The reinstatement and spontaneous recovery effects revealed herein provide evidence of viable new behavioral paradigms for testing interventions against relapse.

Preclinical data have shown that the excitatory metabotropic Gαq-coupled glutamate receptor, mGluR5, has a role in substance abuse and relapse. However, little is known about the contribution of mGluR5 to the expression of conditioned responding elicited by appetitive Pavlovian cues. We investigated this question in rats that were trained to associate a discrete, auditory conditioned stimulus (CS) with a fructose-glucose solution (5.5% fructose/4.5% glucose; 'sugar'). In subsequent tests for the expression of conditioned responding without sugar delivery, CS-elicited fluid port entries were elevated in a context associated with sugar, relative to an equally familiar, neutral context. Inhibiting mGluR5 via systemic injections of a negative allosteric modulator (MTEP; 5 mg/kg) reduced CS port entries in both the sugar context and neutral context. Targeting MTEP microinjections (3 µg/side; 0.3 µl/min) to the nucleus accumbens (Acb) core had no effect on CS port entries at test, whereas the same manipulation in the basolateral amygdala (BLA) produced effects that were topographically dependent. Specifically, microinjecting MTEP in the posterior BLA had no effect on behavior, whereas inhibiting mGluR5 in the anterior BLA enhanced the contextual discrimination of CS port entries. These data are the first to show a role of mGluR5 in the contextdependent expression of appetitive Pavlovian conditioned responding, with a topographically defined arrangement of mGluR5 in the BLA being particularly important for context-based responding to a discrete, appetitive cue. HistologyStandard histological procedures [21] were used to visualize placements of the microinjectors within targeted brain regions (see supplementary materials and methods). Data analyses and availability of materialsStatistical analyses were performed using SPSS 24 (IBM, NY, USA), and included paired ttests, repeated measures ANOVA, mixed-design ANOVA, Bonferroni-corrected post-hoc comparisons, and Pearson correlations. For repeated measures ANOVA, Greenhouse-Geisser sphericity corrections were used when ε < 0.75. The non-parametric Friedman's Two-Way ANOVA was used when data violated assumptions of homogeneity of variance. The behavior we measured was entries into the fluid port during different intervals of the session. These intervals included 10 s before each CS/NS (Pre-CS/NS), the 10 s CS/NS, and the variable inter-trial interval (ITI). Conditioned responding is depicted as an elevation score, calculated by subtracting Pre-CS port entries from CS port entries [30, 31]. Each experiment was run as a single replicate. The underlying raw data and Med-PC code are available on Figshare [32]. Results CS port entries were selectively elevated in the sugar contextWe previously reported a reliable and selective elevation in port entries elicited by a CS that predicted alcohol in an alcohol context, relative to a neutral context [21]. The impact of context on port entries elicited by a CS that predicted sugar is unknown. To examine this question, rats (n=17) were t...

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 drugassociated 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 alcoholand tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

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Wheel running, unlike typical operant behavior, generates its own automatic reinforcement that alters the control exerted by extrinsic reinforcement on wheel running. The current study investigated the implications of the automatic reinforcement of wheel running by arranging different sucrose concentrations as extrinsic reinforcement for operant wheel running in ad--lib fed and food--deprived rats. Eleven female Long Evans rats ran on fixed revolution 30 schedules that delivered a drop of sucrose solution as reinforcement. Sucrose concentration varied across values of 0%, 2.5%, 5%, 10%, and 15% sucrose (w/v). Results showed that under ad--lib feeding, only the highest concentrations increased operant wheel-running rate. By contrast, under deprivation, all concentrations of sucrose increased the rate of wheel running. Despite the differences in sucrose--reinforced operant wheel--running rates by deprivation level (ad lib vs. deprived), wheel--running rates did not differ at the highest concentrations. Prior research on operant lever pressing, a response generating low (or no) automatic reinforcement, has shown considerably higher lever--pressing rates as a function of increasing amounts of sucrose reinforcement when rats are food deprived. Together, these previous observations and the current study suggest that automatic reinforcement generated by an operant decreases the control exerted by extrinsic reinforcement.Additionally, the regulation by extrinsic reinforcement on automatically reinforcing behavior depends on the organism's motivation or deprivation level (ad lib vs. deprived).

Wheel running, unlike typical operant behavior, generates its own automatic reinforcement that alters the control exerted by extrinsic reinforcement on wheel running. The current study investigated the implications of the automatic reinforcement of wheel running by arranging different sucrose concentrations as extrinsic reinforcement for operant wheel running in ad-lib fed and food-deprived rats. Eleven female Long Evans rats ran on fixed revolution 30 schedules that delivered a drop of sucrose solution as reinforcement. Sucrose concentration varied across values of 0%, 2.5%, 5%, 10%, and 15% sucrose (w/v). Results showed that under ad-lib feeding, only the highest concentrations increased operant wheel-running rate. By contrast, under deprivation, all concentrations of sucrose increased the rate of wheel running. Despite the differences in sucrose-reinforced operant wheel-running rates by deprivation level (ad lib vs. deprived), wheel-running rates did not differ at the highest concentrations. Prior research on operant lever pressing, a response generating low (or no) automatic reinforcement, has shown considerably higher lever-pressing rates as a function of increasing amounts of sucrose reinforcement when rats are food deprived. Together, these previous observations and the current study suggest that automatic reinforcement generated by an operant decreases the control exerted by extrinsic reinforcement. Additionally, the regulation by extrinsic reinforcement on automatically reinforcing behavior depends on the organism’s motivation or deprivation level (ad lib vs. deprived).

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