Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat

Vry, Jean De; Slangen, Jef L.

doi:10.1007/bf00180836

Cited by 73 publications

(24 citation statements)

References 18 publications

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“…These results are generally consistent with previous reports showing similarities in the discriminative stimulus effects of PB and diazepam (Overton 1966;J/irbe 1976;Herling et al 1980;Winger and Herling 1982;Balster and Moser 1987) and between barbiturates and benzodiazepines in general (Colpaert et al 1976;Spealman 1985;de Vry and Slangen 1986), although exceptions to this general finding have been reported (Ator andGriffiths 1983, 1989). It can be suggested that enhancement of GABAergic neurotransmission is the basis of barbiturate discrimination, and the overlap in the discriminative Stimulus effects of barbiturates and benzodiazepines is among the strongest evidence for a GABAergic basis of barbiturate discrimination (Colpaert et al 1976;Herling et al 1980;Winger and Herling 1982).…”

Section: Discussionsupporting

confidence: 94%

“…The results of these studies provide a complex profile of both similarities and differences among the discriminative stimulus effects of the barbiturates and benzodiazepines, dependent on the conditions of training and testing. However, under many circumstances substitution studies reveal complete cross generalization within and among the barbiturate and benzodiazepine drug classes in a number of species (Colpaert et al 1976;Herling et al 1980;Winger and Herling 1982;de Vry and Slangen 1986). These cross generalization data support the hypothesis that GABAergic activation serves as the neural basis of the discriminative stimulus effects of barbiturates and benzodiazepines.…”

Section: Drug Discrimination Procedures In Animals Have Been Used To mentioning

confidence: 64%

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Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

Grech

Balster

1993

Psychopharmacology

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The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40-60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino)] butyric acid (SL 75102) also partially substituted for PB, producing means of 39-73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.

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Section: Discussionsupporting

confidence: 94%

Section: Drug Discrimination Procedures In Animals Have Been Used To mentioning

confidence: 64%

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

Grech

Balster

1993

Psychopharmacology

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“…These quantitative differences may suggest differences in the potency or efficacy of the training dose of each compound. Previous studies have demonstrated that training dose influences which drugs substitute as well as the dose-response functions for these drugs (De Vry and Slangen, 1986; Mansbach and Balster, 1991; Young et al, 1992). For example, methanandamide fully substituted in rats trained to discriminate 1.8 mg/kg Δ 9 -THC, but only partially substituted in rats trained to discriminate 5.6 mg/kg Δ 9 -THC (Järbe et al, 2000; Järbe et al, 1998).…”

Section: 0 Discussionmentioning

confidence: 99%

Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats

Wiley

Lefever

Cortes

et al. 2014

Pharmacology Biochemistry and Behavior

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Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ9-tetrahydrocannabinol (Δ9-THC) from vehicle. In addition, the effects of Δ9-THC in rats trained to discriminate JWH-018 from vehicle were assessed. Adult male Sprague-Dawley rats were trained to discriminate 3 mg/kg Δ9-THC or 0.3 mg/kg JWH-018 from vehicle. JWH-018, JWH-073, and JWH-210 fully substituted in Δ9-THC-trained rats and Δ9-THC substituted in JWH-018-trained rats. In contrast, JWH-320, an indole-derived cannabinoid without affinity for CB1 receptors, failed to substitute for Δ9-THC. Pre-treatment with 1 mg/kg rimonabant significantly reduced responding on the JWH-018-associated lever in JWH-018-trained rats. These results support the conclusion that the interoceptive effects of Δ9-THC and synthetic indole-derived cannabinoids show a large degree of overlap, which is predictive of their use for their marijuana-like intoxicating properties. Characterization of the extent of pharmacological differences among structural classes of cannabinoids, and determination of their mechanisms remain important goals.

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“…For example, benzodiazepines, neuroactive steroids, and ethanol have been established as discriminative stimuli, and benzodiazepines produce drug-lever responding in subjects discriminating each of those positive GABA A receptor modulators. Because benzodiazepines do not act at GABA A receptors containing α 4 -δ subunits, these results indicate that other GABA A receptor subtypes are an important component of the discriminative stimulus effects of these positive GABA A receptor modulators (e.g., Bai and Gerak 2011; De Vry and Slangen 1986). Gaboxadol does not produce drug-lever responding in rats (current study) or monkeys (McMahon and France 2005) discriminating midazolam, indicating that the mechanism of action of gaboxadol is different from that of benzodiazepines.…”

Section: Discussionmentioning

confidence: 87%

Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

et al. 2016

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Rationale Gaboxadol is a selective agonist at GABAA receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAA-receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. Objectives The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAA receptors containing α4-δ subunits. Materials Eight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed-ratio 10 schedule for food. Modulators acting at GABAA receptors containing α4-δ subunits (pregnanolone, ethanol, flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle. Results Gaboxadol produced ≥80% gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80% drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32% gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol. Conclusions Drugs that modulate GABAA receptors containing α4-δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABAA-receptor subtype.

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Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat

Cited by 73 publications

References 18 publications

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

Cross-substitution of Δ9-tetrahydrocannabinol and JWH-018 in drug discrimination in rats

Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

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