Regulation of Circadian Genes by Cocaine in Striatal Regions and Their Role in Drug Reward

Disruptions in circadian rhythms are associated with neuropsychiatric disorders, including drug addiction. Indeed, mounting evidence reveals a role for the circadian clock in the regulation of drug reward and reward-related behaviors. Conversely, drugs of abuse are known to dysregulate circadian-associated processes and entrain locomotor behavior. The circadian clock is governed by a master pacemaker in the Suprachiasmatic Nucleus(SCN) of the anterior hypothalamus. However, the components of this circadian clock machinery are expressed throughout the brain and body, allowing for the occurrence of SCN-dependent or independent peripheral oscillators. One such brain circuit in which circadian genes are expressed is the mesolimbic dopaminergic pathway, containing brain regions such as the Nucleus Accumbens(NAc) and the Caudate Putamen (CP), among others. We set out to investigate how repeated cocaine exposure regulates core clock circadian genes in striatal regions and conversely, how core clock circadian genes regulate cocaine’s rewarding effects. Additionally, the potential regulation of rhythmic dopamine receptor expression directly by clock components and how their rhythmic expression is altered by repeated cocaine exposure was assessed. Chapter 3 determined circadian gene regulation in both the NAc and CP by cocaine. Not only did chronic cocaine upregulated a number of circadian genes at a specific timepoint, like Npas2 and the Per genes, but also altered or disrupted 24-hr rhythmic expression of these genes. Chapter 4 investigated the role of core circadian clock genes in cocaine reward, as measured by conditioned place preference. Npas2 mutant mice exhibited a decreased preference for cocaine, an effect that was recapitulated by viral-mediated Npas2 knockdown specifically in the NAc. Per mutant mice displayed an increase in cocaine preference. Knockdown of mPer1 and mPer2 in the NAc led to a trend towards increased preference. Chapter 5 identified a potential role for NPAS2 in the regulation of dopamine receptor rhythmic expression in the NAc, and that chronic cocaine disrupts this rhythmicity. These findings suggest an important role for Npas2 as mediator of cocaine responses in the NAc. Moreover, they further elucidate the bidirectional interactions between the circadian and reward systems, implicating the circadian control of the dopaminergic system in this interplay.