Dissociation of β1 and β2 Adrenergic Receptor Subtypes in Retrieval and Reconsolidation of a Cocaine Conditioned Place Preference

Abstract

Drug-seeking behavior is maintained by encounters with drug-associated cues, and disrupting retrieval or reconsolidation of the drug-cue associations could reduce the risk of relapse. Previous work has shown beta-adrenergic receptor (beta-AR) antagonists can prevent retrieval or reconsolidation of a cocaine conditioned place preference (CPP) when administered either before or after test, respectively (Otis and Mueller, 2011; Otis et al., 2013). However, the specific beta-AR subtypes that mediate retrieval and reconsolidation of a cocaine CPP remain unknown. Here we used selective blockade of & beta-1 or beta-2-AR subtypes to determine the effects on retrieval and reconsolidation of a cocaine CPP. During conditioning, rats were trained to associate one chamber, but not another, with cocaine. Memory retrieval was then tested by allowing the rats access to both chambers, resulting in a CPP for the previously cocaine-paired side. Pre-test injection of the beta-1-AR antagonist betaxolol at 20 mg/kg, i.p. but not 3 mg/kg prevented expression of a cocaine-induced CPP, indicating beta-1-AR involvement in memory retrieval. During subsequent drug-free tests, saline-treated rats continued to show a CPP, whereas betaxolol-treated rats did not. Moreover, treatment with the higher dose of betaxolol prevented subsequent reinstatement to a priming injection of cocaine. Unlike betaxolol administration, pre-test injection of the beta-2-AR antagonist ICI 118,551 (4 or 8 mg/kg, i.p.) had no affect on expression of a cocaine-induced CPP. On subsequent tests, however, vehicle- and 4 mg/kg ICI 118,551-treated rats continued to show a CPP whereas 8 mg/kg ICI 118,551-treated rats did not, indicative of a deficit in reconsolidation following this higher dose. Moreover, ICI 118,551 treatment prevented subsequent reinstatement to a priming injection of cocaine. Thus, we conclude that retrieval of a CPP is dependent on beta-1-ARs whereas reconsolidation of a CPP is dependent on beta-2-ARs. Finally, co-injection of betaxolol (20 mg/kg) and ICI 118,551 (8 mg/kg) prevented CPP expression on that and subsequent CPP tests, resulting in a long-lasting retrieval deficit that prevented reinstatement to a priming injection of cocaine. Our findings support the use of beta-AR antagonists as adjuncts for addiction therapies by preventing retrieval and reconsolidation of drug-associated memories and providing protection against relapse.