Contribution of ventral tegmental GABA receptors to cocaine self-administration in rats.
Recent evidence has suggested that compounds affecting GABAergic transmission may provide useful pharmacological tools for the treatment of cocaine addiction. Using a rat model of self-administration, the present study examined the effects of GABA agonists and antagonists injected directly into the ventral tegmental area (VTA) on cocaine intake in rats trained to self-administer cocaine (0, 125, 250 and 500 microg/infusion) under an FR5 schedule of reinforcement. Separate groups of rats received bilateral intra-VTA injections of the GABA-A antagonist picrotoxin (34 ng/side, n = 7; 68 ng/side, n = 8), GABA-A agonist muscimol (14 ng/side, n = 8), GABA-B agonist baclofen (56 ng/side, n = 7; 100 ng/side, n = 6), picrotoxin (68 ng/side) co-injected with the GABA-B antagonist 2-hydroxysaclofen (100 ng/side, n = 7; 2 microg/side, n = 8) or artificial cerebrospinal fluid (aCSF, n = 6) to assess the effects of the various compounds on the cocaine self-administration dose-response curve. Both picrotoxin and baclofen reduced responding maintained by cocaine, whereas muscimol had no effect on responding. In contrast, neither picrotoxin (n = 6) nor baclofen (n = 8) affected responding maintained by food. Interestingly, 2-hydroxysaclofen effectively blocked the suppression of responding produced by picrotoxin, suggesting that both picrotoxin and baclofen exert their effects via activation of GABA-B receptors. Additionally, these effects appear to be specific to cocaine reinforcement, supporting current investigation of baclofen as a treatment for cocaine addiction.
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Neuroscience Graduate Program, Emory University School of Medicine, Atlanta, GA, USA.
Hemby
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D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005502:Food; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology*; D011963:Receptors, GABA-A / Q000187:drug effects; D012054:Reinforcement, Psychology; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000473:pathology / Q000502:physiology*
D001418:Baclofen; D018755:GABA Agonists; D018756:GABA Antagonists; D009118:Muscimol; D010852:Picrotoxin; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C057491:2-hydroxysaclofen