Region-dependent alterations in glutamate and GABA measured by high-resolution magnetic resonance spectroscopy following acute binge inhalation of toluene in juvenile rats.

Little is known about the neurochemical effects accompanying the high-concentration inhalant exposures characteristic of binge solvent abuse. In adult animals, prior studies with other patterns of exposure indicate that toluene, a commonly abused household and industrial solvent, has significant effects on the glutamatergic and GABAergic neurotransmitter systems and on other neurotransmitter systems as well. In the current investigation, high-resolution "magic angle" spinning proton magnetic resonance spectroscopy (HR-MAS (1)H-MRS) was used to assess the effect of acute binge toluene inhalation on regional brain concentrations of various neurochemicals including glutamate (GLU), GABA, and glutamine (GLN) in juvenile male and female rats. Acute toluene (8000 ppm or 12,000 ppm) significantly reduced levels of hippocampal GABA (-12%) and GLU (-8%), and the GLU/GLN ratio, an index of glutamatergic tone, was significantly reduced (-22%) in the dorsal anterior striatum, driven largely by a 28% increase in GLN. Significant increases in alanine and lactate in several brain regions after acute toluene may be indicative of altered oxygen-dependent metabolism associated with the inhalation of higher concentrations of toluene (e.g., >5000 ppm). Other components of the MR-visible neurochemical profile, such as N-acetylaspartate (NAA), myo-inositol, creatine, and various choline containing compounds, were unchanged by acute toluene. The results are consistent with the notion that binge toluene exposure affects juvenile neurochemistry in systems mediating the rewarding and emotional aspects of substance abuse. Moreover the results provide a framework to understand further (1)H-MRS studies in clinical populations.

Prenatal toluene exposure impairs performance in the Morris Water Maze in adolescent rats.

Volatile organic solvent abuse continues to be a worldwide health problem, including the neurobehavioral teratogenic sequelae of toluene abuse during pregnancy. Although abuse levels of prenatal toluene exposure can lead to a Fetal Solvent Syndrome, there is little research examining these effects on memory. Consumption of toluene can have detrimental effects on the developing hippocampus which could lead to specific spatial learning and memory deficits. This study used a rat model to determine how prenatal exposure to abuse levels of toluene would affect performance in a spatial learning and memory task, the Morris Water Maze (MWM). Pregnant Sprague-Dawley rats were exposed to 0, 8000 or 12,000ppm (ppm) of toluene for 15min twice daily from gestation day 8 (GD8) through GD20. Male and female offspring (N=104) were observed in the MWM for 5days beginning on postnatal day (PN) 28 and again on PN44. While prenatal toluene-exposed animals did not differ in initial acquisition in the MWM, rats prenatally exposed to 12,000ppm toluene displayed performance deficits during a probe trial and in reversal learning on PN44. Overall, this study indicates that prenatal exposure to repeated inhaled abuse patterns of high concentrations of toluene can impair spatial memory function that persists into adolescence.

Changes in developmental body weight as a function of toluene exposure: A meta-analysis of animal studies.

Inhalant abuse is a globally prevalent health issue with particular concerns about substance-abusing pregnant women. In both animal models and clinical case reports of toluene exposure, the primary physiological outcome measure of prenatal inhalant exposure is low birth weight (BW). However, the effect of prenatal toluene exposure on animal BW varies widely in the literature. To clarify this effect and investigate possible design moderators of pup BW, a systematic review and meta-analytic techniques were applied to the existing peer-reviewed animal literature of prenatal and postnatal exposure models to the inhaled solvent toluene. Of 288 studies screened, 24 studies satisfied the inclusion criteria. Evaluation of these studies indicated that toluene exposure was negatively associated with pup BW (d = -0.39), with external inhaled concentration, route of administration, day of weighing, and toluene exposure magnitude moderating this association. Investigators doing animal studies should be cognizant of these factors before investigating the reproductive and developmental outcomes associated with prenatal and postnatal toluene exposure.

Effects of variation in chronic dose of cocaine on contingent tolerance as assessed in a milk-drinking task.

Tolerance to the suppressive effects of cocaine on milk drinking by rats was studied using a contingent tolerance experimental design. Three separate groups (n = 6) of rats received 8.0, 16.0, or 32.0 mg/kg cocaine daily 15 min before a 15-min period of access to sweetened condensed milk for 20 days. Three additional groups of six rats each received the same chronic doses 15 min after access to milk. Milk, water, and food intake as well as body weight were measured daily. Tolerance effects were assessed by comparing initial acute dose-effect determinations with a probe dose-effect redetermination in which all rats again received doses of cocaine pre-session after having experienced the differential pre- or post-session chronic treatment. Behavioral tolerance on the milk intake measure was observed for the 8.0 mg/kg and 16.0 mg/kg doses, but not for the 32.0 mg/kg chronic treatment, even though the latter group exhibited evidence of tolerance in the water intake measure. Chronic treatment with 8.0 and 16.0 mg/kg produced different outcomes in that chronic exposure to 16.0 mg/kg in the presence of milk resulted in generalization of tolerance to both a lower (8.0 mg/kg) and a higher dose (32.0 mg/kg), but the group receiving 8.0 mg/kg did not exhibit generalization of tolerance to higher doses. Modest sensitization effects were observed in the rats treated post-session with either 8.0 or 16.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral tolerance to the force differentiation effects of diazepam and midazolam in rats.

RATIONALE: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs' effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. OBJECTIVES: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. METHODS: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8-10 g) or high force (40-50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. RESULTS: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose-effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections postsession, where there was no opportunity to practice the force-discrimination response while under the drug state. CONCLUSIONS: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.

Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice.

Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5-20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5-30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1-3 mg/kg), fentanyl (0.01-0.3 mg/kg), cocaine (10-30 mg/kg) and pentobarbital (10-30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1-10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1-10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus.

Biphasic effects of 1,1,1-trichloroethane on the locomotor activity of mice: relationship to blood and brain solvent concentrations.

Despite the central nervous system (CNS) being a target of virtually all solvents, few solvents have been thoroughly studied for their effects on unlearned animal behaviors. Of the solvents that have been studied, little is known about the relationship of exposure concentration to behavioral effect, and quantitative data relating the toxicologically important target organ (i.e., brain) dose to behavioral effect are almost non-existent. To examine the concentration- and time-dependency of effects of 1,1, 1-trichloroethane (TRI) on behavior, male albino Swiss-Webster mice were exposed to TRI (500-14,000 ppm) in static inhalation chambers for 30 min, during which locomotor activity was measured. Separate mice were exposed to the same concentrations under identical conditions for 6, 12, 18, 24, and 30 min, to determine blood and brain concentrations versus time profiles for TRI. This allowed for the relationships between blood and brain concentrations of TRI and locomotor activity to be discerned. The lowest TRI concentrations studied (500-2000 ppm) had no statistically significant effect on activity, intermediate concentrations (4000-8000 ppm) increased activity immediately to levels that remained constant over time, and higher concentrations (10,000-14,000 ppm) produced biphasic effects, i.e., increases in activity followed by decreases. 1,1, 1-Trichloroethane concentrations in blood and brain approached steady-state equilibria very rapidly, demonstrated linear kinetics, and increased in direct proportion to one another. Locomotor activity increased monophasically ( approximately 3.5-fold) as solvent concentrations increased from approximately 50-150 microg/g brain and microg/ml blood. As concentrations exceeded the upper limit of this range, the activity level declined and eventually fell below the control activity level at approximately 250 microg/g brain and microg/ml blood. Regression analyses indicated that blood and brain concentrations during exposure were strongly correlated with locomotor activity, as were measures of internal dose integrated over time. The broad exposure range employed demonstrated that TRI, like some classical CNS depressants, is capable of producing biphasic effects on behavior, supporting the hypothesis that selected solvents are members of the general class of CNS depressant drugs. By relating internal dose measures of TRI to locomotor activity, our understanding of the effects observed and their predictive value may be enhanced.

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 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.

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.

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.

Practice-augmented tolerance to triazolam: evidence from an analysis of operant response durations and interresponse times.

In order to investigate contingent tolerance to triazolam (TZ), 16 rats were trained with a water reinforcer to respond under a multiple fixed ratio 30 (FR 30)-differential reinforcement of low rate 20-s (DRL 20) schedule, during daily 20-min sessions. FR 30 and DRL 20 performances were assessed with measures of response rate, response duration, interresponse times, and reinforcers delivered. In addition, operant responses for each schedule component were divided into fast and slow subclasses, based on interresponse times less than 1s and greater than 1s. Initial dose-effect functions for these behavioural measures were obtained for TZ (0.05-0.5mg/kg). After a 30-day chronic TZ (0.5mg/kg) exposure period, during which half of the rats were gavaged pre-session (PRE) and the other half were gavaged post-session (POST), dose-effect functions were redetermined with a wider dose range (0.05-3.0mg/kg). The redetermined dose-effect functions for FR rate indicated that both PRE and POST groups developed resistance to the rate-suppressing effects of TZ. In addition, the PRE group displayed more tolerance than the POST group on some, but not all, measures, especially at doses higher than 0.5mg/kg. The greater tolerance in the PRE group was observed for number of reinforcers in the DRL 20 component, for response duration for the slow subclass of responses in both FR 30 and DRL 20 components, and for the fast subclass of responses in the DRL 20 component. Moreover, in the PRE group, tolerance occurred to the response duration measure even though the chronic dose of 0.5mg/kg had little effect on this measure. These results demonstrate the value of microanalytic methods in addressing the problem of contingent tolerance. In addition, the data suggest that extensive experience of response execution under the influence of a drug can have an "inoculating effect" against the higher doses of the drug even in the absence of large disruptions in behaviour during the drugged practice itself.

Desflurane, enflurane, isoflurane and ether produce ethanol-like discriminative stimulus effects in mice.

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 ETOH's 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.

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.

Prewatering and haloperidol have similar effects on rats' response rate and duration.

Haloperidol (0.1 mg/kg) and 5-min prewatering were given to 12 rats on three occasions each to determine effects on fixed ratio 15 (FR 15) responding for water. Compared to baseline, both treatments significantly reduced rate (prewatering slightly more) and both significantly increased duration. Though similar, drug and prewatering effects showed enough differences to suggest that there are both anhedonic and motoric deficit components to haloperidol's effects on rats' lever-pressing behavior for water.

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.

A method for adjusting exposure levels of volatile solvents based on effects on schedule-controlled behavior.

A novel adjusting procedure was employed to assess the acute behavioral effects of inhaled 1,1,1-trichloroethane (TCE) and m-xylene. Mice were trained to lever press under a fixed ratio 20 schedule of milk reinforcement. During 30-min test sessions, TCE concentrations were altered every 5 min dependent upon rates of responding in the preceding 5-min segment of the session. When response rates during a 5-min interval were not decreased by greater than 30% from control rates, the TCE concentration for the next interval was increased. Reduction in response rates of more than 30% from the previous interval resulted in a lowering of the TCE concentration in the subsequent 5-min interval. TCE produced concentration-dependent decreases in response rates similar to what has been shown previously and many mice adjusted their exposure levels such that there were alternating intervals of increasing and decreasing concentration exposures. This provided a means of determining, in a single test session, no effect (subthreshold) and minimal effect concentrations of TCE for effects on schedule controlled behavior. Alteration of the starting TCE concentration from 1000 to 6000 ppm increased the TCE threshold for effects. When the response rate contingency was removed and TCE concentrations were "played back" from an earlier adjustment session, concentration-effect curves were similar to what were obtained under adjusting conditions. Using the adjusting procedure, we were also able to rapidly obtain a concentration-effect curve and threshold concentrations for m-xylene that are consistent with published results. This procedure for response rate adjusting exposure concentrations should be useful for rapid assessment of inhalant effects on schedule-controlled behavior and for focusing attention on near threshold levels of exposure.

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.

A direct comparison of inhalant effects on locomotor activity and schedule-controlled behavior in mice.

Increases in rates of rodent behavior have been commonly seen with exposure to abused vapors. In the 1st study, 30-min exposures to vapors of toluene, trichloroethane (TCE), or methoxyflurane produced increases in locomotor activity of mice at lower concentrations and decreases at higher concentrations. In the 2nd study, the effects of these vapors on schedule-controlled behavior were determined in mice lever pressing under a multiple fixed-ratio, 20-fixed interval (FI), 3-min schedule. Only concentration-related decreases in response rates were obtained in both components. In the 3rd study, toluene and TCE again produced only decreases in rates of responding under a simple FI 3-min schedule; biphasic effects were produced by methoxyflurane and amyl nitrite. The increases in rates of behavior often seen with abused vapors depend on the testing conditions.

Phencyclidine- and diazepam-like discriminative stimulus effects of inhalants in mice.

It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partial substitution. Fluorothyl and toluene produced no appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration-related partial substitution for PCP, whereas methoxyflurane, TCE, and fluorothyl did not substitute. The substitution of some these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D-aspartate antagonists as well as those of gamma amino butyric acid agonists.