Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism.
The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1-5 microg/microl per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP, 5 microg/microl per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082's action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine's acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082's actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction.
Li
Xia
X
Neuropsychopharmacology Section, Chemical Biology Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Li
Jie
J
Peng
Xiao-Qing
XQ
Spiller
Krista
K
Gardner
Eliot L
EL
Xi
Zheng-Xiong
ZX
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004558:Electric Stimulation / Q000379:methods; D005917:Globus Pallidus / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D018092:Kainic Acid Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000097808:GluK3 Kainate Receptor
D001559:Benzhydryl Compounds; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D018092:Kainic Acid Receptors; D013395:Sucrose; D013549:Sweetening Agents; D005680:gamma-Aminobutyric Acid; D000097808:GluK3 Kainate Receptor; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride