Evaluation of the reinforcing and discriminative stimulus effects of 1,4-butanediol and gamma-butyrolactone in rhesus monkeys.
Metabolic precursors and prodrugs of gamma-hydroxybutyrate (GHB), including 1,4-butanediol (BDL) and gamma-butyrolactone (GBL), have sedative and anesthetic effects and might have positive reinforcing effects. BDL and GBL were evaluated using behavioral procedures that measure positive reinforcing effects and discriminative stimulus effects of drugs that modulate gamma-aminobutyric acid (GABA) at the GABA(A) receptor complex. One group of rhesus monkeys could respond for saline or the barbiturate methohexital (i.v.) in a self-administration paradigm. Two other groups of monkeys discriminated the barbiturate pentobarbital (i.g.) or the benzodiazepine midazolam (s.c.) from saline in a drug discrimination paradigm; another group of monkeys was treated with the benzodiazepine diazepam (5.6 mg/kg/day, p.o.) and discriminated the benzodiazepine antagonist flumazenil (s.c.) from vehicle. In self-administration experiments, methohexital and not BDL (0.1-3.2 mg/kg/injection) or GBL (0.1-3.2 mg/kg/injection) reliably maintained responding above saline levels. BDL and GBL, up to doses that suppressed responding, did not substitute for pentobarbital, midazolam or flumazenil. The onset of action for both drugs to decrease response rate was delayed (90 min for GBL and 150 min for BDL). These results suggest that any abuse-related effects of BDL and GBL are qualitatively different from the abuse-related effects of GABA(A) receptor modulators and further indicate that BDL and GBL do not have positive reinforcing effects in rhesus monkeys experienced with self-administration of a short-acting sedative-hypnotic.
McMahon
Lance R
LR
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Coop
Andrew
A
France
Charles P
CP
Winger
Gail
G
Woolverton
William L
WL
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002072:Butylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects; D012054:Reinforcement, Psychology; D012646:Self Administration
D002072:Butylene Glycols; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; C039681:1,4-butanediol; D010424:Pentobarbital; D015107:4-Butyrolactone; D008874:Midazolam