Cocaine-Seeking Behavior Induced by Orexin A Administration in the Posterior Paraventricular Nucleus of the Thalamus Is Not Long-Lasting: Neuroadaptation of the Orexin System During Cocaine Abstinence

Hypothalamic orexin (Orx) projections to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. Using an established model of cocaine dependence (i.e., long access [LgA] to cocaine), we previously showed that OrxA injections in the posterior PVT (pPVT) reinstated extinguished cocaine-seeking behavior in rats after an intermediate period of abstinence (2–3 weeks). Considering the long-lasting nature of drug-seeking behavior, the present study examined whether the priming effect of intra-pPVT OrxA administration was preserved after a period of protracted abstinence (4–5 weeks) in rats that self-administered cocaine under LgA conditions. Furthermore, to better understand whether a history of cocaine dependence affects the Orx system—particularly the hypothalamic Orx↔pPVT connection—the number of Orx-expressing cells in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) and number of orexin receptor 1 (OrxR1)- and OrxR2-expressing cells in the pPVT were quantified. Orexin A administration in the pPVT induced cocaine-seeking behavior after intermediate abstinence, as reported previously. At protracted abstinence, however, the priming effect of OrxA was absent. A higher number of cells that expressed Orx was observed in the LH/DMH/PFA at both intermediate and protracted abstinence. In the pPVT, the number of OrxR2-expressing cells was significantly higher only at intermediate abstinence, with no changes in the number of OrxR1-expressing cells. These data build on our previous findings that the hypothalamic Orx↔pPVT connection is strongly recruited shortly after cocaine abstinence and demonstrate that the priming effect of OrxA is not long lasting. Furthermore, these findings suggest that throughout abstinence, the Orx↔pPVT connection undergoes neuroadaptive changes, reflected by alterations of the number of OrxR2-expressing cells in the pPVT.

ARIPPRIPAZOLE AND ITS POTENTIAL EFFECT IN REDUCING COCAINE CRAVING IN SCHIZOPHRENIC PATIENTS WITH COCAINE-DEPENDENCE

Goals: Non-systematic literature review of the role of aripiprazole in alleviating cocaine craving in schizophrenic patients with cocaine-dependence (CD). Material and methods: From the review performed, 2 studies outstand: In one study, 6 schizophrenic patients with CD completed 8 weeks of treatment with aripiprazole at a maximum dose of 15 mg/d. The Brief Psychiatric Rating Scale and the Brief Substance Craving Scale (BSCS) were used to measure psychosis and subjective cocaine and alcohol cravings and urine tests for cocaine were performed. In another study, 44 CD patients with schizophrenia or schizoaffective disorder were treated with aripiprazole or perphenazine during 8 weeks. The perphenazine group received the recommended dosage not exceeding 24 mg/d and the patients receiving aripripazole were started on 15 mg/d to a maximum of 30 mg/d or a minimum of 10 mg/d. Primary outcome targeted cocaine-free urine sample proportions, whereas secondary outcome focused on cocaine craving scores. BSCS was used to assess cocaine craving and the positive and negative symptom scale and the clinical global impression scale were used to monitor psychotic symptom severities. Results and conclusion: In the first study, positive urine tests dropped significantly after 2 weeks, mean cocaine and acohol craving scores declined significantly, and declining psychosis scores were associated with declining cocaine and alcohol craving. In the second study, the proportion of negative drug test results did not differ significantly between patients treated with aripiprazol or perphenazine. Regarding the anticraving effect, in the aripiprazol group during week 3 to 8, significant reductions in craving intensity, frequency and duration were seen, while no similar reduction was seen with perphenazine. In conclusion, although the results are still limited, studies suggest that aripiprazol may have a potential effect in dual diagnosis patients with schizophrenia and CD, possibly due to its dopamine activity as a partial agonist/antagonist.