Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.
BACKGROUND
The subtypes of gamma-aminobutyric acid (GABA)(A) receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABA(A) receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing alpha(1), alpha(2/3), and alpha(5) subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for alpha(4/6)-containing receptors, higher affinity for alpha(5)- and lower, but equal, affinity for alpha(1)- and alpha(2/3)-, containing GABA(A) receptors, and antagonizes the discriminative stimulus effects of ethanol.


METHODS
This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval.


RESULTS
Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (>or=80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose-response curve to the right in all monkeys showing generalization. Analysis of apparent pK(B) from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol.


CONCLUSIONS
Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABA(A) receptors that contain alpha(1) subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABA(A) receptor subtypes (e.g., alpha(2/3) and alpha(5)).
Helms
Christa M
CM
Department of Behavioral Neuroscience, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006-6448, USA.
Rogers
Laura S M
LS
Waters
Courtney A
CA
Grant
Kathleen A
KA
D000345:Affinity Labels / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004192:Discrimination, Psychological; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D005795:Generalization, Stimulus; D008252:Macaca fascicularis; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D000077334:Zolpidem
D000345:Affinity Labels; D001386:Azides; D002492:Central Nervous System Depressants; D018755:GABA Agonists; D011725:Pyridines; D001569:Benzodiazepines; D000431:Ethanol; D000077334:Zolpidem; C042957:Ro 15-4513