Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in...

The principal components of neuronal excitability include synaptic and intrinsic membrane parameters. While recent studies indicate that cocaine exposure can induce widespread changes in synaptic function in the neural circuits for reward, intrinsic firing properties have received much less attention. Using whole-cell recording in ex vivo brain slices from cocaine-treated mice, we studied the intrinsic firing characteristics of medium-spiny projection neurons of the nucleus accumbens--a key node in the circuit that controls reward-directed behavior. Our data demonstrate that repeated in vivo cocaine (5 x 15 mg/kg, i.p., once daily, 5 d) induces opposite changes in neurons of the two main subdivisions of the accumbens, the shell and the core. While shell neurons exhibit an initial depression in firing capacity (1-3 d abstinence) that persists for at least 2 weeks, core neurons exhibit increased firing capacity during early abstinence (1-3 d) that declines to basal levels within 2 weeks. Shared adaptations between addictive drugs may mediate core processes of addiction. We find that amphetamine exposure (5 x 5 mg/kg, i.p., once daily, 5 d) that induced a similar degree of locomotor sensitization as cocaine also induced an indistinguishable pattern of NAc intrinsic plasticity. Finally, we provided evidence that opposite regulation of A-type potassium current is an important factor in this bidirectional intrinsic plasticity for both cocaine and amphetamine. We propose that a persistent disparity in core/shell excitability might be an important mediator of the changes in reward circuit activity that drive drug-seeking behavior in animal models of addiction.