Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo.

Repeated amphetamine administration is known to produce changes in corticoaccumbens function that persist beyond termination of drug administration. We have found previously that long-term alteration in dopamine systems leads to changes in gap junction communication, expressed as dye coupling, between striatal neurons. In this study, the cellular bases of amphetamine-induced changes were examined using in vivo intracellular recordings and dye injection in ventral prefrontal-accumbens system neurons of control and amphetamine-treated rats. Rats that had been withdrawn from repeated amphetamine displayed a significant increase in the incidence of dye coupling in the prefrontal cortex and nucleus accumbens, which persisted for up to 28 d after withdrawal. The increased coupling was limited to projection neurons in both prefrontal cortical and accumbens brain regions, as identified by their axonal trajectory or the absence of interneuron-selective immunocytochemical markers. These changes occurred with no substantial loss of tyrosine hydroxylase-immunoreactive terminals in these cortical and accumbens regions, ruling out dopamine degeneration as a precipitating factor. Previous studies showed that nitric oxide plays a role in the regulation of coupling; however, amphetamine-withdrawn rats had fewer numbers of neurons and processes that stained for nitric oxide synthase immunoreactivity. In amphetamine-treated rats, a higher proportion of cortical cells fired in bursts, and a larger proportion of accumbens and prefrontal cortical neurons exhibited bistable membrane oscillations. By increasing corticoaccumbens transmission, amphetamine withdrawal may lead to neuronal synchronization via gap junctions. Furthermore, this adaptation to amphetamine treatment persists long after the drug is withdrawn.