Xiaohu Xie1, Jeffery D Steketee. 1. Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
Abstract
RATIONALE: Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Enhanced excitatory output from the medial prefrontal cortex (mPFC), which can be modulated by group II metabotropic glutamate receptors (mGluR), is thought to play a key role in the development of sensitization to cocaine. OBJECTIVES: The present studies were designed to determine whether the ability of intra-mPFC injections of the group II mGluR agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit cocaine-induced motor activity and dopamine release in the nucleus accumbens is reduced in sensitized animals. RESULTS: Initial studies demonstrated that injection of APDC (0.015-15 nmol/side) into the mPFC dose dependently reduced cocaine-induced (15 mg/kg, i.p.) motor activity. The lowest dose in the present studies that significantly reduced the acute motor-stimulant response to cocaine was 1.5 nmol/side. The specificity of the effects of APDC was confirmed by demonstrating that intra-mPFC co-injection of LY341495 (1.5 nmol/side), a group II mGluR antagonist, prevented the inhibitory actions of APDC. Finally, it was shown that intra-mPFC injection of APDC was able to prevent the initiation of behavioral and neurochemical sensitization to cocaine. Intra-mPFC APDC was also observed to block the expression of cocaine-induced sensitization after short (1 day), but not prolonged (7 and 30 days), abstinence from cocaine. CONCLUSIONS: Taken together, these data suggest that mPFC group II mGluR function is reduced following extended abstinence from repeated cocaine.
RATIONALE: Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Enhanced excitatory output from the medial prefrontal cortex (mPFC), which can be modulated by group II metabotropic glutamate receptors (mGluR), is thought to play a key role in the development of sensitization to cocaine. OBJECTIVES: The present studies were designed to determine whether the ability of intra-mPFC injections of the group II mGluR agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit cocaine-induced motor activity and dopamine release in the nucleus accumbens is reduced in sensitized animals. RESULTS: Initial studies demonstrated that injection of APDC (0.015-15 nmol/side) into the mPFC dose dependently reduced cocaine-induced (15 mg/kg, i.p.) motor activity. The lowest dose in the present studies that significantly reduced the acute motor-stimulant response to cocaine was 1.5 nmol/side. The specificity of the effects of APDC was confirmed by demonstrating that intra-mPFC co-injection of LY341495 (1.5 nmol/side), a group II mGluR antagonist, prevented the inhibitory actions of APDC. Finally, it was shown that intra-mPFC injection of APDC was able to prevent the initiation of behavioral and neurochemical sensitization to cocaine. Intra-mPFC APDC was also observed to block the expression of cocaine-induced sensitization after short (1 day), but not prolonged (7 and 30 days), abstinence from cocaine. CONCLUSIONS: Taken together, these data suggest that mPFC group II mGluR function is reduced following extended abstinence from repeated cocaine.
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