1. ¹Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
2. ²Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
3. ³Department of Psychology, University of California, Los Angeles, CA, USA

Correspondence: Dr WP Melega, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Box 951735, 28-117 BRI, Los Angeles, CA 90095-1735, USA. Tel: +1 310 206 1797; Fax: +1 310 206 9934; E-mail: wmelega@mednet.ucla.edu

Received 27 December 2006; Revised 6 June 2007; Accepted 6 June 2007; Published online 11 July 2007.

Abstract

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1–3 M, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [³H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [³H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [³H]SCH 23390 and [³H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.