96-h methamphetamine self-administration elicits striatal dopamine depletion in male and female rats: a model of binge-like use.

Abstract

BACKGROUND: Methamphetamine is a psychostimulant with significant public health implications. Chronic methamphetamine use is linked to profound dysregulation of the dopaminergic system, cognitive deficits, and psychiatric symptoms. While traditional experimenter administered "binge" dosing models reliably produce dopaminergic neurotoxicity, they fail to capture the volitional, drug intake characteristic of human methamphetamine use. Although self-administration paradigms better reflect human drug-taking behavior, they have yet to consistently reproduce the neurochemical deficits seen in the non-contingent models. METHODS: In this study, we employed a very long-access (96-h) methamphetamine self-administration model over eight weeks to evaluate whether contingent, volitional drug intake produces dopaminergic neurotoxicity. Male and female rats were given extended access to methamphetamine (0.06 mg/kg/infusion) for 96-h sessions weekly, with saline-yoked controls. Neurochemical analysis focused on striatal dopamine and metabolites to assess drug-induced alterations. RESULTS: Rats exhibited significant escalation in methamphetamine intake over eight weeks, with no sex differences in total intake. Importantly, striatal dopamine levels were significantly reduced in both male and female methamphetamine self-administering rats compared to saline-yoked controls, representing the first demonstration of dopamine depletion following voluntary administration methamphetamine self-administration. Dopamine depletion was significantly correlated with total methamphetamine intake. Interestingly, no significant changes were observed in dopamine metabolites (DOPAC, HVA). CONCLUSIONS: These findings demonstrate that volitional methamphetamine intake under a 96-h access model induces robust dopaminergic deficits, paralleling those seen in non-contingent binge dosing. This model provides a translationally relevant paradigm, capturing both the behavioral and neurobiological aspects of human methamphetamine use, supporting its utility for investigating neurotoxicity and potential treatments.