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BEHAVIORAL PHARMACOLOGY

Discriminative Stimulus Effects of -Hydroxybutyrate: Role of Training Dose

Departments of Psychiatry and Pharmacology (W.K., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Department of Pharmaceutical Sciences (W.C., S.L.M., A.C.), University of Maryland, Baltimore, Maryland

-Hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study examined whether the relative importance of GABA_A, GABA_B, and GHB receptors in the discriminative stimulus effects of GHB depends on the training dose. In comparison with a previous 100 mg/kg GHB-saline discrimination, pigeons were trained to discriminate either 178 or 56 mg/kg GHB from saline. Increasing the training dose shifted the GHB gradient to the right, and decreasing it shifted the gradient to the left. Similar shifts occurred with the GHB precursor -butyrolactone, which substituted for GHB, and with the GABA_B agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) and the benzodiazepine diazepam, each of which produced at most 54 to 68% GHB-appropriate responding. The benzodiazepine antagonist flumazenil, the benzodiazepine inverse agonist ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-]-[1,4]-benzodiazepine-3-carboxylate (Ro 15-4513), and the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) produced a maximum of 66 to 97% GHB-appropriate responding in animals discriminating 56 or 100 mg/kg GHB and a maximum of 1 to 49% in animals discriminating 178 mg/kg. NCS-382 did not attenuate the effects of GHB. The GABA_B antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348) blocked GHB at all training doses. The results suggest that increasing the training dose of GHB increases the pharmacological selectivity of its discriminative stimulus effects. At a high training dose, diazepam-insensitive GABA_A receptors, for which flumazenil and Ro 15-4513 have affinity, may no longer be involved. Diazepam-sensitive GABA_A receptors and GABA_B receptors appear to play a similar role at all training doses. There was no evidence for GHB receptor involvement.

Address correspondence to: Dr. Wouter Koek, Departments of Psychiatry and Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7792, San Antonio, TX 78229-3900. E-mail: koek{at}uthscsa.edu