Neuroscience& BiobehavioralReviews.Vol. 15, pp. 233-241. t~ Pergamon Press plc. 1991. Printed in the U.S.A.

0149-7634/91 $3.00 + .00

CNS Depressant Effects of Volatile Organic Solvents E R I C B. E V A N S 2 A N D R O B E R T L. B A L S T E R 3

Department of Pharmacology and Toxicology, Medical College of Virginia Virginia Commonwealth Universi~, Richmond, VA 23298 R e c e i v e d 31 A u g u s t 1990

EVANS, E. B. AND R. L. BALSTER. CNS depressant effects of volatile organic solvents. NEUROSCI BIOBEHAV REV 15(2) 233-241, 1991 .--Volatile chemicals used widely as solvents can produce acute effects on the nervous system and behavior after inhalation exposure, and many are subject to abuse. This review considers the nature of the acute effects of volatile organic solvents by comparing their actions to those of classical CNS depressant drugs such as the barbiturates, benzodiazepines and ethanol. Like CNS depressant drugs, selected inhalants have been shown to have biphasic effects on motor activity, disrupt psychomotor performance, have anticonvulsant effects, produce biphasic drug-like effects on rates of schedule-controlled operant behavior, increase rates of punished responding, enhance the effects of depressant drugs, serve as reinforcers in self-administration studies and share discriminative stimulus effects with barbiturates and ethanol. Toluene and 1,1,1-trichloroethane, as well as subanesthetic concentrations of halothane, have been the most extensively studied; however, it is unclear whether important differences may exist among solvents in their ability to produce a depressant profile of acute effects. The possibility that selected solvents can have acute effects similar to those of depressant drugs may shed light on the nature of their acute behavioral toxicology and on their abuse. Organic solvents Inhalation

Behavior

CNS depressants

Benzodiazepines

VOLATILE organic solvents are a diverse group of compounds representing many chemical classes (Table 1). As solvents for fats, waxes, resins, oils, rubber, paints, and varnishes they are often used for cleaning and degreasing, and are present in many products. Among the household products containing solvents are cleaning fluids, nail-polish removers, paints, and adhesives. Fuels also contain solvents such as toluene and isopentane, Because of their widespread use, human exposures to solvents are common. One aspect of exposure to solvents is of particular concern: the voluntary self-administration of solvents by inhalation to achieve intoxication. Solvent abuse remains a significant public health problem. In the 1989 High School Survey conducted by the National Institute on Drug Abuse (64), it was found that 2.3% of the nationwide sample of high school seniors had used a solvent as an inhalant within the past 30 days. Although not as prevalent as recent marihuana use (16.7%), the prevalence of inhalant abuse was greater than the much more highly publicized abuse of crack cocaine (1.4%) and heroin (0.3%). A similar picture emerges from the National Institute on Drug Abuse-sponsored National Household Survey on Drug Abuse (63). In the most recent survey data available, where a national sample of households were questioned in 1985, approximately 7% of respondents over the age of 12 reported having ever used an inhalant. Projected to the U.S. popu-

Barbiturates

Alcohol

GABA

lation, this would suggest that nearly 13 million people had abused inhalants, nearly 2 million within the last 30 days. The abuse of inhalants is not evenly distributed in the population; the greatest problems occur in the 12-17-year age group with Hispanic and Native American youth being greatly overrepresented (7). Much less is known about the basis of inhalational solvent abuse than for other forms of drug abuse. ACUTE EFFECTS OF SOLVENTS Much of the toxicology literature on solvents concerns the consequences of long-term, low-concentration exposures. In this review we want to focus on the effects of acute, nonlethal, highconcentration exposures such as those that occur in spills and with inhalant abuse. The nature of the CNS effects produced by these exposures is poorly understood. It is clear that many solvents can produce acute, reversible, "drug-like" effects on behavior (28). In some textbooks and reference resources solvents are said to be "'narcotic at high concentrations." This is unfortunate terminology since many associate narcotic effects with morphine-like drugs; however, there is little evidence that solvents produce opiate-like effects. On the other hand, there is emerging evidence that at least some solvents produce pharmacological and

~The preparation of this review was supported by National Institute on Drug Abuse Grant DA-03112. "Postdoctoral fellow supported by National Institute of Environmental Health Sciences training grant ES-07087. 3Requests for reprints should be addressed to Dr. Robert L. Balster, Department of Pharmacology and Toxicology, Box 613, Medical College of Virginia, Richmond, VA 23298-0613.

233

234

EVANS AND BALSTER

TABLE 1 EVALUATION OF THE DEPRESSANT EFFECTS OF ORGANIC SOLVENTS

Chemical Class

Aromanc Hydro,zarbons Toluene Xylene Halogenated Hydrocarbons 1. I. I-Trichloroethane

Motor Impairment

Spontaneous Activity

t39.59)

(23, 39, 49, 98)

(59,101)

(975 (97)

(60)

I. 1.2-Tnchloroethane I. I. I-Trlchlort~thylene Perchloroethylene

Anticon'¢l,lJsallI

(495

Operant Behavior

Punished Responding

~27, 31.57, 58) (81.91. 100) (60)

(24.97)

Tolerance and Dependence

(39,725

Reinforcing Properties

Discriminative EffecL~

Depressant Interactions

(95. 96. 103)

(50. 68. 70. 71)

(24)

(69,70)

(I011

(6) (16)

(49) (49)

Methylene chloride Chloroform

{84)

(49)

Ketone.,, Acetone Methyl ethyl ketone

1104)

(103)

(35, 46. 945

1935

(255 (32)

Methyl n-amyl ketone

(15

Alcoholx Ethanol

159,101 )

(70)

(10. 73. 1055

Anesthetic Agents Halothane Enflurane Isoflurane

(59)

(21,22) (22)

(94)

{69.70)

(465

Numbers in table refer to references where these evaluations were presented.

behavioral effects similar to those of classical CNS depressant drugs (5). This class of drugs is generally considered to include barbiturates, a number of nonbarbiturate sedatives, benzodiazepines, and alcohol. Although there are some differences in the pharmacological profiles of these diverse drugs, the general similarities in their actions are well known. Alcohol, of course, is an organic solvent, but is rarely taken by inhalation. This review will consider the evidence that exposures to selected solvents produce effects in animals similar to those of the classical CNS depressant drugs and alcohol, and will point to areas where more research is needed. The profile of effects of CNS depressants has been well described in the literature (38,79), and includes effects on motor performance, spontaneous locomotor activity, anticonvulsant effects, disruption of operant behavior, antianxiety effects, the production of tolerance and dependence, reinforcing and discriminative stimulus effects, and the ability to enhance the effects of concurrently administered depressant drugs. A relatively few solvents have been extensively investigated, with most research having used alkylbenzenes such as toluene and xylene and aliphatic hydrogenated hydrocarbons such as 1,1,1trichloroethane (Table 1). There have also been some studies of subanesthetic concentrations of inhalation anesthetics such as halothane, and it is important to remember that some solvents, such as trichloroethylene, have been used medically as anesthetics. Although this review will not specifically address the pharmacology of inhalation anesthesia, it is likely that many anesthetics at subanesthetic concentrations may also share pharmacological properties with solvents and CNS depressants; therefore, especially relevant studies of anesthetics will be considered. Indeed, a major evidence for commonalties in the effects of inhalants and CNS depressant drugs is the evidence for similarities in the anesthesia they produce (11, 52, 56). Nitrous oxide, a gaseous anes-

thetic, will be excluded from this review since it may have a unique profile of acute effects.

MOTOR IMPAIRMENT

A dose-related continuum of effects that progresses from motor excitation to sedation, motor impairment, anesthesia, coma, and ultimately death by respiratory depression, is produced by all CNS depressants. A similar continuum of effects has been reported following accidental high-level occupational exposures to solvents (11,82). Laboratory animal studies of acute solvent exposures provide evidence for the production of ataxia and impairment of motor performance. In rats, brief exposure (5 minute) to toluene (5,000 to 15,000 ppm) caused concentration-dependent increases in ataxia as measured by scoring of open-field behavior (39). Following exposure to the highest concentration of toluene tested (15,000 ppm), ataxia progressed to immobility and loss of righting reflex. A simple method used to access impaired motor function measures the ability of mice to climb to the top of a horizontal screen after it has been inverted (15). In this screen test, prototypic CNS depressants (benzodiazepines and barbiturates) produce dose-dependent decreases in the number of mice reaching the top of the screen (15,92). This test has also been used to evaluate toluene; the isomers of xylene; l,l,l-trichloroethane; and subanesthetic concentrations of halothane. For each of these compounds an acute 30-minute exposure resulted in concentrationdependent impairment of motor performance (59,60). The ECso values revealed the alkylbenzenes to be the most potent (toluene 2012 ppm; xylene isomers: meta 3790 ppm, ortho 3640 ppm, and para 2676 ppm), followed by halothane (4188 ppm) and 1,1,1-

DEPRESSANT EFFECTS OF SOLVENTS

trichloroethane (5216 ppm). Very similar results were also reported in another investigation of 1,1,1-trichloroethane (101). It is evident that, like CNS depressant drugs, at least some solvents can disrupt simple motor performances. Animal studies of solvent effects on more specific and sensitive measures of coordination and psychomotor impairment have not been done. This area of research is likely to be particularly important in the context of occupational exposures in settings requiring coordinated motor performances. SPONTANEOUS LOCOMOTOR ACTIVITY

CNS depressant drugs and alcohol often have biphasic effects on spontaneous locomotor activity of rodents, increasing activity at low doses and decreasing it at high doses (8,48). In general, solvent exposure also results in biphasic changes in motor activity. Toluene increased motor activity in mice at intermediate concentrations (560-1780 ppm), and decreased activity at a greater exposure level (3000 ppm) (49,98). Gause et al. (23) and Himnan (39) observed increases in motor activity during recovery from brief exposures to anesthetic concentrations of toluene. Similar biphasic effects are produced by chlorinated hydrocarbons. In mice, 1-hour exposures to methylene chloride (850 to 2200 ppm), perchloroethylene (320 and 3600 ppm), trichloroethylene (1200 and 2300 ppm), or 1,1,1-trichloroethane (2000 ppm) initially had stimulatory effects on activity, though by the end of the exposures and continuing postexposures, decreases in motor activity were observed (49). In the same experiment, exposure to a strongly scented cologne had no effects on motor activity. This indicated that the solvent effects were not likely due to their odorant properties. In summary, like CNS depressant drugs and alcohol, the solvents tested all predominantly decrease motor activity and disrupt motor performance at moderate to high concentrations. With exposure to low concentrations, or as the blood levels begin to rise early during a high-level exposure, an excitatory effect on motor activity is observed. It is important to recognize that biphasic effects on spontaneous motor activity are not uniquely produced by CNS depressant drugs. For example, subsequent to morphine administration both increases and decreases in motor activity have been recorded (2,20). Nonetheless, this profile of motor effects produced by solvent vapors is consistent with a depressant-like profile of action. ANTICONVULSANT EFFECTS

CNS depressant drugs such as barbiturates and benzodiazepines are commonly employed to treat and prevent the occurrence of convulsions. In the laboratory, CNS depressants are active in a variety of anticonvulsant models in animals (9, 67, 86, 102). To evaluate whether volatile organics share anticonvulsant properties with CNS depressants, toluene and m-xylene were tested for their ability to alter pentylenetetrazol-induced convulsions (97). Intraperitoneal injections of either toluene or m-xylene prolonged the time to onset of straub tail, clonus, tonic extension, and death in mice in a dose-dependent manner. Inhalation of toluene (EDso = 1311 ppm after 4-hour exposures) also protected from death produced by pentylenetetrazol. Thus, the two volatile substances tested, both akylbenzenes, appear to have anticonvulsant properties. It should also be pointed out that, as with barbiturates (12,17), some solvent analogs can produce convulsant effects; perhaps the most widely studied example being flurothyl (51). Unfortunately, little is known about the range of solvents that

235

produce anticonvulsant effects. OPERANT BEHAVIOR

Learned behaviors are also sensitive to the effects of psychoactive drugs and chemicals, with operant behavior being widely studied. In typical studies of operant behavior a specific response, such as a press on a lever, is followed by reinforcement, such as the delivery of a food pellet. Eventually, the lever pressing of the subject is reliably maintained by reinforcement. The acute effects of solvent vapors on operant behavior has recently been reviewed by Glowa (28,29). As with inhalational anesthetics and other psychoactive drags, the effects of solvents on operant behavior clearly are concentration-dependent and reversible (21, 22, 28, 29, 31, 58, 61). Furthermore, these acute effects are observed at concentrations which are well below those which produce overt toxicological signs (25, 26, 88). The acute effects of some solvents on operant behavior, particularly the aromatic hydrocarbons, are often similar to those of CNS depressant drugs. Typically, CNS depressants have biphasic effects on rates of schedule-controlled behavior, increasing rates of responding at low doses, and decreasing them at high doses (78). Inhalation of toluene vapors resulted in biphasic effects on behavior under control of various schedules of reinforcement. Low toluene concentrations (1000 ppm) increased fixedinterval rates of responding in mice and rats, while higher concentrations (2000-3000 ppmJ decreased rates (27,31J. Likewise, toluene had biphasic effects on response rates in rats (100) and pigeons (91) performing under a fixed consecutive number schedule. Under this schedule, subjects were required to complete at least 8 responses on one lever before a response on another lever would result in reinforcement. Avoidance performance in rats (81) and responding under a differential-reinforcement-oflow-rate schedule in mice (57) were also increased following exposure to toluene (1500-1600 ppm). Like many drugs, toluene (2000-5000 ppm) exposure can produce only decreases in the rates of responding when high baseline rates are maintained under fixed-ratio schedules (58). Xylene also produced biphasic effects on rates of responding as a function of exposure concentration. In mice, low concentrations of xylene isomers (1400-4000 ppm) increased DRL responding, while higher concentrations (52006200 ppm) decreased responding (60). The biphasic effects of alkylbenzenes on operant behavior provides additional support for similarities between solvents and classic CNS depressants; however, they represent only one chemical class of volatile solvents. Not all volatile organics predominantly produce biphasic effects on schedule-controlled behavior. For example, exposure of mice to halogenated hydrocarbons have generally not resulted in biphasic effects, l,l,l-Trichloroethane resulted in only rate decreases on fixed-ratio responding (6). and 1,1,2-trichloroethane had only rate decreasing effects on multiple fixed-ratio, fixed-interval responding (16). Furthermore, ketones, such as methyl n-amyl ketone, had only rate-decreasing effects on rat multiple schedule performance (1), and methyl ethyl ketone produced concentration-dependent decreases in fixed-interval responding in mice (32). In contrast, unlike the results with other ketones, l-hour exposures to acetone (150 ppm) did increase rates of multiple fixed ratio, fixed interval responding (25). In conclusion, studies of the acute effects of aromatic hydrocarbon solvents on operant behavior provide evidence of druglike, reversible effects which resemble those produced by depressant drugs. A number of studies have found that aromatic hydrocarbons, like CNS depressant drugs, have biphasic effects on rates of responding. However, since biphasic effects on operant behavior are not unique to CNS depressants, these results are not con-

236

EVANS AND BALSTER

clusive evidence of CNS depressant effects. In addition, the inconsistency of response rate increasing effects suggests that qualitative differences may exist among types of solvents. More systematic examination of the effects of these vapors on operant behavior would allow for further classification of solvents and the development of structure-activity relationships for CNS effects. EFFECTS ON PUNISHED RESPONDING

Benzodiazepines reliably and selectively increase operant behavior that has been suppressed by punishment (14,80). Because of this, potential anxiolytic compounds are routinely screened for their ability to increase rates of punished responding, Barbiturates also reliably increase punished responding and frequently so does ethanol (30,54). Other classes of psychoactive drugs do not commonly have selective effects on punished behavior (78); therefore, antipunishment effects can be considered a general property of CNS depressants. Toluene has been shown to increase responding suppressed by electric shock in rats (97). Two-hour exposures to toluene with subsequent behavioral testing produced increases in responding in both components of the multiple fixed-interval 5-minute, fixedinterval 5-minute punishment schedule. At 1780 and 3000 ppm, the increases in punished responding produced by toluene were substantially larger than those observed during the unpunished component. Geller et ai. (24) also reported that toluene produced increases in punished responding. Ten-minute exposures to toluene increased the number of shocks rats received when tested in a standard Geller-Seifter procedure. Increases in punished responding following toluene exposure were similar in magnitude to those following diazepam administration. More research is clearly needed on the effects of solvents on responding suppressed by punishment. Only toluene has been evaluated, with positive results in both studies. TOLERANCE AND DEPENDENCE

It is well established that chronic administration of ethanol and barbiturates results in the development of tolerance and dependence (19, 33, 42, 43). A few experiments have examined the effects of repeated administration of toluene and have yielded equivocal evidence for tolerance development. Mice trained to respond under a differential-reinforcement-of-low-rate (DRL) 10second schedule for milk exhibited no tolerance following 7 days of 30-minute exposures to toluene (6000 ppm) (57). This was evidenced by no shift in toluene's concentration-effect curve for response and reinforcement rate effects. Taylor and Evans, using cynomologus monkeys, also failed to demonstrate tolerance to behavioral effects of toluene (87). The monkeys received headonly 50-minute exposures for 3 days to 4500 ppm toluene vapor, while simultaneously being tested on a variable-delayed matching-to-sample behavioral task. Toluene's impairment of matching-to-sample performance on day three was no different than the decrements observed on day one of exposure. In contrast, two experiments in rats demonstrated tolerance to the behavioral disruptive effects of repeated toluene exposure. Rees et al. (72) exposed rats to toluene (1780 to 4500 ppm) for 2 hours and subsequently evaluated their performance under a multiple fixedconsecutive-number schedule of reinforcement. During the fh'st few days of toluene exposure, decrements in performance and increases in total session time were noted in some rats. With continued exposures the initial effects of toluene exposure diminished, as indicated by improvements in performance and decreases in session time. Another experiment tested the effects of repeated

toluene exposure on open field-behavior (39). Rats received 15minute, head-only exposures to 10,000 ppm twice daily for six weeks. Concentration-effect curves for inhibition of rearing and incidence of ataxia were shifted to the right of the initial concentration-effect curves, however, the shift was small and only appeared at one or two concentrations. Furthermore, other behavioral measurements (e.g., headshakes and motor activity) showed increased sensitivity with repeated exposure to toluene. One study in mice examined whether tolerance developed to the behavioral effects of the 1,1,1-trichloroethane (61). Daily 20minute exposures to 6000 ppm produced consistent and equivalent decrements in fixed ratio responding throughout the 15 days of repeated exposure. Furthermore, concentration-effect curves (1000-8000 ppm) determined before, during, and after the repeated exposure were not significantly different. To date, there are no reports of cross tolerance between solvents and CNS depressants; however, there are reports of cross tolerance between inhalational anesthetics and CNS depressants. Cross tolerance to isoflurane has been observed in mice made tolerant to the effects of ethanol (46), and rats chronically fed a diet containing 6% alcohol exhibited cross tolerance to the anesthetic effects of halothane (94). In addition, it is known that chronic alcoholics have greater general anesthetic requirements (35). Taken collectively, these experiments do not provide strong evidence of the development of tolerance to the effects of solvent exposures. It may be that the exposure regimes were not intensive enough since the exposures in these experiments were less than 1 hour/day and only continued for 3-15 days. None of these experiments on tolerance measured withdrawal signs upon discontinuation of repeated solvent exposure. The only indication of solvent dependence to date is one study performed in barbital-dependent monkeys where chloroform administration suppressed barbiturate withdrawal signs (104). However, there is some evidence for the development of dependence to inhalational anesthetics. Upon cessation of short exposures (2-60 minutes) to high concentrations of ethylene, diethyl ether, or cyclopropane, withdrawal convulsions were elicited in mice (83). Evidence for dependence development, and particularly cross-dependence with depressant drugs, would be important for assessing the similarities between classical CNS depressants and organic solvents. REINFORCING PROPERTIES

Most drugs that are abused by humans are readily self-administered by laboratory animals (45,55). CNS depressants are no exception; ethanol and barbiturate self-administration has been demonstrated in monkeys employing these techniques (34, 55, 93). Yanagita et al. (103) developed a technique to study vapor self-administration in rhesus monkeys. Each subject was implanted with a nasal catheter through which was delivered a volume of vapor contingent upon a lever-press response. Two monkeys each were tested with chloroform, ether, and lacquer thinner (the major constituent of the lacquer thinner was toluene) for a period of 14 to 25 days. During this period the subjects had unlimited access to these vapors. Within a week, the subjects initiated and maintained self-administration with a daily intake occasionally exceeding 100 inhalations. Excessive administration of all agents resulted in ataxia, salivation and mydriasis. Frequent self-administrations of chloroform resulted in light anesthesia in the two subjects studied. Wood et al. (99) developed a procedure for studying inhalant self-administration in squirrel monkeys using nitrous oxide reinforcement. The subjects were placed in a chair where a cylindrical Plexiglas helmet was placed over their head into which gas or

DEPRESSANT EFFECTS OF SOLVENTS

vapor could be delivered. During l-hour daily sessions, monkeys learned to press a push-button to produce a 60-second exposure to 60% nitrous oxide. Using the same approach, Wood (95,96) demonstrated that monkeys would key press to produce a 15-second exposure to various concentrations of toluene. The monkeys readily self-administered toluene with the frequency depending on vapor concentration (0.056 to 1.0%). The highest frequency was 141 inhalations per hour at 0.1%. Despite the difficulties in arranging the conditions to study vapor self-administration in animals, it has been demonstrated that toluene and chloroform have reinforcing properties. The discovery that these solvents possess reinforcing properties not only provides further evidence for their pharmacologic similarities to CNS depressants, but also provides additional insight into inhalant abuse. DISCRIMINATIVE STIMULUS PROPERTIES

If solvents are capable of producing behavioral and pharmacological effects similar to those of abused depressant drugs such as barbiturates and alcohol, it could be hypothesized that the subjective effects of solvent intoxication are similar to those produced by barbiturates and alcohol. Using a drug discrimination procedure it is possible to access the perception of drug effects in laboratory animals (4,76). Animals are trained to discriminate between injections of a drug and vehicle. In a two-lever behavioral chamber, responding on only one lever is reinforced when drug is injected and responding on the other only when vehicle is injected. After a number of training sessions, subjects learn to respond predominantly on the lever associated with drug or vehicle administration. Once the discrimination has been trained, novel compounds are tested for their ability to produce similar discriminative stimulus effects. Following administration of a test compound, if the animal responds on the drug lever then stimulus generalization is said to have occurred. The discriminative stimulus effects of a number of solvents, CNS depressant and depressant-like drugs from various pharmacologic classes have been compared with those of pentobarbital, ethanol and toluene (Table 2). In experiments where mice were trained to discriminate between a vehicle and a CNS depressant, either pentobarbital or ethanol, testing of other drugs revealed that only a benzodiazepine, another barbiturate and ethanol substituted for the training stimulus, consistent with the distinctive intoxication shared by CNS depressants (5, 69, 70). Nonbarbiturate or nonbenzodiazepine depressant drugs, e.g., morphine, chlorpromazine and phenytoin, did not substitute, providing evidence for pharmacological specificity of depressant discrimination. When vapors were tested in either the ethanol- or pentobarbital-trained mice, it was found that an inhalation anesthetic and solvents from two different chemical classes substituted, but not flurothyl (562-1300 ppm), an inhalant which has convulsant properties, nor isoamyl nitrite (150-1050 ppm), a vapor which has pronounced vasodilatory actions (68,69). A comparison of the discriminative stimulus properties of solvents to CNS depressants were also examined in mice trained to discriminate toluene injections from vehicle. Generalization occurred for inhaled toluene (150-3600 ppm) and pentobarbital (5-30 mg/kg), but not morphine (3-20 mg/kg) (71). This study reaffu'rns that toluene shares stimulus properties with barbiturates, and not with another depressant-like drug such as morphine. These results also demonstrate that the toluene discrimination was not specific to the route of administration, thereby ensuring that the discriminative stimulus properties of toluene did not result from irritant or olfactory effects. Furthermore, to demonstrate that the above results were not specific to one species, rats have also been

237

TABLE 2 DRUG/SOLVENT SUBSTITUTION STUDIES

Training Substance*

Substitution

No Substitution

Pentobarbital (20 mg/kg, IP)

Ethanolb Methohexitalb Oxazepamc Halothanec 1,1, l-Trichloroethane c Toluene '~

Morphineb Chlorpromazine b Isoamyl Nitrite¢ Flurothylc

Toluene (100 mg/kg, IP)

Inhaled Toluenec Pentobarbitalc Methohexital f Oxazepam f

Morphinee Chlorpromazine f

Ethanol (1 or 1.25 g/kg, IP)

Toluene d Halothaned 1, I, l-Trichloroethane d Oxazepamd

Phenytoin8 Hydroxyzineg

*In all experiments the other training stimulus was vehicle. aRees et al. (68). bBalster and Moser (5). CRees et al. (69). dRees et al. (70). CRees et al. (71). fKnisely et al. (50). 8Knisely and Balster, unpublished results.

trained to discriminate between injections of toluene and vehicle. Like in the mouse, toluene-like discriminative stimulus effects were produced by a barbiturate (methohexital, 0.5-10 mg/kg) and a benzodiazepine (oxazepam, 0.5-20 mg/kg), but not a phenothiazine (chlorpromazine, 0.3-10 mg/kg) (50). Drug discrimination studies have provided evidence that classification of drugs according to their discriminative stimulus properties generally results in groups of compounds producing similar intoxications and subjective effects in humans (76). Thus these studies provide evidence that toluene, halothane, and 1,1,1trichloroethane produce a depressant-like intoxication which is similar to that produced by the classic CNS depressants ethanol, oxazepam, and pentobarbital. These results with selected vapors suggest that their abuse potential may be related to their ability to produce a depressant-like intoxication, and that drug discrimination procedures in animals may be useful to further investigate this potential (3). INTERACTIONS WITH CNS DEPRESSANTS

Administration of CNS depressants in combination typically results in at least additive effects. Combined use of ethanol and barbiturates or other nonbarbiturate sedatives is a leading cause of poisoning deaths (10,73). Likewise, human case histories have provided evidence that ingestion of ethanol and exposure to the carbon tetrachloride or trichloroethylene result in an enhanced toxicity (65,84). Data obtained in animals also provide evidence for an interaction between depressant drugs and inhaled solvent vapors. Oral ethanol administration enhanced the behavioral as well as the lethal effects of l,l,l-trichloroethane (101). Intubations of increasing doses of ethanol (0.125-4.0 g/kg) before a 30-minute exposure shifted the lethality concentration-effect curves for 1, l,l-trichloroethane progressively to the left. Behavioral effects of 1,1, l-trichloroethane, as measured by the ability of mice to climb to the top of an inverted screen, were also aug-

238

mented by pretreatment with ethanol. For the inverted screen test, the ECso for 1,1, l-trichloroethane treatment alone was 5,173 ppm and pretreatment with 1 g/kg ethanol, a dose which had little or no effect when given alone, decreased the ECso to 2,200 ppm. The magnitude of the interaction between ethanol and l , l , l trichloroethane, as quantified using isobolograms, depended upon the dose of ethanol, the concentration range of 1,1, l-trichloroethane, and the effect measured. In general, behavioral effects of 1,1. I-trichloroethane were more greatly enhanced by ethanol than lethal effects. At a number of dose and concentration combinations, the effects were dose-additive or even supra-additive, providing evidence that the interaction of solvents with ethanol may be quantitatively as large as the interactions among CNS depressants drugs themselves (92). Geller et al. (24) examined the ability of toluene and diazepam, alone and in combination, to increase responding suppressed by punishment in rats. During the punishment component of a multiple schedule, rats pretreated with diazepam and exposed to toluene received a significantly greater number of shocks than the sum of the shocks taken when either were administered alone. A few studies have found no interaction between volatile solvents and CNS depressants. In a study by Savolainen et al. (74), the behavioral and biochemical effects of chronic styrene exposure (300 ppm 6 hours daily, 5 days a week for 4 to 17 weeks) in combination with ethanol (15% v/v, drinking water) were measured in rats. The effects on unconditioned behaviors (ambulation, rearing, or preening) and cerebral glial biochemistry (acid proteinase, glutathione, and NADPH-diaphorase) of the styreneethanol combination were no different than the effects of ethanol or styrene given alone. In a similar experiment, Savolaninen et al. (75) exposed rats to xylene (300 ppm 6 hours daily, 5 days a week for 2 weeks) and ethanol (15% v/v, in the drinking water). Once again, ethanol coadministered with xylene resulted in effects on unconditioned behavior and various brain and liver enzymes that were no different from administering either substance alone. In another study in rats, chronic toluene exposure (2000 ppm 8 hours daily, for 2 weeks) in conjunction with oral ethanol consumption (6%) also failed to result in significant interactions (66). Neither learning nor performance of a conditioned avoidance response was affected by ethanol and toluene alone or in combination. In the same experiment, hearing loss was assessed by using an auditory warning stimulus during the conditioned avoidance response task. Hearing loss was produced by toluene in combination with ethanol, however, no greater loss than that subsequent to toluene alone exposure was detected. It should be noted in the three experiments just described which found no interaction between a solvent and ethanol, dose- or concentration-response functions for the interacting substances were not established (i.e., all three studies only tested one solvent and ethanol concentration/dose combination). In addition, exposures to both the vapors and ethanol were repeated rather than acute. Thus the relevance of these negative findings to conclusions concerning solvent-depressant drug interactions is uncertain. The few studies that have examined acute interactions in a dose/concentration-dependent fashion have shown that toluene and I, 1, I-trichloroetbane enhance the effects of CNS depressant drugs. The generality of these findings to other solvents is not known; clearly, more research is needed in this area. The possibility Of interactions between either voluntary or environmental solvent exposure and widely used and abused drugs such as alcohol and benzodiazepines may have significant implications for human exposures. In addition, the possibility that mixtures of solvents may result in interactions among the components has very important implications for establishing standards for allowable exposures for individual agents.

EVANS AND BALSTER

POSSIBLE CELLULAR MECHANISMS OF ACTION FOR SOLVENTS

Evidence has been presented that some inhaled solvents produce acute effects resembling in many ways those of classical CNS depressant drugs. If solvents have depressant-like effects on behavior, it would be extremely important to establish if common cellular mechanisms exist for these effects. As with other aspects of solvent pharmacology, very little is known about the cellular actions of these agents in the nervous system. Speculation on the cellular basis for the depressant effects of solvents is made difficult by the inadequate understanding of the cellular basis for the effects of depressant drugs and ethanol themselves. Although a number of well-supported theories exist for the actions of selected classes of depressants, for example the benzodiazepines, a comprehensive explanation accounting for the shared actions of diverse depressants is not well established. In general, the actions of the simple lipophilic compounds such as ethanol and volatile anesthetics are often attributed to alterations in membrane structure and function (44,77). On the other hand, the actions of benzodiazepines and barbiturates are usually explained by their modulation of inhibitory amino acid neurotransmission, focusing on selective, receptor-mediated effects. These two families of hypotheses need not be mutually exclusive; however, both can serve as a basis of discussion for possible cellular actions of solvents. The most attractive area for speculation on the possible cellular basis for the effects of solvents derives from their similarities to inhalation anesthetics and ethanol. Alcohols, solvents and anesthetics are small, volatile, lipophilic molecules. Thus it might be hypothesized that the effects of subanesthetic concentrations of certain solvents and inhalational anesthetics may arise from similar cellular actions that produce anesthesia at higher concentrations. In general, theories concerning the cellular mechanisms of anesthesia can be classified into two types based upon the subcellular targets: lipids membranes or proteinaceous receptors for neurotransmitters. The membrane theory derives from the correlation between lipophilicity and anesthetic potency for various anesthetics and has been expanded to include proposed changes in membrane function resulting from their interactions with anesthetics (44,77). A similar mechanism has been proposed for the effects of ethanol and other alcohols (37, 44, 53). More recently, anesthesia has been proposed to result from actions on the GABAgated chloride channel (13, 41, 47, 62). A particularly attractive feature of these hypotheses is that effects on GABA-mediated neurotransmission brings together research on the cellular actions of anesthetics and research with alcohol (36, 85, 89), and benzodiazepines and barbiturates (40). Unfortunately, solvents such as toluene and 1,1,1- trichloroethane, which produce depressant-like pharmacological effects, have not been examined for their cellular effects on these systems. It seems likely that both the membrane-altering properties of solvents, and their ability to alter amino acid neurotransmission, will be fruitful areas of research for the cellular mechanisms for their acute behavioral and pharmacological effects. It should be kept in mind, however, that there is no certainty that all of their diverse effects can be accounted for by a single mechanism. Indeed, different mechanisms may exist for their anesthetic effects and more subtle behavioral effects at subanesthetic concentrations. There is considerable current interest in the cellular basis for the abuse of alcohol, and the results of this research are very likely to have implications for further understanding of the abuse of solvents. In this regard, studies directly comparing the cellular actions of alcohols, anesthetics and selected solvents may be a particularly useful approach to develop a better understanding of the basis for their shared effects.

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SUMMARY We have presented evidence that selected solvents can produce a behavioral and pharmacological profile of effects in animals similar to that o f the CNS depressant class o f drugs, which includes ethanol, barbiturates, and benzodiazepines. Solvents have been shown to disrupt motor performance, increase spontaneous locomotor activity, have anticonvulsant effects, produce biphasic drug-like reversible effects on operant behavior, have antianxiety drug-like effects on behavior suppressed by punishment, serve as reinforcers in self-administration studies and to share discriminative stimulus effects with barbiturates and ethanol. In addition, some solvents have been shown to interact with depressant drugs in a manner not unlike the interaction among depressant drugs. On the other hand, there is little evidence that tolerance readily develops to the behavioral effects o f solvent inhalations nor for the development o f physical dependence, although very few stud-

ies have investigated these phenomenon extensively. The most widely studied solvents have been toluene and 1,1, ltrichloroethane. Some evidence is presented that subanesthetic concentrations o f inhalation anesthetics, such as halothane, can produce similar effects. These represent only a very small sample o f the large diversity of volatile organic chemicals with likely effects on the nervous system. Clearly, much more research is needed to establish the range o f solvents with depressant-like effects and to determine if classes o f solvents can be found with qualitatively different profiles of acute effects. Nonetheless, we believe that sufficient data exist for including selected solvents in the general class o f CNS depressant drugs. This hypothesis has important implications for understanding the abuse o f solvents. In addition, truly comprehensive theories for the cellular basis for the actions o f depressant drugs will need to account for the shared actions o f these diverse classes o f drugs and chemicals.

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