Human Methamphetamine Pharmacokinetics Simulated in the Rat: Behavioral and Neurochemical Effects of a 72-h 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.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…Changes in sensitivity on the ascending limb of the quinpirole dose-response curve have been hypothesized to be due to upregulation of D3R and/or downregulation of D2R (Collins et al, 2011); PET and receptor autoradiography studies support this mechanism after longterm MA exposure (Kuczenski et al, 2009;Boileau et al, 2012). It also remains possible that changes in DA transporter (DAT) and subsequent changes in extracellular DA may interact with quinpirole's effects at D3R and D2R.…”

Methamphetamine-Associated Psychosis

“…Like METH addicts, animals that are chronically treated with a low (non-toxic) dose of METH gradually develop psychotic-like symptoms, such as a decrease in motor activity, an increase in stereotypies, decreased interest to external stimuli and surroundings, and decreased social functioning (Kuczenski et al 2009). Also, some of the changed behavioral patterns (e.g., behavioral sensitization) persist even long after the cessation of drug treatment, and have a tendency to relapse or exacerbation upon re-exposure to the drug.…”

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

“…Since the MA dose, exposure history, and dosing interval are critical factors in characterizing MA effects on DA signaling (Segal et al 2003;Madden et al 2005;Kuczenski et al 2009), it is of particular interest to determine how the escalating-dose paradigm (Segal et al 2003) could alter DA functioning in the mesoaccumbens pathway. The impact of non-contingent MA on DA regulation at doses and a dosing schedule that are within the range reported in self-administration paradigms may reveal how plasticity in DA signaling in the mesoaccumbens pathway could be related to increased MA intake seen in the self-administration paradigms.…”