Methamphetamine Induces Long-Term Alterations in Reactivity to Environmental Stimuli: Correlation with Dopaminergic and Serotonergic Toxicity

Methamphetamine (METH) abuse is known to induce persistent cognitive and behavioral abnormalities, in association with alterations in serotonin (5-HT) and dopamine (DA) systems, yet the neurobiological mechanisms underpinning this link are elusive. Thus, in the present study we analyzed the long-term impact of an acute toxic regimen of METH (4 mg/kg, subcutaneous x 4 injections, 2 h apart) on the reactivity of adult male rats to environmental stimuli, and correlated it to toxicity on 5-HT and DA innervations. Two separate groups of METH-injected rats were compared to their saline-treated controls on object exploration and startle paradigms, at either 1 or 3 weeks after METH administration, respectively. Twenty-four hours after behavioral testing, animals were sacrificed, and the neurotoxic effects of the METH schedule on DA and 5-HT terminals were measured through immunochemical quantification of their transporters (DAT and 5-HTT). At both 1 and 3 weeks after treatment, METH-injected rats exhibited a significant decline in the number of exploratory approaches to unfamiliar objects, which was significantly correlated with a parallel reduction in DAT immunoreactivity (IR) in the nucleus accumbens (NAc) core. Furthermore, METH-treated rats displayed a significant enhancement in startle magnitude after 3 (but not 1) weeks, which was inversely correlated with a decrement in 5-HTT IR in the Cg3 infralimbic area of prefrontal cortex. Our results suggest that METH induces long-term changes in object exploration and startle responsiveness, which may be respectively underpinned by reductions in DAergic and 5-HTergic brain terminals.