dizocilpine-maleate and 1-1-1-trichloroethane

The present study examined the involvement of the GABAA, N-methyl-D-aspartate (NMDA), nicotinic acetylcholine, and mu-opioid receptor systems in the transduction of the discriminative stimulus effects of the abused inhalant 1,1,1-trichloroethane (TCE). Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 12,000-ppm inhaled TCE vapor from air. Substitution and antagonism tests and TCE blood concentration analysis were subsequently conducted. TCE blood concentrations decreased rapidly after cessation of exposure, falling by 66% within 5 min. TCE vapor concentration-dependently substituted for the 12,000-ppm training stimulus. The volatile anesthetic halothane concentration-dependently and fully substituted for TCE. The benzodiazepine midazolam partially substituted for TCE, producing a maximum of 68% TCE-lever selection. The benzodiazepine antagonist flumazenil attenuated midazolam substitution for TCE, but not the discriminative stimulus effects of TCE itself. The noncompetitive NDMA receptor antagonists phencyclidine and dizocilpine failed to substitute for TCE. Nicotine and the central nicotinic receptor antagonist mecamylamine also failed to produce any TCE-lever selection, nor did they antagonize the discriminative stimulus of TCE. The mu-opioid receptor agonist morphine did not substitute for TCE. The opioid antagonist naltrexone failed to antagonize the discriminative stimulus of TCE. Overall, the present results, combined with previous studies, suggest that the discriminative stimulus effects of TCE are mediated primarily by positive GABAA receptor modulatory effects though a mechanism distinct from the benzodiazepine binding site.

Topics: Administration, Inhalation; Animals; Binding Sites; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Flumazenil; Male; Mice; Mice, Inbred Strains; Midazolam; Morphine; Phencyclidine; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Receptors, Opioid, mu; Signal Transduction; Trichloroethanes

In vitro and in vivo studies have shown that abused solvents affect different neurotransmitter systems, including the GABAergic, glutamatergic, and opioidergic. The first purpose of this study was to determine in mice whether an acute exposure to 4,000 ppm toluene or 12,000 ppm 1,1,1-trichloroethane (TCE) modifies receptor binding levels to: (a) DAMGO, a mu-opioid receptor selective agonist; (b) MK-801, a noncompetitive selective NMDA-receptor antagonist; and (c) flunitrazepam, a benzodiazepine binding site selective agonist. In addition, in separate groups of animals, nociceptive effects of toluene alone or co-administered with morphine were evaluated in the hot-plate test. Mice were exposed to toluene or TCE in static exposure chambers for 30 min, and their brains were removed 24 h later for autoradiography. Acute toluene inhalation produced a significant decrease in mu-opioid receptor binding levels in cingulate and piriform cortices, caudate putamen, thalamus, amygdala, and periaqueductal gray, whereas TCE significantly decreased mu-opioid receptor levels, but only in thalamus and periaqueductal gray. Both toluene and TCE decreased benzodiazepine receptor binding levels in discrete brain areas, but had no effect on NMDA receptor levels. In the hot-plate test, a single toluene exposure counteracted morphine antinociceptive response when the solvent exposure time was immediately followed by morphine treatment, but not when morphine was administered 24, 48, 72, and 96 h later. However, co-administration of morphine and toluene 24, 48, 72, and 96 h after the single solvent exposure resulted in morphine-induced analgesia blockade. Present results suggest that mu-opioid receptors are an important molecular target for organic solvents, and that the inhalation of these compounds may affect the analgesic properties of opioids.

Topics: Animals; Binding Sites; Brain; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Inhalation Exposure; Mice; Morphine; Narcotics; Pain Measurement; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Solvents; Toluene; Trichloroethanes

There is in vitro evidence that some of the effects of abused volatile solvents may be produced by actions at the NMDA receptor. In addition, some solvents produce phencyclidine-like discriminative stimulus effects. The major goal of the present study was to further compare abused solvents to NMDA antagonists by testing them in two strains of mice trained to discriminate 0.17 mg/kg of the very selective uncompetitive NMDA antagonist, dizocilpine, from saline and contrast those results with several GABA(A)-positive modulators, PCP and ethanol. The results indicated that the discriminative stimulus produced by 0.17 mg/kg dizocilpine was highly specific in both mouse strains. PCP produced 91% dizocilpine-lever responding in C57BL/6J mice, but only 56% dizocilpine-lever responding in DBA/2J mice. Pentobarbital, midazolam and ethanol produced at least some overlap in discriminative stimulus effects with dizocilpine in one or both mouse strains. In contrast, toluene, 1,1,1-trichloroethane (TCE), xylene and methoxyflurane produced saline-appropriate responding almost exclusively. These data indicate that, at least under the specific conditions tested, abused volatile solvents do not have substantial dizocilpine-like discriminative stimulus effects in either C57BL/6J or DBA/2J mice, providing little support that NMDA antagonism plays a central role in the production of this abuse-related effect.

Topics: Animals; Discrimination Learning; Dizocilpine Maleate; GABA Modulators; Illicit Drugs; Methoxyflurane; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Midazolam; Pentobarbital; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Solvents; Toluene; Trichloroethanes; Xylenes