We evaluated whether the beta-adrenergic antagonist propranolol could attenuate or erase the learned associations, or emotional memories, that underlie craving elicited by drug-related cues, administering propranolol during the reconsolidation window shortly after the memories were reactivated by cues. Healthy outpatients who used cocaine while receiving methadone maintenance were asked to recall specific cocaine-use events and neutral events in preliminary interviews. In the intervention sessions, we administered propranolol (40 mg) or placebo before presentation of personalized auditory imagery scripts and cue sets developed from the interviews. Group assignment was randomized, and medications were matched so that neither the participants nor the research staff knew what drug was given. Participants returned to the lab twice a week for urine drug screens. Cue reactivity was assessed by craving scales and physiological responses as participants were reexposed to the script/cue sets 1 week and 5 weeks after the propranolol/placebo session. Unexpectedly, participants in the propranolol group showed greater cue reactivity than those in the placebo group. This effect was present during propranolol administration and seemed to persist (though without reaching statistical significance) during the later test sessions. These results do not support the use of propranolol for attenuation of cue/cocaine associations in opioid-maintained patients. In another study, we evaluated the effects of homework-task simplification and electronic-diary reminders on completion of written homework during cognitive-behavioral therapy (CBT) for addiction. All participants received all combinations of our two interventions in a counterbalanced Latin-square design. Neither of the interventions increased homework completion, and based on ecological momentary assessment (EMA), standard but not simplified homework seemed to buffer the craving that followed environmental exposure to drug cues in daily life. The findings demonstrated the usefulness of EMA in assessing treatment effects, but did not support the hypothesis that homework simplification would increase compliance. We are continuing to evaluate patient characteristics that may guide developments in personalized medicine. Using inducible pluripotent stem cells (iPSCs), we produced DA neurons from opioid-dependent and control participants carrying different 3 VNTR (variable number tandem repeat) polymorphisms in the gene for the dopamine transporter (DAT or SLC6A3). We found that the 3 VNTR polymorphism affected DAT expression and that treatment of the neurons with valproic acid alters the expression of several genes important for dopaminergic functioning, including DAT, Nurr1 and TH. Valproic acid also significantly increased expression of D2 receptors, especially in cell lines derived from the opioid-dependent participants. Our data suggest that human iPSC-derived DA neurons are a useful in vitro experimental model to examine the effects of genetic variation on gene regulation, to examine underlying mechanisms of addiction and other disorders, and to serve as a platform for treatment development. Finally, we continue to develop Geographical Momentary Assessment (GMA), an approach to measurement and understanding of the relationships among mood, drug use, and environmental exposure to psychosocial stressors in participants daily travels. GMA is largely a descriptive technique, but we remain committed to transforming description into intervention. For example, we have shown that electronic-diary studies can provide amazing insight into the daily lives of substance abusers during treatment and data that are sensitive to behavioral changes during even brief periods of abstinence. The technologies that enable us to collect data on drug use, craving, and stress in the field may also be used for delivery of treatment in the field, perhaps in response to the patients movement toward previously identified triggers.
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