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The Journal of Neuroscience, March 14, 2007, 27(11):2958-2968; doi:10.1523/JNEUROSCI.4247-06.2007

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Behavioral/Systems/Cognitive
Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex

Chiung-Chun Huang,¹ Ping-Chun Yang,¹ Hsiao-Ju Lin,¹ and Kuei-Sen Hsu^1,2

¹Department of Pharmacology, College of Medicine, and ²Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan

Correspondence should be addressed to Dr. Kuei-Sen Hsu, Department of Pharmacology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan. Email: richard{at}mail.ncku.edu.tw

Drug-induced neuroadaptations within the medial prefrontal cortex (mPFC) are thought to underlie the development of cocaine sensitization. Here, we report that repeated cocaine administration in vivo impaired the long-term depression (LTD) induced by bath application of group II metabotropic glutamate receptor (mGluR) agonists DCG-IV [2S, 2'R, 3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine] or LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid] at excitatory synapses onto layer V pyramidal neurons of rat mPFC. In contrast, this impairment was not found in slices from rats treated with saline or a single dose of cocaine. Such effect of cocaine was selectively prevented when cocaine was coadministered with the selective D₁-like receptor antagonist SCH23390 [(R)-(+)-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine]. In slices from control rats, a brief application of either protein kinase C (PKC) activator phorbol-12,13-dibutyrute or adenosine A₃ receptor agonist 2-chloro-N⁶-(3-iodobenzyl)-adenosine-5-N-methyluronamide mimicked the effect of repeated cocaine treatment to impair the induction of LTD. Bilateral intra-mPFC infusion of PKC inhibitor bisindolylmaleimide I or adenosine A₃ receptor antagonist MRS1220 (N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide) before cocaine injection prevented cocaine-induced impairment of LTD induction. Furthermore, endogenous adenosine tone is greater in slices from cocaine-treated rats than from the saline-treated controls. When the metabolism of cAMP to adenosine was blocked, the extent of LTD in slices from saline and cocaine-treated rats was similar. These results suggest that cocaine-induced impairment of group II mGluR-mediated LTD is caused, at least in part, by an increase in adenosine subsequent to the rise in cAMP after D₁-like receptor activation, which leads to an adenosine A₃ receptor-mediated upregulation of PKC activity and thereby triggers an inhibition of group II metabotropic glutamate receptor function.

Key words: cocaine; medial prefrontal cortex; metabotropic glutamate receptor; long-term depression; adenosine; addiction

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Received Sept. 29, 2006; revised Feb. 6, 2007; accepted Feb. 6, 2007.

Correspondence should be addressed to Dr. Kuei-Sen Hsu, Department of Pharmacology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan. Email: richard{at}mail.ncku.edu.tw

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