HUMAN METHAMPHETAMINE PHARMACOKINETICS SIMULATED IN THE RAT: BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF A 72- HOUR BINGE

Abstract

Bingeing is one pattern of high dose methamphetamine (METH) abuse which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly-defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats we used a computer-controlled, intravenous METH procedure (dynamic infusion) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life. Animals were treated over 13 weeks with escalating METH doses, using dynamic infusion, and then exposed to a binge in which drug was administered every 3 h for 72h. Throughout the binge, behavioral effects included unabated intense oral stereotypies in the absence of locomotion and in the absence of sleep. Decrements in regional brain dopamine, norepinephrine and serotonin levels, measured at 1 and 10 h after the last injection of the binge, had, with the exception of caudate-putamen dopamine and frontal cortex serotonin, recovered by 48 h. At 10 h after the last injection of the binge, [ ³H]ligand binding to dopamine and vesicular monoamine transporters in caudate-putamen were reduced by 35% and 13%, respectively. In a separate METH binge treated cohort, post-binge behavioral alterations were apparent in an attenuated locomotor response to a METH challenge infusion at 24h after the last injection of the binge. Collectively, the changes we characterized during and following a METH binge suggest that for humans under similar exposure conditions, multiple time-dependent neurochemical deficits contribute to their behavioral profiles.