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Biomedical subjects

R L Balster

Publications and source records attributed to R L Balster.

228 records · Page 13Linked to original sources
PubMedDate not supplied

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.

Anesthetics, Inhalation↗
PubMedDate not supplied

Neural basis of inhalant abuse.

It should be apparent from this review that far less is known about the neural basis for inhalant abuse than for other forms of drug abuse. This reflects a lack of research interest in this area (Balster, 1997). Indeed, conclusions are difficult to draw. In the case of the volatile alkyl nitrites, the most reasonable hypothesis at this time is that the cellular basis for their abuse resides in their actions on smooth muscles to produce vasodilation and relaxation, however, direct effects on the brain cannot be ruled out. Although there is some evidence that analgesic effects of nitrous oxide may involve opiate systems, even this conclusion is controversial. There is no evidence that opiate systems play a role in nitrous oxide intoxication or reinforcement. The mechanisms for these effects are unknown. They may reflect the same actions on lipid membranes or on hydrophobic sites on unspecified proteins that have been proposed as mechanisms for nitrous oxide anesthesia. In the case of the volatile solvents, fuels and anesthetics we are faced with a wide variety of specific chemicals which may produce different profiles of pharmacological effects. There is evidence that the prototypic abused solvents toluene and trichloroethane produce acute effects similar to subanesthetic concentrations of general anesthetics, as well as to the effects of classical CNS depressant drugs, such as alcohol and the barbiturates. For the anesthetics, evidence suggests that enhancement of GABAergic inhibition may be an important cellular target for their acute effects, just as it is for alcohol and other depressant drugs. For toluene, as with alcohol, recent evidence suggests a possible role for inhibition of glutamatergic neurotransmission involving NMDA receptors. Toluene has also been shown to have some dopaminergic effects which may be important to its abuse. As for the large number of other abused vapors, practically no information can be found on their cellular actions, and certainly not on actions that may be relevant to their abuse. This entire area would seem an important direction for future research.

Administration, Inhalation↗
PubMedDate not supplied

Neurobehavioral consequences of intermittent prenatal exposure to high concentrations of toluene.

The effects of several concentrations of toluene on physical and behavioral development were examined in CD-1 mice prenatally exposed during the last week of gestation. Pregnant mice were exposed to either 200, 400, or 2000 ppm toluene (TOL) for 60 min three times a day during gestational days 12-17. A sham group was exposed concurrently to filtered air. No group differences were observed in maternal weight gain or food consumption, common measures of maternal toxicity. Initial litter characteristics including gestation length, number of litters delivered, and litter size were also similar. At birth, mean initial individual pup weight from representative male and female 2000 TOL-exposed pups was less than sham-exposed pups; however, entire litter weight did not differ. Pups were evaluated on postnatal days 1-20. Pups exposed to 2000 TOL gained less weight and performed more poorly on the behavioral tests of the righting reflex, grip strength, and inverted screen. In contrast, pups exposed to either 200 or 400 TOL did not differ from sham-exposed pups on any of the measures of development or behavior. These data provide evidence for the neurobehavioral teratogenicity of prenatal exposure to high levels of toluene late in gestation. Because this exposure regimen of intermittent high-concentration exposure was designed to simulate human exposures that might occur with toluene abuse, these results are consistent with case reports of adverse consequences of inhalant abuse by pregnant women.

Animals↗
PubMedDate not supplied

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.

Animals↗
PubMedDate not supplied

Identification of a new phencyclidine analog, 1-(1-phenylcyclohexyl)-4-methylpiperidine, as a drug of abuse.

A previously unreported phencyclidine (PCP) analog. 1-(1-phenylcyclohexyl)-4-methylpiperidine (I) in which the piperidine ring has been substituted with 4-methylpiperidine, has been observed to be an abused drug in Virginia. The I was obtained coated over parsley in an approximate concentration of 1.7% (w/w). I . HCl was isolated, purified, and compared to authentic I . HCl (sample obtained from DEA and synthesized in the laboratory) using melting point, IR, 1H-NMR, GC and GC/MS. Unequivocal identification of I . HCl was based on its 13C-NMR. The intraperitoneal LD50 of I . HCl in male mice was 301.1 mumoles/kg (267.1--339.2, 95% confidence limits) and the ED50 was 43.0 mumoles/kg (37.3--54.3). The therapeutic index, LD50/ED50, for I . HCl was 7.0 and is much lower than that observed with phencyclidine, 38.0.

Animals↗
PubMedDate not supplied

Acute effects of some volatile nitrites on motor performance and lethality in mice.

Mice were examined for effects on lethality and motor performance on an inverted screen test following inhalation exposure to isoamyl, n-butyl and isobutyl nitrite. All three nitrites produced concentration-related effects on both measures, with EC50s for motor performance only about one-half of the LC50s for lethality. Isoamyl and isobutyl nitrite were equally potent on both lethality and motor performance measures, whereas n-butyl nitrite was significantly more potent than isoamyl and isobutyl for lethality. Slope estimates of the concentration-effect curves for lethality were significantly greater than those of the motor performance measure. The steepness of the concentration-effect curves and low LC50/EC50 ratios relative to abused organic solvents suggest that behaviorally active concentrations of volatile nitrites may put users at risk to other health consequences.

Aerosols↗
PubMedDate not supplied

The effects of inhaled toluene, halothane, 1,1,1-trichloroethane, and ethanol on fixed-interval responding in mice.

Adult male mice were trained to lever press under a fixed-interval (FI) 60-sec schedule for milk presentation during 15-min sessions. Concentration-effect curves were then determined at the termination of 30-min inhalation exposures to various volatile agents--halothane, toluene, 1,1,1-trichloroethane (1,1,1-TCE), and ethanol. The mice were also tested after ethanol administered orally. Each compound produced both response rate increases and decreases, initially or during the recovery phase. Recovery from the response rate decreasing effects generally occurred during the 15-min sessions. The highest concentration of toluene and the high dose of oral ethanol produced the longest duration of effects. Response rates in the first 3 min of the session were used to evaluate peak effects following inhalation. Linear regression analyses of these data indicated the potency order to be toluene greater than halothane greater than 1,1,1-TCE greater than ethanol. Patterning of responding characteristics of FI performance was affected after high concentrations of all but ethanol vapor. This study provided evidence that the effects of two industrial solvents, toluene and 1,1,1-TCE, were qualitatively similar to those of two volatile CNS depressants, halothane and ethanol, as well as to those reported for other centrally-acting drugs.

Conditioning, Operant↗
PubMedDate not supplied

Behavioral toxicity of chloral in mice: an approach to evaluation.

The potential for behavioral toxicity of the water contaminant chloral (CHL) was ascertained from acute, 14 day and 90 days of exposure in adult mice and perinatal exposure. Acute motor incoordination produced by CHL occurred 5 min after gavage and persisted for about 2 hr. The ED50 for acute CHL effects was 84.2 mg/kg, a value less than 1/10th of the acute LD50. Exposure for 14 days to either 14.4 or 144.0 mg/kg/day of CHL by gavage did not produce any deleterious effects on body weight, behavioral observations, locomotor activity, motor coordination or swimming endurance which were measured 24-48 hr after exposure was terminated. Subchronic, 90 day exposure to 0.70 or 0.07 mg/ml CHL in drinking water (15.7 and 159.8 mg/kg/day) did not affect the palatibility of drinking water since total fluid intakes were not reduced. Mice exposed to these doses of CHL did not gain weight as rapidly as control mice. Exposure to 159.8 mg/kg/day produced a decrease in body temperature after 45 days of exposure and a second temperature measurement indicated that mice exposed to both 15.7 and 159.8 mg/kg/day were hypothermic on day 91. Mice were also evaluated on various behavioral tests and none of these measures were altered by 90 days of CHL exposure. Mice perinatally exposed to 21.3 and 204.8 mg/kg/day CHL in drinking water had normal body weights, normal development of neurobehavioral reflexes and normal motor coordination. The retention of passive avoidance learning was reduced on both the 1 hr and 24 hr retention tests for mice exposed to the higher CHL concentration. CHL did not produce motor incoordination at relatively low doses following a single acute exposure. Repetitive exposure to CHL at levels of about 1/10th and 1/100th the acute LD50 for 14 or 90 days did not produce delayed or persistent behavioral changes. Non-specific effects on body temperature and body weight gains were observed for mice exposed for 90 days. There is little evidence that exposure to CHL is likely to result in delayed or persistent behavioral toxicity to adults exposed to contaminated drinking water supplies while CHL during the prenatal and early postnatal period at levels as high as 204.8 mg/kg/day can result in detrimental behavioral effects.

Animals↗
PubMedDate not supplied

Phencyclidine-like discriminative stimulus properties of the stereoisomers of dioxadrol.

Rats (N=6) were trained to discriminate 3.0 mg/kg i.p. phencyclidine (PCP) from saline in a 2-lever fixed-ratio 32 operant discrimination procedure for food presentation. Generalization tests were conducted with other doses of PCP as well as with various doses of the stereoisomers of dioxadrol. Dose-dependent PCP-like discriminative stimulus effects were obtained with dexoxadrol but not with levoxadrol, however overall rates of responding were decreased to a comparable extent by 30 mg/kg of both compounds. PCP was 3.6 times more potent than dexoxadrol in producing stimulus control of responding. These data provide some evidence for stereoselectivity of action for dioxadrol, however nonPCP-like effects of levoxadrol are present at doses only 3 times greater than those doses of dexoxadrol that result in PCP-lever responding. Therefore, absolute stereospecificity beyond 3-fold cannot be demonstrated by these data.

Analgesics↗
PubMedDate not supplied

Trichloromethane-induced taste aversions in mice.

In Experiment 1 four groups (N = 10) of individually housed mice were given access to deionized water for 30 min daily. When fluid consumption stabilized, they were given 30-min access to a 0.3% saccharin solution. This was followed by oral doses of 3, 10 or 30 mg/kg trichloromethane (TCM) or the vehicle (Emulphor). Beginning 24 hr later the subjects were given a two-bottle choice test (saccharin vs water) followed by the appropriate injection in that group. This procedure continued for 10 days. A dose of 30 mg/kg produced a taste aversion on the first choice test and a reduction in total fluid intake which continued throughout the 10-day test period, while doses of 3 and 10 mg/kg TCM or vehicle did not affect either measure. To determine whether the aversion produced by 30 mg/kg TCM was specific to gavage, animals in Experiment 2 received IP injections of 10, 30 or 100 mg/kg TCM or vehicle. All TCM groups showed taste aversions which lasted for the 10-day test period. Although concomitant fluid reductions occurred for all doses on day one, only the 100 mg/kg group maintained this drop throughout the 10-day test period. Thus, TCM produces taste aversions when given at relatively low doses by both oral and IP routes of administration.

Animals↗