Scott E. Bowen

Deaths associated with inhalant abuse in Virginia from 1987 to 1996

Inhalant abuse has existed for a considerable period of time and it is currently one of the most prevalent drug abuse problems in the world. One repercussion from using these compounds is that abuse may result in lethality. In an attempt to better understand the deaths associated with inhalant abuse, the authors surveyed the death records from the Commonwealth of Virginia from 1987 to 1996. Examination of the state records identified 39 deaths related to inhalant abuse during this time period. While no significant increase or decrease in the death rate was observed across the time period investigated, all regions of Virginia were affected, with the rates being highest in the northern and eastern regions of the state. Age of death ranged from 13 to 42 years with the majority of deaths (70%) occurring at 22 years of age or younger. Ninety-five per cent of the individuals were male, with volatile substance abuse deaths accounting for 0.3% of all deaths in males aged 13-22 years. The chief volatile substances used were gas fuels (46%), predominately butane and propane, chlorofluorocarbons (26%), chlorinated hydrocarbons and alkylbenzenes (21%), and other volatile substances including volatile anesthetics. Deaths associated with the abuse of butane and toluene were more likely to be traumatic, but all substances appeared capable of killing directly by their toxic effects, probably through cardiac and/or respiratory mechanisms. The ramifications of these findings for regulation and prevention are addressed.

The effects of abused inhalants on mouse behavior in an elevated plus-maze

Previous research has shown that abused inhalants (i.e., the volatile solvents) share some of the pharmacological properties of drugs used in the treatment of anxiety. In an attempt to further examine commonalities in the effects of inhalants and central nervous system depressant drugs, the behavioral effects of inhaled 1,1,1-trichloroethane, toluene, methoxyflurane and the convulsant vapor flurothyl were examined and compared to those of diazepam in the elevated plus-maze, a test used to predict antianxiety effects. After inhalant exposure or diazepam injection, mice were placed in the center of an elevated plus-maze and the number of entries and time spent in each type of arm (open versus closed) were measured during 5-min tests. Exposure to increasing concentrations of toluene produced concentration-related increases in the total number of open arm entries and the total time spent on the open arms, a pattern of behavioral effects similar to that produced by diazepam. A similar pattern was observed for increasing concentrations of 1,1,1-trichloroethane and methoxyflurane but changes in open arm activity were only observed at concentrations that increased locomotor activity. Conversely, only decreases in open arm time and number of entries were observed for flurothyl. The increasing evidence for commonalities in the behavioral effects of volatile solvents and depressant drugs may provide a foundation for understanding the neurobehavioral basis of inhalant abuse.

Effects of inhaled 1,1,1-trichloroethane on locomotor activity in mice

To quantify the motoric effects of an abused solvent, photocells were added to two exposure systems. The first system utilized a static exposure chamber that recirculated vapor-laden air. A second dynamic system allowed for removal of waste gases with replenishment of fresh air combined with test vapors. In the present studies, male mice were examined for effects on locomotor activity following 30-min inhalation exposures to several concentrations of 1,1,1-trichloroethane (TCE), a widely used and abused solvent. TCE produced significant increases in locomotor activity at intermediate concentrations. Minimally effective concentrations for activity-increasing effects in the dynamic and static systems were 1,250 ppm and 2,500 ppm, respectively. At higher concentrations, motor activity was decreased with the highest dynamic system concentration (10,000 ppm), resulting in 26% of baseline control values. Biphasic, motor activity increasing and decreasing effects of TCE as a function of exposure concentration may reflect the CNS-depressant drug-like effects of abused solvents.

Functional observational battery comparing effects of ethanol, 1,1,1-trichloroethane, ether, and flurothyl

Several recent reports have demonstrated that acute solvent exposure in animals produces a profile of neurobehavioral effects similar to that of classical CNS depressant drugs such as the barbiturates and ethanol. The present investigation further delineated the behavioral pharmacology of three solvents [1,1,1-trichloroethane (TCE), ether, and flurothyl] using a functional observational battery (FOB) composed of 21 qualitative and quantitative measures of behavior. The profiles of acute effects produced by TCE and ether were similar to one another and similar to the profile of effects produced by the IP administration of ethanol. This profile of depressant effects included changes in posture, decreased arousal, disturbances in gait, decreased forelimb grip strength, increased landing foot splay, and impaired psychomotor coordination. Flurothyl exposure also produced dose-related effects on many of the measures in the FOB; however, unlike the depressant vapors, flurothyl did not affect measures of muscle tone and equilibrium such as forelimb grip strength and landing foot splay, or measures of sensorimotor reactivity, including the touch response and tail pinch response. In addition, flurothyl produced handling-induced convulsions in some mice. Recovery from the acute effects of these vapors was rapid and began within minutes of removal from the exposure chamber. These results provide further evidence that exposure to certain solvents produces a profile of reversible effects qualitatively similar to that produced by depressant drugs and alcohol, and that the FOB can be used to compare and contrast profiles of depressant and excitatory effects of inhalants.

Desf lurane, Enf lurane, Isof lurane and Ether Produce Ethanol-Like Discriminative Stimulus Effects in Mice1

In the present studies, drug discrimination procedures were used to compare the discriminative stimulus effects of ethanol (ETOH) and several volatile anesthetics. Male albino mice were trained to discriminate between IP injections of ETOH (1.25 g/kg) and saline in a two-lever operant task in which responding was under the control of a fixed-ratio 20 (FR20) schedule of food presentation. Stimulus generalization was examined after 20-min inhalation exposures to desflurane (4,000-32,000 ppm), enflurane (3,000-12,000 ppm), isoflurane (1,000-8,000 ppm) and ether (4,000-32,000 ppm). Concentration-related increases in ETOH-lever responding were observed for all four volatile anesthetics. For enflurane and ether, maximal levels of > 85% ETOH-lever responding were obtained at one or more concentrations. For desflurane and isoflurane, the maximal mean percentages of ETOH-lever responding were somewhat lower, but 6 out of 7 mice showed full substitution with desflurane and 5 out of 7 for isoflurane. The shared discriminative properties of these compounds with ETOH suggest that these anesthetics may share some of ETOHs pharmacological properties. These results are similar to previous research results showing ETOH-like discriminative stimulus effects in mice with other anesthetics and abused volatile inhalants (i.e. halothane, toluene and 1.1,1-trichloroethane) and may reflect the CNS-depressant drug-like effects of inhaled anesthetics and abused solvents.

A Comparison of the Acute Behavioral Effects of Inhaled Amyl, Ethyl, and Butyl Acetate in Mice☆

The acute neurobehavioral effects of three acetates (amyl, ethyl, and n-butyl acetate) were investigated after 20-min inhalation exposures in mice using locomotor activity and a functional observational battery (FOB). Ethyl and n-butyl acetate produced significant decreases in locomotor activity at the highest concentrations examined, while amyl acetate was without effect. Minimally effective concentrations for activity-decreasing effects were 2000 ppm for ethyl acetate and 8000 ppm for n-butyl acetate. The potency order was similar in the FOB where ethyl acetate was more potent in disrupting the neurobehavioral measures. The FOB profile of effects for all three acetates included changes in posture, decreased arousal, increased tonic/clonic movements, disturbances in gait, delayed righting reflexes, and increased sensorimotor reactivity. Furthermore, handling-induced convulsions were produced in some mice acutely exposed to each of these acetates. Recovery from the acute effects of these acetates was rapid and began within minutes of removal from the exposure chamber. The acetates produced a profile of neurobehavioral effects that were different from those reported for depressant solvents (i.e., toluene, 1,1,1-trichloroethane) that are subject to abuse. Evidence is emerging for qualitative differences in the acute neurobehavioral effects of various volatile chemicals.

Effects of modulation of nitric oxide on acoustic startle responding and prepulse inhibition in rats

The nitric oxide-arginine pathway is intimately connected to the release of dopamine and glutamate, two neurotransmitter systems that may be dysfunctional in schizophrenia. In addition, nitric oxide synthase inhibitors share several behavioral effects with the psychotomimetic drug, phencyclidine. Previous research has found that phencyclidine-like drugs disrupt prepulse inhibition of the acoustic startle response, an animal model of sensorimotor gating, an attentional process that is disrupted in certain neuropsychiatric disorders in humans (e.g., acute schizophrenia). The purpose of the present study was to examine the effects of nitric oxide modulators in this model. Following injection with a nitric oxide modulator or phencyclidine, rats were placed in startle chambers in which they were exposed to acoustic pulses presented alone or preceded by a prepulse. As in previous reports, phencyclidine disrupted prepulse inhibition at doses that did not affect startle during pulse alone trials. In contrast, the nitric oxide synthase inhibitors, N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently decreased startle during pulse alone trials, but neither drug affected prepulse inhibition. A nitric oxide precursor, L-arginine, produced similar results. Sodium nitroprusside (a nitric oxide releaser) and 7-nitroindazole (a third nitric oxide synthase inhibitor) did not affect startle amplitudes during pulse alone or prepulse + pulse trials. The present results suggest that modulation of nitric oxide synthesis or availability does not disrupt sensorimotor gating of the acoustic startle response and is probably not involved in mediation of this type of attentional deficit in humans.

The Effects of Inhaled Isoparaffins on Locomotor Activity and Operant Performance in Mice

Very little is known qualitatively or quantitatively about the acute central nervous system effects of isoparaffin solvents that are widely used in household and commercial applications. Four isoparaffinic hydrocarbon solvent products differing in predominant carbon number and volatility (ISOPAR-C, -E -G, -H) were tested for their acute effects on locomotor activity and operant performance after inhalation exposure in mice. For both measures, concentration-effect curves were obtained for 30-min exposures using a within-subject design. The more volatile products, ISOPAR-C and -E, were as easily vaporized under our conditions as vapors such as toluene and TCE, which have acute effects on human behavior and are abused. ISOPAR-G was slowly volatilized and ISOPAR-H could not be completely volatilized within our 30-min exposures, suggesting that acute human exposures may be less likely and that it may be more difficult to abuse them. ISOPAR-C, -E, and -G produced reversible increases in locomotor activity of mice at 4000 and 6000 ppm while ISOPAR-C and -E produced reversible concentration-dependent decreases in rates of schedule-controlled operant behavior in approximately the same concentration range as they affected locomotor activity. The fact that only locomotor activity increases were observed with these isoparaffins provides evidence that they produce a different pattern of effects than those reported for abused solvents such as toluene and TCE. Further research will be needed to determine if this different pattern of effects on animal behavior between isoparaffins and abused solvents is correlated with a different pattern of acute intoxication and abuse potential in humans.

Evaluation of the acute behavioral effects and abuse potential of a C8–C9 isoparaffin solvent

We hypothesized that the abuse potential of certain types of inhalants could be evaluated in animals by determining the overlap in their profile of behavioral effects with that of CNS depressant drugs and other depressant-like abused inhalants. For our first attempt in evaluating a solvent with an unknown abuse potential we tested ISOPAR-E. ISOPAR-E is a mixture of predominantly C8-C9 isoparaffinic hydrocarbons that is being used more and more frequently as a solvent in industrial and consumer products, including, but not limited to, typewriter correction fluids. Presently, nothing is known about the potential for abuse of products containing this solvent. In the present studies, we compared the volatility of ISOPAR-E and the abused solvent 1,1,1-trichloroethane (TCE) in our exposure systems. Additionally, five behavioral procedures were conducted in mice to compare the effects of the two compounds. The results demonstrate that: (1) ISOPAR-E was less volatile than TCE; (2) ISOPAR-E produced a somewhat different profile of effects than did TCE as assessed with a functional observational battery; (3) unlike TCE, ISOPAR-E did not affect performance on tests of motor coordination; (4) TCE and ISOPAR-E produced concentration-related decreases in schedule-controlled operant performance with recovery from TCE being somewhat more rapid; (5) ISOPAR-E produced cross dependence in TCE-dependent mice; and (6) both TCE and ISOPAR-E produced substantial levels of ethanol-lever responding in a drug discrimination procedure, although the ethanol-like effects of ISOPAR-E only occurred at response rate decreasing concentrations. Overall, there was a poorer separation of behavioral and lethal concentrations for ISOPAR-E than for TCE. Although a somewhat different profile of behavioral effects was obtained with ISOPAR-E and TCE, we cannot say with certainty if enough similarities exist with abused inhalants to predict that ISOPAR-E would be subject to depressant-like abuse. Nonetheless, the feasibility of preclinical assessment of abuse potential of inhalants was demonstrated.

Discriminative stimulus (DS) properties of nicotine in the C57BL/6 mouse

Previous research conducted in this and other laboratories has examined the role of genetic factors in determining sensitivity to (-)-nicotine in a variety of behavioral and physiological measures in the rat. More recent research further indicates that genetic factors can also influence the level of sensitivity to (-)-nicotine when serving as a discriminative stimulus (DS) in different rat strains. However, there has been little work examining the influence of genotype on the discriminative stimulus (DS) properties of (-)-nicotine in mice, a species that has played a major role in understanding the relationship between genetics and (-)-nicotine pharmacological effects. To further our understanding of the role of genetics and the ability of (-)-nicotine to exert DS control of behavior in the mouse, a group of C57BL/6 mice was trained to discriminate 0.4 mg/kg (-)-nicotine from saline using a two-lever operant procedure. (-)-Nicotines discriminative stimulus in C57BL/6 mice appears to be similar to that generated in the rat. Results from behavioral tests with other drugs indicated that d-amphetamine exhibited a partial generalization, while (+)-nicotine fully generalized with nicotine. Tests of antagonism with mecamylamine and scopolamine further showed the cholinergic specificity of the (-)-nicotine DS in the mouse; mecamylamine but not scopolamine completely antagonized the (-)-nicotine DS. This work lays the groundwork for future comparisons of different mouse strains sensitivities to (-)-nicotines discriminative stimulus as well as using this behavioral model to search for new nicotinic receptor agonists and antagonists.