The GABA(B) antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat.
BACKGROUND
Several reports have demonstrated that the gamma-aminobutyric acid (GABA)(B) agonist baclofen attenuates the reinforcing effects of cocaine in rats, and recent evidence indicates that it might have a similar effect on heroin self-administration.


OBJECTIVE
The specific GABA(B) receptor antagonist CGP56433A was used to further evaluate the involvement of GABA(B) receptors in the baclofen-induced suppression of cocaine and heroin self-administration.


METHODS
In the first series of experiments, dose-response curves were generated to examine the effect of CGP56433A (0.6, 1.0, or 1.8 mg/kg, i.p.) on cocaine (1.5 mg/kg per injection) and heroin (25 microg/kg per injection) self-administration reinforced under a fixed-ratio (FR1) or progressive ratio (PR) schedule. Separate sets of experiments then examined the effect of the co-administration of CGP56433A and baclofen on responding for cocaine or heroin under both schedules.


RESULTS
Pretreatment with CGP56433A had no effect on cocaine or heroin self-administration, while baclofen dose dependently reduced responding for both cocaine and heroin under both the FR1 and PR schedule. CGP56433A (1.8 mg/kg) blocked the effect of baclofen on cocaine but not on heroin self-administration.


CONCLUSIONS
The specific GABA(B) antagonist CGP56433A attenuated the effect of baclofen on cocaine self-administration, suggesting that GABA(B) receptors are critical in mediating the anti-cocaine effect of baclofen. In combination with other studies, the data demonstrate that the susceptibility of baclofen and other GABA(B) agonists to receptor blockade depends on the behavioral response being studied. Whether this indicates different receptor mechanisms are involved (e.g., pre- versus post-synaptic effects or differential receptor reserve) remains to be determined.
Brebner
Karen
K
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083, USA.
Froestl
Wolfgang
W
Roberts
David C S
DC
D000818:Animals; D001418:Baclofen / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D006556:Heroin Dependence / Q000523:psychology*; D008297:Male; D010721:Phosphinic Acids / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D001565:Benzoates; D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; C105509:(3-(1-((3-(cyclohexylmethyl)hydroxyphosphinyl)-2-hydroxypropyl)amino)ethyl)benzoic acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001418:Baclofen