Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats.
OBJECTIVE
The role of benzodiazepine (BZ) receptor mechanisms in modulating the stimulus effects of the BZ partial inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) are not well understood. The purpose of the present experiments was to assess the role of BZ and non-BZ receptor stimulation in the discriminative stimulus effects of beta-CCE in rats.


METHODS
Adult male rats were trained to discriminate either a relatively high dose (10 mg/kg, n = 8) or a relatively low dose (5.0 mg/kg, n = 7) of beta-CCE from saline under a fixed-ratio 10 schedule of food presentation.


RESULTS
Under the high-dose training condition, beta-CCE engendered an increase in responding on the drug-paired lever up to 100% drug-lever responding, with no decrease in response rate. Diazepam, pentobarbital, flumazenil, (+)-amphetamine, and morphine did not share stimulus effects with 10 mg/kg beta-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-beta-carboline-3-carboxylate also did not engender > or = 80% beta-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ partial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulus effects of beta-CCE. Flumazenil antagonized the effects of beta-CCE with an in vivo apparent pA2 value of 6.1 (slope = -0.86). Under the low-dose condition, beta-CCE engendered an increase in drug-lever responding, with no changes in response rate. In contrast to the high-dose condition, diazepam, pentobarbital, and (+)-amphetamine engendered high levels of beta-CCE-lever responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full beta-CCE-lever responding.


CONCLUSIONS
These results indicated that the stimulus effects of the high dose of beta-CCE appeared consistent with mediation by the drug's partial inverse agonist effects at BZ receptors. The discriminative stimulus effects of beta-CCE at the lower training dose, however, appeared to be relatively non-specific.
Rowlett
J K
JK
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216, USA.
Wilcox
K M
KM
Woolverton
W L
WL
D000818:Animals; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*
D002243:Carbolines; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil; C024915:beta-carboline-3-carboxylic acid ethyl ester; D003975:Diazepam