Punishment-resistant alcohol intake is mediated by the nucleus accumbens shell in female rats.

Alcohol use is widespread across many societies. While most people can control their alcohol use, a vulnerable sub-population develops alcohol use disorder, characterized by continued alcohol use despite negative consequences. We used a rat model of alcohol self-administration despite negative consequences to identify brain activity associated with this addiction-like behaviour.

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.

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.

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.

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.

A persistent alcohol cue memory trace drives relapse to alcohol seeking after prolonged abstinence.

Alcohol use disorder is characterized by a high risk of relapse during periods of abstinence. Relapse is often triggered by retrieval of persistent alcohol memories upon exposure to alcohol-associated environmental cues, but little is known about the neuronal circuitry that supports the long-term storage of alcohol cue associations. We found that a small ensemble of neurons in the medial prefrontal cortex (mPFC) of mice was activated during cue-paired alcohol self-administration (SA) and that selective suppression of these neurons 1 month later attenuated cue-induced relapse to alcohol seeking.

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.

Anterior Insular Cortex is Critical for the Propensity to Relapse Following Punishment-Imposed Abstinence of Alcohol Seeking.

Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder.

A sleeping giant: Suvorexant for the treatment of alcohol use disorder?

There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and acamprosate. To date, these have been largely inadequate at preventing relapse at a population level and this may be because they only target certain aspects of AUD. Recently, suvorexant, a dual orexin receptor antagonist, has been FDA approved for the treatment of insomnia.

Context-induced relapse after extinction versus punishment: similarities and differences.

Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A).

Distinct Accumbens Shell Output Pathways Promote versus Prevent Relapse to Alcohol Seeking.

Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context.

Reduced alcohol-seeking in male offspring of sires exposed to alcohol self-administration followed by punishment-imposed abstinence.

Emerging evidence has demonstrated that paternal alcohol use can modify the behavior of offspring, particularly male offspring. However, preclinical studies to date have not used voluntary self-administration of alcohol to examine alcohol-related behaviors in offspring. Here, we tested the hypothesis that paternal alcohol self-administration followed by punishment-imposed abstinence alters alcohol consumption and seeking in male offspring.

The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats.

The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as designer receptors exclusively activated by designer drugs (DREADDs) permit the remote control of neuronal function by systemic drug administration. These approaches have dramatically advanced our understanding of the neural control of behaviour.

The Anterior Insular Cortex→Central Amygdala Glutamatergic Pathway Is Critical to Relapse after Contingency Management.

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist.

Punishment of alcohol-reinforced responding in alcohol preferring P rats reveals a bimodal population: Implications for models of compulsive drug seeking.

Individual variations in animal behaviour can be used to describe relationships between different constructs, as well as the underlying neurobiological mechanisms responsible for such variation. In humans, variation in the expression of certain traits contributes to the onset of psychopathologies, such as drug addiction. Addiction is characterised by persistent drug use despite negative consequences, but it occurs in only a sub-population of drug users.

Lateral Hypothalamic GABAergic Neurons Encode Reward Predictions that Are Relayed to the Ventral Tegmental Area to Regulate Learning.

Eating is a learned process. Our desires for specific foods arise through experience. Both electrical stimulation and optogenetic studies have shown that increased activity in the lateral hypothalamus (LH) promotes feeding.

Cue-induced food seeking after punishment is associated with increased Fos expression in the lateral hypothalamus and basolateral and medial amygdala.

In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking.

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence.

Unlabelled: In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence.

Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats.

Rationale And Objective: In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement.

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats.

In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015).

A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use.

Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model.

Background: Cue-induced methamphetamine craving increases after prolonged forced (experimenter-imposed) abstinence from the drug (incubation of methamphetamine craving). Here, we determined whether this incubation phenomenon would occur under conditions that promote voluntary (self-imposed) abstinence. We also determined the effect of the novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, on incubation of methamphetamine craving after forced or voluntary abstinence.

Recent updates on incubation of drug craving: a mini-review.

Cue-induced drug craving progressively increases after prolonged withdrawal from drug self-administration in laboratory animals, a behavioral phenomenon termed 'incubation of drug craving.' Studies over the years have revealed several important neural mechanisms contributing to incubation of drug craving. In this mini-review, we first discuss three excellent Addiction Biology publications on incubation of drug craving in both human and laboratory animals.