1. ¹Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA, USA
2. ²Department of Neurology and Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA, USA

Correspondence: Dr GO Hjelmstad, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA. Tel: +1 510 985 3927; Fax: +1 510 985 3101; E-mail: gregh@gallo.ucsf.edu

Received 14 February 2007; Revised 23 April 2007; Accepted 26 April 2007; Published online 6 June 2007.

Abstract

In the present study, we investigated the effects of psychostimulant exposure on -opioid peptide (KOP) receptor signaling in the rat mesolimbic system. A single subcutaneous (s.c.) injection of amphetamine (2.5 mg/kg) reduced the KOP receptor-mediated inhibition of glutamate release in the nucleus accumbens shell, as a consequence of KOP receptor desensitization. This effect was blocked by dopamine (DA) receptor antagonists or the nonselective opioid antagonist, naltrexone (1 mg/kg, s.c.), and mimicked by the KOP receptor agonists U69593 (0.32 mg/kg, s.c.) and dynorphin (1 M), indicating that an amphetamine-induced release of dynorphin is producing a long-lasting desensitization of the KOP receptor. Despite the fact that amphetamine also increases dynorphin release in the ventral tegmental area (VTA), KOP receptor function in this region was not affected by amphetamine; there was no difference in the KOP receptor-mediated change in firing rate or resting membrane potential measured in VTA neurons from saline- or amphetamine-treated animals. This study demonstrates that amphetamine can produce regionally selective adaptations in KOP receptor signaling, which may, in turn, alter the effects of subsequent drug exposure.