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Rationale: GABA positive allosteric modulators (GABA PAMs), such as diazepam and zolpidem, are used clinically for anxiety and insomnia, but abuse liability is a concern. Novel GABA PAMS may have lower abuse liability while retaining clinical utility. Objective: The present study compared abuse-related effects of the non-selective GABA PAM diazepam, the α1-selective GABA PAM zolpidem, and three novel GABA PAMs (JY-XHe-053, XHe-II-053, and HZ-166) using intracranial self-stimulation (ICSS) in rats. These novel compounds have relatively low efficacy at α1-, α2-, and α3-containing GABA receptors, putative in vivo selectivity at α2/α3-containing GABA receptors, and produce anxiolytic-like effects with limited sedation in non-human primates. Methods: Adult, male Sprague-Dawley rats ( n = 17) were each implanted with a bipolar electrode in the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule of reinforcement for electrical brain stimulation. The potency and time course of effects were compared for diazepam (0.1-10 mg/kg), zolpidem (0.032-3.2 mg/kg), and the three novel compounds (JY-XHe-053, XHe-II-053, and HZ-166; all 3.2-32 mg/kg). Results: Zolpidem and diazepam produced transient facilitation of ICSS at small doses and more sustained rate-decreasing effects at larger doses. JY-XHe-053 and HZ-166 produced weak and inconsistent ICSS facilitation, whereas XHe-II-053 had no effect on ICSS. Conclusions: These results support a key role for α1-containing GABA receptors in mediating GABA PAM-induced ICSS facilitation. These results are concordant with drug self-administration studies in monkeys in suggesting that GABA PAMs with low α1 efficacy and putative α2/α3 selectivity have lower abuse liability than high-efficacy non-selective or α1-selective GABA PAMs. [ABSTRACT FROM AUTHOR]

Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. Objective: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. Methods: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. Results: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. Conclusions: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems.... [ABSTRACT FROM AUTHOR]

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kg β-FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured. [ABSTRACT FROM AUTHOR]

Presents a study which developed a method for comparing dose-effect functions for cocaine self-administration with magnitude-effect functions for food-maintained behavior in mice. Materials and methods; Evaluation of food-maintained operant behavior.