title: Gamma-aminobutyric acidB (GABAB)-receptor mediation of different in vivo effects of gamma-butyrolactone.
abstract: The endogenous brain constituent, gamma-hydroxybutyric acid (GHB), as well as its prodrug, gamma-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the gamma-aminobutyric acid(B) (GABA(B)) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA(B) receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA(B)-receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation/hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA(B)-receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation /hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA(B) receptor.
authors.affiliation: CNR Institute of Neuroscience, Cagliari, Italy. macarai@unica.it
authors.forename: Mauro A M
authors.initials: MA
authors.lastname: Carai
authors.forename: Carla
authors.initials: C
authors.lastname: Lobina
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Cabras
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000633:toxicity; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology* / Q000633:toxicity; D018080:Receptors, GABA-B / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D012997:Solvents / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D001567:Benzocycloheptenes; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D006993:Hypnotics and Sedatives; D009025:Morpholines; D009943:Organophosphorus Compounds; D011355:Prodrugs; D018080:Receptors, GABA-B; D012997:Solvents; C066471:NCS 382; C066430:CGP 35348; D015107:4-Butyrolactone