Methamphetamine-induced locomotor activity and behavioral sensitization: are dopamine d3 receptors involved?

Drug sensitization is a behavioral phenomenon that occurs following repeated administration of methamphetamine (METH) and similar CNS stimulants. The mechanism of drug sensitization is unknown, but is believed to be due to downregulation of dopamine D3 receptors. It is hypothesized that repeated administration of dopamine D3 agonists results in downregulation of D3 receptors in methamphetamine-induced (METH-IND) sensitization. Furthermore, repeated administration of dopamine D3 antagonists and METH cause upregulation of D3 receptors and block METH-IND sensitization. The objective of this study was to determine the role of D3 receptors in METH-IND sensitization. To test these hypotheses, male mice received chronic injections (i.p.) of 2 mg/kg of the dopamine D3 agonist, PD128907 plus 0.5 mg/kg of METH or 8 mg/kg of D3 antagonist, U99194A and 0.5 mg\kg of METH daily for 7-days. Drugs were withdrawn on day 8, and METH-IND sensitization was determined on day 18. Locomotor activity was measured for 75 minutes immediately after METH administration in an activity monitor. Acute administration of PD128907 decreased METH-IND locomotion, p < 0. 01, and acute U99194A increased it. However, chronic administration of these drugs did not alter the locomotor effects of METH (p > 0.05). These findings support in-part the hypothesis that dopamine D3 receptors are downregulated in METH-IND sensitization.