Discriminative Stimulus Effects of Positive GABA_AModulators and Other Anxiolytics, Sedatives, and Anticonvulsants in Untreated and Diazepam-Treated Monkeys

Abstract

Positive GABA A modulators and other sedatives, anxiolytics, and anticonvulsants were used to evaluate mechanisms underlying the discriminative stimulus effects of midazolam in untreated monkeys and of flumazenil in monkeys treated with diazepam (5.6 mg/kg/day). Positive GABA A modulators at benzodiazepine (e.g., flunitrazepam and abecarnil) and neuroactive steroid sites (e.g., androsterone) substituted for midazolam in all monkeys; the neuroactive steroids dihydroandrosterone and epipregnanolone substituted for midazolam in two of three monkeys. All positive GABA A modulators attenuated flumazenil in diazepam-treated monkeys; doses of flunitrazepam and abecarnil larger than doses substituting for midazolam were required to attenuate flumazenil, whereas doses of neuroactive steroids smaller than doses substituting for midazolam attenuated flumazenil. Drugs with mechanisms that do not predominantly involve allosteric modulation of GABA (e.g., buspirone, ketamine, valproic acid, and diphenhydramine) did not substitute for midazolam or flumazenil. However, valproic acid enhanced the midazolam discriminative stimulus and attenuated the flumazenil discriminative stimulus; diphenhydramine attenuated the midazolam discriminative stimulus. These results suggest that drugs not sharing a mechanism of action with benzodiazepines can modulate the behavioral effects of benzodiazepines. In addition, this study demonstrates that endogenous ligands, presumably by acting at neuroactive steroid sites on the GABA A receptor complex, share discriminative stimulus effects with benzodiazepines. This study also suggests that positive GABA A -modulating neuroactive steroids are especially potent in attenuating behavioral effects that are related to diazepam withdrawal.

Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys

“…The failure of muscimol and gaboxadol to modify the midazolam discriminative stimulus suggests that SL 75102 is not responsible for progabide enhancing the midazolam discriminative stimulus. In a previous study, the indirectacting GABA A receptor agonist and GABA transaminase inhibitor valproic acid enhanced the discriminative stimulus effects of midazolam (McMahon and France 2003). It is not clear why indirect-acting (valproic acid and progabide) and direct-acting GABA A receptor agonists (muscimol and gaboxadol) differentially enhance the discriminative stimulus effects of midazolam.…”

“…positive GABA A modulators) have sedative, anxiolytic and anticonvulsant effects, and drug discrimination has been used to examine whether positive GABA A modulators at different sites are qualitatively similar. For example, positive GABA A modulators at each of these sites substitute for midazolam in rhesus monkeys, whereas sedatives, anxiolytics and anticonvulsants that do not positively modulate GABA at GABA A receptors do not substitute for midazolam (McMahon et al 2001;McMahon and France 2003). In contrast to the qualitatively similar effects of positive GABA A modulators in rhesus monkeys discriminating midazolam, differences among positive GABA A modulators have been reported in other species discriminating midazolam, e.g.…”

“…Three monkeys had been trained to respond under fixed-ratio (FR) schedules (stimulus shock termination) and had received positive GABA A modulators and other sedatives, hypnotics and anticonvulsants (e.g. McMahon and France 2003). Two other monkeys were pharmacologically and experimentally naïve prior to these studies.…”

SSR591813, a Novel Selective and Partial α4β2 Nicotinic Receptor Agonist with Potential as an Aid to Smoking Cessation

“…Such acute agonist-induced sensitization to effect of an antagonist has been viewed as evidence of a state of acute dependence. This methodology, validated for opioid and benzodiazepine dependence (Easterling and Holtzman, 1999;McMahon and France, 2003), was applied to nicotine dependence. Thus, rats were trained to discriminate mecamylamine (3 mg/kg s.c., 15 min before testing) after a single administration of nicotine (1 mg/kg s.c., 120 min before testing) further referred as nicotine3mecamylamine, from two injections of saline (saline3saline).…”

“…To investigate the affective aspects of nicotine withdrawal, we used a model based on reports of acute dependence in humans (Bickel et al, 1988) and validated in rodents for opioid and benzodiazepine withdrawal (McMahon and France, 2003;Easterling and Holtzman, 1999). In humans, administration of naloxone several hours after an acute injection of morphine produces an opiate withdrawal syndrome and in rats, it produces an aversive state that can serve as a discriminative stimulus ("withdrawal" stimulus).…”