Repeated low-dose methamphetamine produces dynamic neuroadaptations in the mouse nucleus accumbens and prefrontal cortex.

摘要

This dissertation examines the effects of withdrawal from repeated low-dose methamphetamine upon the dopamine and glutamate systems of the nucleus accumbens and prefrontal cortex. Presented here are studies which examine the hypothesis that repeated low-dose methamphetamine produces time-dependent alterations in dopamine and glutamate transmission which are distinct from those produced by either high-dose methamphetamine, or low-dose amphetamine and cocaine. Specifically, these studies address the following aims: 1) Characterize the short- and long-term consequences of repeated low-dose methamphetamine upon basal and stimulated release of dopamine and glutamate in the nucleus accumbens and medial prefrontal cortex; 2) Explore potential mechanism through which repeated methamphetamine administration produces changes in nucleus accumbens and medial prefrontal cortex neurotransmission. The data herein demonstrate that withdrawal from repeated methamphetamine exposure dynamically alters basal and stimulated release of dopamine and glutamate within these brain structures. Moreover, these data point to a number of molecular and functional abnormalities in the receptors and transporters which regulate dopamine and glutamate release and reuptake as potential underpinnings of the changes observed in neurotransmission. These findings are discussed individually within the context of the current psychostimulant literature, as well as how these neuroadaptations may work in concert to produce robust abnormalities in neurotransmission and drug-associated behavior.