Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors. There are no effective medications for treating relapse in cocaine addicts. Dopamine (DA) mediates reward-related learning and drugs of abuse can change reward circuits in the brain mesolimbic DA system. DA D3 receptors are preferentially expressed in limbic regions. We and others have used D3 receptor mutant mice and D3 receptor-selective antagonists to demonstrate that these receptors are a major mediator of the rewarding effects of cocaine. Despite its key role in mediating the neurobiological effects of cocaine, medications directly targeting D3 receptors, however, are still limited to preclinical studies. Targeting D3 receptors requires precise knowledge on how D3 receptors contribute to all aspects of drug-induced behaviors and pharmacological ligands with improved D3 receptor specificity. The vast majority of studies so far have attempted to pharmacologically attenuate reinstatement to drug-seeking. We have obtained new preliminary results suggesting that reconsolidation and extinction of cue-cocaine memories may provide alternative action windows for D3 receptor-based therapies. The objective of this developmental proposal is to initiate studies to expand our knowledge on potential new ways to reduce craving and relapse by better understanding and targeting D3 receptor-mediated mechanisms. We propose to engineer and characterize a novel mouse model in which levels of D3 receptors can be up- or down-regulated in the brain. We will then use this mouse model, together with pharmacological methods and the intravenous cocaine self-administration paradigm, to investigate the hypothesis that manipulating D3 receptor levels or activity reduces cocaine- seeking by interrupting the reconsolidation and accelerating the extinction of drug-induced reward memory. The proposed work will have a high impact in that the results will lay important groundwork for developing novel D3 receptor-based therapies in humans, for validating and improving utilities of new D3 receptor agonists and antagonists in reducing relapse, and for investigating how D3 receptors contribute to vulnerability to developing cocaine-seeking and to other cocaine-induced behaviors in the future.

R21DA036921

2015-02-01

2017-08-31