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Contextual control over drug relapse depends on the successful reconsolidation and retention of context-response-cocaine associations in long-term memory stores. The basolateral amygdala (BLA) plays a critical role in cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior; however, less is known about the cellular mechanisms of this phenomenon.The present study evaluated the hypothesis that protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII) activation in the BLA is necessary for the reconsolidation of context-response-cocaine memories that promote subsequent drug context-induced cocaine-seeking behavior.Rats were trained to lever-press for cocaine infusions in a distinct context, followed by extinction training in a different context. Rats were then briefly re-exposed to the previously cocaine-paired context or an unpaired context in order to reactivate cocaine-related contextual memories and initiate their reconsolidation or to provide a similar behavioral experience without explicit cocaine-related memory reactivation, respectively. Immediately after this session, rats received bilateral microinfusions of vehicle, the PKA inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS), or the CaMKII inhibitor, KN-93, into the BLA or the posterior caudate putamen (anatomical control region). Rats were then tested for cocaine-seeking behavior (responses on the previously cocaine-paired lever) in the cocaine-paired context and the extinction context.Intra-BLA infusion of Rp-cAMPS, but not KN-93, following cocaine memory reconsolidation impaired subsequent cocaine-seeking behavior in a dose-dependent, site-specific, and memory reactivation-dependent fashion.PKA, but not CaMKII, activation in the BLA is critical for cocaine memory re-stabilization processes that facilitate subsequent drug context-induced instrumental cocaine-seeking behavior.

Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon.Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15 mg/kg, i.p.) and context-saline (1 ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15 mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2 and 2 mg/kg, Experiment 2), using counterbalanced within-subjects testing designs.Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline.Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention.

CB1 receptors (CB1Rs) mediate many of the psychoactive effects of cannabinoids, and marijuana intoxication can produce neurocognitive deficits with a similarity to those seen in schizophrenia, including impairments of attention.We thus sought to characterize the effects of a CB1R-selective agonist and antagonist on attention in the rat using a lateralized reaction time task (LRT). We hypothesized that CB1R agonists would impair performance and that CB1R antagonists might improve performance.Subjects were trained to perform the LRT, a procedure that measured their ability to attend to and detect brief visual target stimuli. After training, we tested the effects of the CB1R agonist WIN55,212-2 (WIN; 0-2.5 mg/kg) or the CB1R antagonist SR141716A (SR; 0-1.0 mg/kg), administered alone or in combination, on visual attention performance using task conditions in which target stimulus salience was varied systematically across trials.The highest dose of WIN reduced correct choices in well-trained rats, with impairment greatest at the shortest stimulus durations. The highest dose of WIN also increased omissions and slowed response times. By contrast, SR itself did not produce any measurable effects on performance but was able to prevent the impairment produced by WIN.These results suggest that CB1Rs mediate the attentional performance impairments caused by acute administration of cannabinoid agonists and begin to unravel the possible contribution of cannabinoid systems to the pathophysiological substrates of cognitive dysfunction in schizophrenia.