Presentation of cues involved in prior learning can elicit retrieval of memory for the learning. Retrieved memories are unstable before they are reconsolidated back into long-term storage. While unstable, the memories can be disrupted such that behaviors previously supported by the memories are significantly altered or eradicated. Drug addiction is multidetermined but one major etiological factor in the development and maintenance of addictive behavior is drug-associated memories, which form as a consequence of frequent pairings between drug-associated cues and drug administration. A growing body of basic neuroscience research suggests that administration of the ?-adrenergic antagonist propranolol contiguous with cue-elicited retrieval of memory for drug reinforced learning can lead to disruption of reconsolidation (DoR) as indicated by attenuation/elimination of drug-reinforced behavior(s). We recently completed a NIDA funded-R21 showing, for the first time in cocaine dependent (CD) persons, that administration of 40 mg propranolol vs. placebo following a single session of cocaine cue exposure or CCE (i.e., exposure to cocaine cues/paraphernalia in a laboratory setting) resulted in substantially attenuated craving and cue reactivity during a test session of CCE performed 24 hours later. A test session of CCE 1 week later revealed only trend level evidence of craving attenuation in the propranolol vs. placebo group. Although insufficiently powered to do so, we preliminarily examined cocaine use during the 1-week follow-up period. The propranolol treated participants did report a greater reduction in dollar amount of cocaine used, but this difference was not statistically significant. While thes findings are encouraging, the essential next step in the development of a DoR-based treatment is to enhance the response dampening 'signal' detected in the R21 and assess its durability, generalizability and effects on cocaine use. We will attempt to augment the DoR effect by (a) doubling the number of propranolol- medicated retrieval sessions of CCE, and (b) increasing the dose of propranolol. Accordingly, 3 groups of CD participants will receive two sessions of CCE, each separated by a 24 hr. period and both conducted while the participants remain in hospital. One group (PBO) will receive placebo following each CCE session while the second (40PP) and third (80PP) group will receive 40 mg and 80 mg propranolol, respectively. Participants will return two days, and 1, 3, and 6 weeks after discharge and will be administered a CCE session to assess for maintenance/generalization of DoR effects on craving and cue reactivity to familiar and novel cocaine cues. Participants will also be assessed 3 times weekly for cocaine use (self-report & urine drug screen) during follow-up. It is expected that groups 40PP and 80PP, relative to PBO, will evidence greater attenuation of craving, cue reactivity and cocaine use during follow-up. Also, these effects will be greater in group 80PP than 40PP. Confirmation of these expectations will set the stage for a clinical trial where the outcome enhancing properties of this novel pharmacy-behavior therapy could be systematically evaluated.
Our recently completed, NIDA-funded study has provided the first evidence that administration of the medication propranolol, following exposure to cocaine cues, can alter drug-associated memories and reduce craving and other drug cue-elicited responses in cocaine addicted persons. The proposed research will employ two strategies to augment the memory altering effects of propranolol observed in our recently completed study, and document lasting effects not only on craving and cue-elicited reactions, but also on cocaine use. Positive findings will set the stage for a formal clinical trial that could lead to significanly improved treatment outcomes for this treatment-resistant addiction.
| Germeroth, Lisa J; Carpenter, Matthew J; Baker, Nathaniel L et al. (2017) Effect of a Brief Memory Updating Intervention on Smoking Behavior: A Randomized Clinical Trial. JAMA Psychiatry 74:214-223 |
