Reducing effect of the positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats.
The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.
Orrù
Alessandro
A
Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari (CA), Italy.
Lai
Paola
P
Lobina
Carla
C
Maccioni
Paola
P
Piras
Patrizia
P
Scanu
Laura
L
Froestl
Wolfgang
W
Gessa
Gian Luigi
GL
Carai
Mauro A M
MA
Colombo
Giancarlo
G
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018080:Receptors, GABA-B / Q000378:metabolism
C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D003517:Cyclopentanes; D018757:GABA Modulators; D058786:GABA-B Receptor Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D010636:Phenols; D011743:Pyrimidines; D018080:Receptors, GABA-B