Specific reduction of alcohol's motivational properties by the positive allosteric modulator of the GABAB receptor, GS39783--comparison with the effect of the GABAB receptor direct agonist, baclofen.
BACKGROUND
Activation of the GABA(B) receptor--either by means of direct agonists (like baclofen) or positive allosteric modulators (like GS39783)--has been observed to suppress alcohol drinking and reinforcement in rats and mice. The present study was conducted to assess and compare the effect of baclofen and GS39783 on the motivational properties of alcohol.


METHODS
Selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever (on an fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) or sucrose (3%, w/v) in daily 30-minute sessions. Once lever-responding reached stable levels, rats were exposed to sessions with a progressive ratio schedule of reinforcement. The effect of nonsedative doses of baclofen (0, 1, and 3 mg/kg, i.p.) and GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on breakpoint for alcohol and sucrose (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol and sucrose) was determined.


RESULTS
Baclofen administration resulted in a dose-dependent decrease in breakpoint for alcohol; this effect was not specific, as baclofen also reduced--to a comparable extent--breakpoint for sucrose. Conversely, GS39783 administration resulted in a dose-dependent and completely specific reduction in breakpoint for alcohol.


CONCLUSIONS
The present results (i) confirm previous data on baclofen's capacity to suppress, although nonspecifically, alcohol's motivational properties, and (ii) extend to alcohol's motivational properties the capacity of GS39783 to inhibit alcohol drinking and reinforcement in rats.
Maccioni
Paola
P
C.N.R. Institute of Neuroscience, Cagliari, Italy.
Fantini
Noemi
N
Froestl
Wolfgang
W
Carai
Mauro A M
MA
Gessa
Gian Luigi
GL
Colombo
Giancarlo
G
D000437:Alcoholism / Q000235:genetics / Q000523:psychology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D008297:Male; D009042:Motivation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects*; D012054:Reinforcement, Psychology; D012646:Self Administration
D002492:Central Nervous System Depressants; D003517:Cyclopentanes; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011743:Pyrimidines; D018080:Receptors, GABA-B; D000431:Ethanol; D001418:Baclofen