title: The positive allosteric modulator of the GABA(B) receptor, rac-BHFF, suppresses alcohol self-administration.
abstract: The present study was designed to extend to the newly synthesized rac-BHFF [(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one] the investigation on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol self-administration in rats. To this end, selectively bred Sardinian alcohol-preferring (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 (0.7%, w/v) in daily 30-min sessions. Once responding reached stable levels, the effect of rac-BHFF (0, 50, 100, and 200mg/kg; i.g.) on responding for alcohol and sucrose was determined. Pretreatment with rac-BHFF produced a dose-dependent suppression in responding for alcohol; reduction in the total number of responses for alcohol, in comparison to vehicle-treated rats, averaged approximately 30%, 65%, and 90% in 50, 100, and 200mg/kg rac-BHFF-treated rats, respectively. Pretreatment with 200mg/kg rac-BHFF markedly increased the latency to the first response on the alcohol lever. The effect of pretreatment with rac-BHFF on alcohol self-administration was highly specific, since (a) responding for sucrose was reduced (to approximately 50%, in comparison to vehicle-treated rats) only by pretreatment with 200mg/kg rac-BHFF, and (b) latency to the first response on the sucrose lever was completely unaltered by any rac-BHFF dose. Treatment with rac-BHFF did not alter spontaneous locomotor activity in an independent group of sP rats. The present data constitute a further piece of evidence on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol's reinforcing properties in rats.
authors.affiliation: CNR Neuroscience Institute, Viale Diaz 182, I-09126 Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Mauro A M
authors.initials: MA
authors.lastname: Carai
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Pari
authors.initials: P
authors.lastname: Malherbe
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D000704:Analysis of Variance; D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000097:blood; D003216:Conditioning, Operant / Q000187:drug effects; D000431:Ethanol / Q000097:blood; D018757:GABA Modulators / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects*; D012055:Reinforcement Schedule; D013395:Sucrose
chemical_list: C532129:(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; D001572:Benzofurans; D002492:Central Nervous System Depressants; D018757:GABA Modulators; D018080:Receptors, GABA-B; D000431:Ethanol; D013395:Sucrose