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Background and Purpose Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behavior. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner, however, the underlying mechanisms are unclear. Experimental Approach The coimmunoprecipitation, BRET and cross-antagonism assays were used to demonstrating the existence of receptor heterodimers. The function of heterodimers was evaluated by behavioral studies of locomotor sensitization. Key Results We demonstrated that dopamine D1 receptor (D1R) antagonist SCH23390 antagonized the signaling originated by stimulation of μ opioid receptor (μOR) with agonists in transfected cells expressing two receptors and in wild type but not D1R knockout (KO) mouse striatal tissues, suggesting that D1R antagonist SCH23390 was able to modify μOR function via receptor heteromers, since the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a biochemical characteristic of receptor heteromers. The existence of D1R/μOR heterodimers was further supported by biochemical and biophysical assays. Moreover, in vivo we demonstrated that, on condition that dopamine release was absent (e.g. destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ agonist-induced behavioral responses in rats. Additionally, we demonstrated that D1R or μOR KO mice, which were unable to form D1R/μOR heterodimers, failed to express locomotor sensitization to morphine. Conclusion and Implications These results suggest that D1R/μOR heterodimers may be involved in dopamine independent expression of locomotor sensitization to opiates.

Addiction is characterized by drug craving, compulsive drug taking and relapse, which is attributed to aberrant neuroadaptation in brain regions implicated in drug addiction, induced by changes in gene and protein expression in these regions after chronic drug exposure. Accumulating evidence suggests that the dorsal hippocampus (DH) plays an important role in mediating drug-seeking and drug-taking behavior and relapse. However, the molecular mechanisms underlying these effects of the DH are unclear. In the present study, we employed a label-free quantitative proteomic approach to analyze the proteins altered in the DH of heroin self-administering rats. A total of 4015 proteins were quantified with high confidence, and 361 proteins showed significant differences compared with the saline control group. Among them, cyclin-dependent kinase 5 (CDK5) and ras homolog family member B (RhoB) were up-regulated in rats with a history of extended access to heroin. Functionally, inhibition of CDK5 in the DH enhanced heroin self-administration, indicating that CDK5 signaling in the DH acts as a homeostatic compensatory mechanism to limit heroin-taking behavior, whereas blockade of the Rho-Rho kinase (ROCK) pathway attenuated context-induced heroin relapse, indicating that RhoB signaling in the DH is required for the retrieval (recall) of addiction memory. Our findings suggest that manipulation of CDK5 signaling in the DH may be essential in determining vulnerability to opiate taking, whereas manipulation of RhoB signaling in the DH may be essential in determining vulnerability to relapse. Overall, the present study suggests that the DH can exert dissociative effects on heroin addiction through CDK5 and RhoB signaling.

Background and Purpose Substantial evidence shows that negative reinforcement resulting from the aversive affective consequences of opiate withdrawal may play a crucial role in drug relapse. Understanding the mechanisms underlying the loss (extinction) of conditioned aversion of drug withdrawal could facilitate the treatment of drug addiction. Experimental Approach Naloxone-induced conditioned place aversion (CPA) of Sprague-Dawley rats was used to measure conditioned aversion. An NMDA receptor antagonist and MAPK kinase inhibitor were applied through intracranial injections. The phosphorylation of ERK and cAMP response element-binding protein (CREB) was detected using Western blot. Key Results The extinction of CPA behaviour increased the phosphorylation of ERK and CREB in the dorsal hippocampus (DH) and basolateral amygdala (BLA), but not in the central amygdala (CeA). Intra-DH injection of AP5 or intra-BLA injection of AP-5 or U0126 before extinction training significantly attenuated ERK and CREB phosphorylation in the BLA and impaired the extinction of CPA behaviour. Although intra-DH injections of AP-5 attenuated extinction training-induced activation of the ERK-CREB pathway in the BLA, intra-BLA injection of AP5 had no effect on extinction training-induced activation of the ERK-CREB pathway in the DH. Conclusions and Implications These results suggest that activation of ERK and CREB in the BLA and DH is involved in the extinction of CPA behaviour and that the DH, via a direct or indirect pathway, modulates the activity of ERK and CREB in the BLA through activation of NMDA receptors after extinction training. Understanding the mechanisms underlying the extinction of conditioned aversion could facilitate the treatment of drug addiction. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2