Memory Reconsolidation: Role of ß-Adrenoceptors and NMDA Receptors.

Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol-related memories are prone to disruption by the ß-adrenergic receptor antagonist propranolol (10 mg/kg) and the NMDA receptor antagonist MK801 (0.1 mg/kg) following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were re-exposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on two further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency toward reduced alcohol seeking (p = 0.06). Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly ß-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.