Discriminative stimulus properties of toluene in the mouse

Rees, David C.; Knisely, Janet S.; Jordan, Stephen D.; Balster, Robert L.

doi:10.1016/0041-008x(87)90273-0

Cited by 28 publications

(10 citation statements)

References 17 publications

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“…The rapidity with which the stimulus effects of 2000 ppm toluene vapor dissipate suggest that despite its high lipid solubility, the majority of the inhaled toluene dose is likely eliminated via exhalation or quickly metabolized. The present data confirmed those from prior drug discrimination studies demonstrating that the substitution of cross-test drugs for toluene in individual animals often only occurs at a single dose and that the optimal substitution dose is highly variable between subjects (Knisely et al, 1990; Rees et al, 1985; Rees et al, 1987a; Rees et al, 1987b). For instance, in the midazolam dose-effect curve, mean substitution for toluene never exceeded 66%, yet 7 of 8 mice demonstrated full substitution for toluene at one or more midazolam test dose.…”

Section: Discussionsupporting

confidence: 89%

“…Toluene produces somewhat inconsistent results when tested in animals trained to discriminate barbiturates or benzodiazepines from vehicle (Bowen et al, 1999; Rees et al, 1985) as well as uncompetitive NMDA antagonists from vehicle (Bowen et al, 1999; Shelton and Balster, 2004). In animals trained to discriminate toluene injections from vehicle, partial generalization was produced by barbiturates and benzodiazepines but not antipsychotics (Knisely et al, 1990; Rees et al, 1987b). …”

Section: Introductionmentioning

confidence: 99%

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Benzodiazepine-like discriminative stimulus effects of toluene vapor

Shelton

Nicholson

2013

European Journal of Pharmacology

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In vitro studies show that the abused inhalant toluene affects a number of ligand-gated ion channels. The two most consistently implicated of these are γ-aminobutyric acid type A (GABAA) receptors which are positively modulated by toluene and N-methyl-D-aspartate (NMDA) receptors which are negatively modulated by toluene. Behavioral studies also suggest an interaction of toluene with GABAA and/or NMDA receptors but it is unclear if these receptors underlie the abuse-related intoxicating effects of toluene. Seventeen B6SJLF1/J mice were trained using a two-choice operant drug discrimination procedure to discriminate 10 min of exposure to 2000 ppm toluene vapor from 10 min of exposure to air. The discrimination was acquired in a mean of 65 training sessions. The stimulus effects of 2000 ppm toluene vapor were exposure concentration-dependent but rapidly diminished following the cessation of vapor exposure. The stimulus effects of toluene generalized to the chlorinated hydrocarbon vapor perchloroethylene but not 1,1,2-trichloroethane nor the volatile anesthetic isoflurane. The competitive NMDA antagonist CGS-17955, the uncompetitive antagonist dizocilpine and the glycine-site antagonist L701,324 all failed to substitute for toluene. The classical nonselective benzodiazepines midazolam and chlordiazepoxide produced toluene-like stimulus effects but the alpha 1 subunit preferring positive GABAA modulator zaleplon failed to substitute for toluene. The barbiturates pentobarbital and methohexital and the GABAA-positive modulator neurosteroid allopregnanolone did not substitute for toluene. These data suggest that the stimulus effects of toluene may be at least partially mediated by benzodiazepine-like positive allosteric modulation of GABAA receptors containing alpha 2, 3 or 5 subunits.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Benzodiazepine-like discriminative stimulus effects of toluene vapor

Shelton

Nicholson

2013

European Journal of Pharmacology

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“…It was also far shorter than the 35 to 100 day range needed to train a discrimination of 100 mg/kg i.p. toluene in Swiss-Webster mice (Rees et al 1987c) as well as the 121 mean sessions required to train a 100 mg/kg i.p. toluene discrimination in rats (Knisely et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…In the first of these studies, conducted in mice, 100 mg/kg i.p. toluene was trained as a discriminative stimulus (Rees et al 1987c). Following training, substitution tests were conducted with inhaled toluene, i.p.…”

Section: Introductionmentioning

confidence: 99%

Inhaled toluene vapor as a discriminative stimulus

Shelton

2007

Behavioural Pharmacology

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Objectives-There have been few studies exploring the discriminative stimulus effects of inhalants and none that have trained an interoceptive discrimination using the inhaled route. This study was designed to assess if it was possible to train an inhaled toluene discrimination. The second objective was to determine whether the discrimination was based on interoceptive or exteroceptive stimulus effects.Methods-Eight B6SJLF1/J mice were trained to discriminate 10 min of exposure to 6000 ppm inhaled toluene vapor from air using a standard food-reinforced operant procedure.Results-Toluene vapor produced robust, concentration dependent, discriminative stimulus effects with concentrations of 4000 ppm and higher producing full substitution. Substitution of inhaled toluene vapor for the training condition was exposure-time dependent. A minimum of 7 min of exposure to 6000 ppm was required to produce complete substitution. Injected i.p. toluene produced dose-dependent full substitution for inhaled toluene vapor. Both inhaled and i.p. ethylbenzene produced similar levels of partial substitution for 6000 ppm toluene vapor. Inhaled isoflurane vapor produced no substitution for toluene vapor.Conclusions-These results show that a toluene vapor discrimination can be successfully trained in mice and the discrimination is selective for toluene compared to ethylbenzene and isoflurane. The results also suggest that the discrimination was likely to have been based primarily on interoceptive rather than exteroceptive stimulus effects.

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“…The numbers of individuals exposed to it are therefore very large. The solvent is considered to have only low toxicity (Brucker et al 1981;Boewer et al 1988), but a number of investigations have shown that toluene exposure can result in pathological and biochemical changes in liver, central nervous system and other organs, both in people exposed to toluene (O'Brien et al 1971;Guzelian et al 1988) and in animal experiments (Rea et al 1984;Rees et al 1987;Hsieh et al 1989). The biological monitoring of individuals exposed to toluene is very important in evaluating the extent of exposure, but it remains in question which urinary metabolite, hippuric acid (HA) or o-cresol, is better as an index of expoure.…”

Section: Introductionmentioning

confidence: 99%

Kinetic studies on toluene metabolism in ethanol- and phenobarbital-induced rat liver microsomes in vitro

Wang

Nakajima

1991

Arch Toxicol

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In vitro metabolism of toluene was investigated at substrate concentrations of 0.03-6.25 mM in liver microsomes from control and ethanol- and phenobarbital (PB)-treated rats. Three metabolites, benzylalcohol (BA), o- and p-cresol, were measured by high-performance liquid chromatograph. BA was the main metabolite of toluene, whereas o- and p-cresol contributed only 1.1-1.5% and 1.7-2.8% of total metabolites, respectively, in microsomes from control rats. Ethanol treatment showed little effect on the percentages of three metabolites, but PB increased the percentages of o- and p-cresol to as high as 5.5% and 8.0%, respectively, following the increase in toluene concentration. There were two different isozymes with different Km involved in the side-chain hydroxylation of toluene in microsomes from control and ethanol-treated rats. One had a low Km value (0.13-0.17 mM) and could be greatly induced with ethanol treatment. The other was a high Km isozyme (0.60-0.87 mM). PB-induced isozyme showed a similar Km value to that of the high Km isozyme existing in microsomes from control and ethanol-treated rats. Two isozymes were involved in the formation of p-cresol in microsomes of control rats: the low-Km type had a similar value (0.15 mM) to the low isozyme of BA formation, but the high Km isozyme had a larger value (2.04 mM) than the high isozyme of BA. Only one enzyme responsible for o-cresol formation was detected in microsomes of control rats, and had a similar Km (2.11 mM) to that of the high Km isozyme of p-cresol.(ABSTRACT TRUNCATED AT 250 WORDS)

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Discriminative stimulus properties of toluene in the mouse

Cited by 28 publications

References 17 publications

Benzodiazepine-like discriminative stimulus effects of toluene vapor

Benzodiazepine-like discriminative stimulus effects of toluene vapor

Inhaled toluene vapor as a discriminative stimulus

Kinetic studies on toluene metabolism in ethanol- and phenobarbital-induced rat liver microsomes in vitro

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