Dopaminergic Regulation of Nucleus Accumbens Cholinergic Interneurons Demarcates Susceptibility to Cocaine Addiction



      Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) play critical roles in processing information related to reward. However, the contribution of ChINs to the emergence of addiction-like behaviors and its underlying molecular mechanisms remain elusive.


      We employed cocaine self-administration to identify two mouse subpopulations: susceptible and resilient to cocaine seeking. We compared the subpopulations for physiological responses with single-unit recording of NAc ChINs, and for gene expression levels with RNA sequencing of ChINs sorted using fluorescence-activated cell sorting. To provide evidence for a causal relationship, we manipulated the expression level of dopamine D2 receptor (DRD2) in ChINs in a cell type–specific manner. Using optogenetic activation combined with a double whole-cell recording, the effect of ChIN-specific DRD2 manipulation on each synaptic input was assessed in NAc medium spiny neurons in a pathway-specific manner.


      Susceptible mice showed higher levels of nosepoke responses under a progressive ratio schedule, and impairment in extinction and punishment procedures. DRD2 was highly abundant in the NAc ChINs of susceptible mice. Elevated abundance of DRD2 in NAc ChINs was sufficient and necessary to express high cocaine motivation, putatively through reduction of ChIN activity during cocaine exposure. DRD2 overexpression in ChINs mimicked cocaine-induced effects on the dendritic spine density and the ratios of excitatory inputs between two distinct medium spiny neuron cell types, while DRD2 depletion precluded cocaine-induced synaptic plasticity.


      These findings provide a molecular mechanism for dopaminergic control of NAc ChINs that can control the susceptibility to cocaine-seeking behavior.
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      Linked Article

      • A Mechanism of Cocaine Addiction Susceptibility Through D2 Receptor–Mediated Regulation of Nucleus Accumbens Cholinergic Interneurons
        Biological PsychiatryVol. 88Issue 10
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          People with addiction differ from casual drug users by their uncontrollable drug intake despite the adverse consequences associated with drug use. The compulsive drug-seeking and drug-taking behaviors that define addiction are also observed in rodent models that were first established almost 2 decades ago. Studies have shown that there is a percentage of individuals in human and rodent populations that are susceptible to drug use while others are resilient (1,2). Susceptibility to developing any substance use disorder is influenced by genetic and epigenetic variation along with psychosocial factors.
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