Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

Drug-seeking behavior is maintained by encounters with drug-associated cues. Preventing retrieval of drug-associated memories that these cues provoke would therefore limit relapse susceptibility; however, little is known regarding the mechanisms of retrieval. Here, we show that beta-adrenergic receptor activation is necessary for the retrieval of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. When administered before a CPP trial, propranolol, but not saline, prevented retrieval of a cocaine-associated CPP. In subsequent drug-free trials, rats previously treated with propranolol continued to show a retrieval deficit, as no CPP was evident. This retrieval deficit was long lasting and robust, as the CPP did not re-emerge during a test for spontaneous recovery 14 days later or reinstate following a priming injection of cocaine. Moreover, the peripheral beta-adrenergic receptor antagonist sotalol did not affect retrieval. Thus, retrieval of cocaine-associated memories is mediated by norepinephrine acting at central beta-adrenergic receptors. Our findings support the use of propranolol, a commonly prescribed beta-blocker, as an adjunct to exposure therapy for the treatment of addiction by preventing retrieval of drug-associated memories during and long after treatment, and by providing protection against relapse. Neuropsychopharmacology (2011) 36, 1912-1920; doi:10.1038/npp.2011.77; published online 4 May 2011