Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development.

Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders. In this review, we provide an updated summary of parallel preclinical and human studies that support this hypothesis. Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behavior and amplify responding elicited by discrete, drug-predictive cues. Akin to drug-associated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders. Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies. This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions. We conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches: pharmacology, brain stimulation, mindfulness-based relapse prevention, and cognitive behavioral group therapy. Throughout, we focus on alcohol- and tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

Modulation of sensitivity to alcohol by cortical and thalamic brain regions.

The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABAA agonist + GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.

The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.