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The Journal of Neuroscience, May 18, 2005, 25(20):5029-5037; doi:10.1523/JNEUROSCI.0854-05.2005

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Behavioral/Systems/Cognitive
Endogenous -Opioid Receptor Systems Regulate Mesoaccumbal Dopamine Dynamics and Vulnerability to Cocaine

Vladimir I. Chefer,² Traci Czyzyk,¹ Elizabeth A. Bolan,² Jose Moron,² John E. Pintar,^1 * and Toni S. Shippenberg^2 *

¹Department of Neuroscience and Cell Biology, Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and ²Integrative Neuroscience Section, Behavioral Neurosciences Branch, National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224

Genetic and pharmacological approaches were used to examine -opioid receptor (KOR-1) regulation of dopamine (DA) dynamics in the nucleus accumbens and vulnerability to cocaine. Microdialysis revealed that basal DA release and DA extraction fraction (E_d), an indirect measure of DA uptake, are enhanced in KOR-1 knock-out mice. Analysis of DA uptake revealed a decreased K_m but unchanged V_max in knock-outs. Knock-out mice exhibited an augmented locomotor response to cocaine, which did not differ from that of wild-types administered a behavioral sensitizing cocaine treatment. The ability of cocaine to increase DA was enhanced in knock-outs, whereas c-fos induction was decreased. Although repeated cocaine administration to wild types produced behavioral sensitization, knock-outs exhibited no additional enhancement of behavior. Administration of the long-acting KOR antagonist nor-binaltorphimine to wild-type mice increased DA dynamics. However, the effects varied with the duration of KOR-1 blockade. Basal DA release was increased whereas E_d was unaltered after 1 h blockade. After 24 h, release and E_d were increased. The behavioral and neurochemical effects of cocaine were enhanced at both time points.

These data demonstrate the existence of an endogenous KOR-1 system that tonically inhibits mesoaccumbal DA neurotransmission. Its loss induces neuroadaptations characteristic of "cocaine-sensitized" animals, indicating a critical role of KOR-1 in attenuating responsiveness to cocaine. The increased DA uptake after pharmacological inactivation or gene deletion highlights the plasticity of mesoaccumbal DA neurons and suggests that loss of KOR-1 and the resultant disinhibition of DA neurons trigger short- and long-term DA transporter adaptations that maintain normal DA levels, despite enhanced release.

Key words: -opioid receptor; nucleus accumbens; dopamine; microdialysis; cocaine; nor-binaltorphimine

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Received Nov 12, 2004; revised April 11, 2005; accepted April 12, 2005.

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