Reduction of alcohol's reinforcing and motivational properties by the positive allosteric modulator of the GABA(B) receptor, BHF177, in alcohol-preferring rats.
BACKGROUND
The positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, have been found to reduce alcohol self-administration in alcohol-preferring rats. The present study was designed to assess the effect of the newly synthesized positive allosteric modulator of the GABA(B) receptor, BHF177, on alcohol's reinforcing and motivational properties in selectively bred Sardinian alcohol-preferring (sP) rats.


METHODS
sP rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (1 to 3%, w/v) in daily 30-minute sessions. Once responding reached stable levels, rats were allocated to 2 different experiments: in the first experiment, rats were exposed to sessions with the FR4 schedule of reinforcement; in the second experiment, rats were exposed to sessions with a conventional progressive ratio (PR) schedule of reinforcement. In both experiments, the effect of BHF177 (0, 12.5, 25, and 50 mg/kg; i.g.) on responding for alcohol and sucrose (FR experiment: 1%, w/v; PR experiment: 3%, w/v) was determined.


RESULTS
In the FR experiment, pretreatment with 25 and 50 mg/kg BHF177 produced a 30 and 45% reduction, respectively, in responding for alcohol. In the PR experiment, pretreatment with 50 mg/kg BHF177 resulted in a 35% reduction in breakpoint for alcohol (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol). In both experiments, the effect of BHF177 on alcohol self-administration was specific, since responding for sucrose was unaltered by BHF177 pretreatment.


CONCLUSIONS
The present results extend to BHF177 the capacity of the 2 previously tested positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to specifically suppress alcohol's reinforcing and motivational properties in alcohol-preferring rats.
Maccioni
Paola
P
CNR Institute of Neuroscience, Cagliari, Italy.
Carai
Mauro A M
MA
Kaupmann
Klemens
K
Guery
Sébastien
S
Froestl
Wolfgang
W
Leite-Morris
Kimberly A
KA
Gessa
Gian Luigi
GL
Colombo
Giancarlo
G
D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D009042:Motivation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
D002492:Central Nervous System Depressants; D018757:GABA Modulators; D011743:Pyrimidines; D018080:Receptors, GABA-B; D000431:Ethanol