Visualizing dendritic morphology in the striatum following repeated treatment with methamphetamine

The repeated intermittent administration of psychostimulant drugs produces long lasting changes in behavior and psychological function that are believed to be due to alterations in the function of specific neural circuits. For example, repeated treatment with cocaine or d-amphetamine produces alterations in the density of dendritic spines, structural modifications that may indicate a reorganization of synaptic connectivity. Most of the earlier studies on drug-dependent structural plasticity focused on the ventral striatum (nucleus accumbens). However, the dorsal striatum (caudate putamen) is also known to change as a function of experience with drugs of abuse. Therefore, the purpose of this dissertation was to characterize the effects of methamphetamine, the more frequently abused form of amphetamine, on experience-dependent neuroplasticity in the caudate putamen. We report that repeated exposure to methamphetamine decreased the density of spines on medium spiny neurons (MSNs) in the dorsomedial caudate putamen and increased them in the dorsolateral caudate putamen. Given that sub-regions within the caudate show different patterns of structural plasticity, we examined other forms of experience-dependent neuroplasticity within two other major subdivisions of the striatum---the patch and matrix. To determine if methamphetamine differentially engages the patch vs. matrix following past experience with methamphetamine the expression of Fos protein was examined in the both striatal compartments. Past experience with methamphetamine facilitated ("sensitized") the ability of subsequent drug exposure to enhance Fos expression in the patch but not matrix. However, the effects of methamphetamine pretreatment on dendritic structure were not localized to one compartment. Specifically, the density of thin spines on MSNs in both the patch and matrix compartments of the dorsomedial striatum was lower in methamphetamine versus saline pretreated animals. No structural differences were observed between compartments in the dorsolateral caudate putamen. Thus, it appears that methamphetamine alters patterns of synaptic connectivity in both the major subcompartments of the dorsal striatum. The ability of repeated drug treatment to produce regionally-specific changes in the dorsal striatum may alter the operation of specific cells and circuits, and thus contribute to some of the long-lasting changes in behavior and psychological function associated with repeated exposure to methamphetamine.