Circuitry Progression of Cocaine-induced Cellular Adaptation

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Abstract Drug addiction has been conceptualized as the endpoint of cascades of transitions from initial voluntary and limited drug use to habitual and escalated drug use, and eventually to compulsive use. Results from brain region-specific studies lead to a prominent hypothesis that the initial cocaine use is primarily motivated by the nucleus accumbens (NAc)-based reinforcing effects, and transitions to more persistent or habitual drug use by recruiting the dorsal striatum (DS), resulting in escalated cocaine use and resistance to extinction. While the behavioral transition from limited to escalated cocaine use has been observed in both humans and rodent models, the key cocaine-induced cellular adaptations that progress from the NAc to DS to promote this behavioral transition remain underexplored. Targeting this knowledge gap, we focus on the intrinsic membrane excitability (IME) of NAc and DS medium spiny neurons (MSNs). IME determines the ability of neurons to fire action potentials in response to excitatory inputs, and thus directly determines the output of the neurons. Previous results demonstrate a critical IME adaptation—cocaine experience decreases IME of NAc MSNs, and this cocaine-induced IME adaptation in the NAc contributes to psychomotor effects of cocaine, cocaine withdrawal-associated general hypoactive state of the NAc, and cocaine seeking after drug withdrawal. The preliminary results show that during a short-term (5d) cocaine self-administration procedure, mice exhibited limited cocaine taking, and this cocaine procedure only induced the IME adaptation in NAc MSNs, but not DS MSNs. After prolonged (21d) cocaine self-administration, mice exhibited escalated cocaine taking, and the IME adaptation was observed in both NAc and medial/dorsal DS MSNs. Thus, cocaine-induced IME adaptation progresses from the NAc to DS after prolonged cocaine self-administration, correlated to escalated cocaine taking. Furthermore, experimentally preventing cocaine-induced IME adaptation in NAc MSNs prevented the progression of IME adaptation to DS MSNs during prolonged cocaine self-administration, suggesting a critical informational flow from the NAc to DS. This application will explore the anatomical basis mediating the NAc-to- DS progression of cocaine-induced IME adaptation and the behavioral consequence of this progression. The central hypothesis is that the NAc-to-DS progression of cocaine-induced IME adaptation after prolonged cocaine self-administration is mediated, in part, by the striatonigrostriatal ascending spiral, a circuit complex connecting the NAc and DS through reciprocal projections with the ventral tegmental area and substantia nigra, and this NAc-to-DS progression of cocaine-induced IME adaptation promotes the behavioral transition from limited to escalated cocaine use. The proposed experiments will characterize a critical form of cocaine- induced cellular adaptation that progresses from the NAc to DS after prolonged cocaine self-administration. The expected results may provide a circuit mechanism and concrete cellular substrates that mediate the progression of limited drug use toward escalated and eventually compulsive drug use.