Models of Methamphetamine-Induced Neurotoxicity

Abstract

Methamphetamine (METH) exposure is associated with significant behavioral impairments and striatal dysfunction. In this chapter, the effects of METH on both humans and animal models are discussed, with a particular emphasis on METHinduced toxicity to striatal dopamine and disruption of corticostriatal functions. These disruptions include deficits in the expression of gene products, including activity-regulated cytoskeletal-associated protein, and striatally mediated learning and memory functions. In aggregate, considerable data from human, non-human primate, and rodent studies support the conclusion that exposure to METH leads to long-lasting disruptions of striatal dopamine. While the extent to which this disruption in humans reflects actual toxic loss of dopamine neuron terminals in the caudate-putamen and is associated with disruption of corticostriatal cognitive processes continue to be matters of debate, the data from animal models of METH exposure support the conclusion that even partial damage to striatal dopamine innervation is sufficient to result in significant changes in molecular, cellular, circuit, and behavioral functions of the striatum, and these effects are tractable using non-contingent, as well as contingent, models of METH administration in animals. Given that non-contingent administrations of METH model all reported consequences of METH exposure in humans in a replicable manner, such models may be preferable for studies delineating the consequences of METH-induced neurotoxicity and testing approaches to therapeutically manage METH use disorders in the presence of such neurotoxic consequences.