Effects of repeated exposure to cocaine on group II metabotropic glutamate receptor function in the rat medial prefrontal cortex: behavioral and neurochemical studies.
BACKGROUND
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.


OBJECTIVE
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.
Xie
Xiaohu
X
Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
Steketee
Jeffery D
JD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D011392:Proline; D003042:Cocaine