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PubMed1999

Acute toluene induces biphasic changes in rat spontaneous locomotor activity which are blocked by remoxipride.

The behavioral hyperactivity elicited by most drugs of abuse has been linked to changes in mesolimbic dopamine neurotransmission. However, the locomotor stimulant effects of toluene, a constituent in many abused inhalants, has not been clearly associated with this site of action. The present study was designed to examine the hypothesis that toluene-induced hyperactivity is also dependent upon intact dopamine neurotransmission. Using photocell-equipped cages, 600-1200 mg/kg toluene produced an inverted U-shaped dose response. However, in the presence of 5 mg/kg remoxipride, a selective D2-dopamine antagonist toluene-induced hyperactivity was reduced by 57%. The effects of remoxipride appear to be selective as a pretreatment, as it did not reduce either spontaneous locomotor activity or the stimulatory effects of the muscarinic antagonist scopolamine. These results clearly show that toluene induces locomotor hyperactivity through a dopamine-dependent mechanism. Because the mesolimbic dopamine system has been shown to play a role in the rewarding properties of drugs of abuse, its activation by toluene may also underlie the abuse potential of this and other inhalants.

Animals↗
PubMed2000

Nitrite inhalants spontaneously liberate nitric oxide, which is not responsible for the immunotoxicity in C57BL/6 mice.

Nitrite inhalant abuse has been correlated epidemiologically with HIV seropositivity and with Kaposi's sarcoma. Using a mouse model, we have shown that inhaled isobutyl nitrite caused anemia and severely depressed immunity. In the present study, we showed that both isobutyl and cyclohexyl nitrites in air liberated nitric oxide (NO). An immunotoxic dose of 900 ppm isobutyl nitrite liberated 115 ppm NO. Mice were exposed in an inhalation chamber to 115 ppm NO, 900 ppm isobutyl nitrite, or 900 ppm cyclohexyl nitrite for 45 min/day. Following a single exposure, NO did not affect peripheral blood cell counts, while isobutyl and cyclohexyl nitrites reduced cell numbers. After 14 daily exposures, isobutyl nitrite, but not cyclohexyl nitrite or NO, reduced peritoneal macrophage tumoricidal activity. The nitrite esters likely caused immunotoxicity by mechanisms other than NO release.

Animals↗
PubMed1999

Inhalant use among urban American Indian youth.

AIMS: To assess the prevalence of inhalant use among urban American Indian youth and to examine differences between inhalant users and non-users. DESIGN: Baseline (T1) self-report questionnaires completed in 5th-6th grade and at seven annual follow-up assessments (T2-T8). SETTINGS: Seattle metropolitan area. PARTICIPANTS: Two hundred and twenty-four Indian youth. MEASUREMENTS: Youth-completed measures of substance use, ethnic self-identity, involvement in traditional Indian activities, family conflict, family history of alcoholism, peer and sibling deviance, self-esteem, delinquency, aggression, anxiety, depression, sensation seeking, conduct disorder and alcohol dependence. FINDINGS: Lifetime inhalant use was reported by 12.3% of adolescents. At T1, inhalant users had significantly lower perceived self-worth and average annual household incomes and significantly greater density of familial alcoholism and expression of aggressive and delinquent conduct than non-users. Aggressive behavior was the most important T1 predictor of inhalant use. Lifetime conduct and alcohol dependence disorders were 3.3 and 2.6 times more prevalent among inhalant users than non-users at T5. Inhalant users had more extensive deviant peer networks, were more sensation-seeking, and evidenced lower perceived self-worth than non-users at T8. CONCLUSIONS: Inhalant use was less prevalent in this particular sample of urban Indian adolescents than in most studies of reservation Indian youth. As with other studies of inhalant abuse, aggressive and delinquent males of low SES and low-perceived self-worth with family histories of alcohol dependence, were at highest risk for inhalant use.

Administration, Inhalation↗
PubMed1988

Bizarre behavior following the ingestion of levo-desoxyephedrine.

This is the first reported case of transvestism in a heterosexual male that occurred only after ingestion of the contents of six to eight Vicks inhalers. The patient's gender cross-dressing was associated with sexual excitement and masturbatory behavior. This case is consistent with other cases of gender cross-dressing and sexual excitement following inhaler abuse, but in the previous cases reported the subjects were homosexual men. Levo-desoxyephedrine, also known as levo-methamphetamine, the main active ingredient in Vicks Inhalers, is known to have amphetamine-like properties. Stereotypic behavior is consistent with behavior that follows the use of amphetamine. Transvestism has traditionally been thought to be based on a psychodynamic model; however, the authors postulate several biochemical mechanisms whereby levo-desoxyephedrine may play a role in the bizarre behavior exhibited by this 32-year-old man. It is suggested that inhalers be placed in a new class of drugs that can be dispensed only by a pharmacist or physician.

Adult↗
PubMed1979

Illicit drug use among urban adolescents. A decade in retrospect.

Over the past decade (1967 to 1977), 76,000 adolescents were screened for a history and somatic signs of illicit drug use at a detention center for juveniles and at an adolescent inpatient unit of a university-affiliated hospital. Dramatic changes in the patterns of drug abuse are reported. Opiate use was prominent in the first half of the decade with a peak in 1970 to 1971 and marijuana use more prominent in the last five years. Inhalant abuse as represented by glue and halogenated cleaning fluids was documented only early in the decade, while the existence of stimulant and depressant abuse follows still other patterns over the decade. Hospital admissions for serious somatic complications of illicit drug use, namely, overdose, drug-related death, hepatic coma, detoxification, and viral hepatitis, were correlated only with trends in the use of opiates. Awareness of drug abuse patterns among adolescents is important for the health professional so that complications can be diagnosed and treated and educational efforts properly directed.

Adolescent↗
PubMed1998

Effects of acute inhalation exposure to 1,1,1-trichloroethane on the hypothalamo-pituitary-adrenal axis in male Sprague-Dawley rats.

1,1,1-Trichloroethane (TRI) is a commonly used industrial solvent with a considerable potential for inhalation abuse. Previous studies in our laboratory and elsewhere have shown that this agent exerts a suppressant effect on operant responding, as well as a number of additional neurobehavioral effects that are similar to those of central nervous system (CNS) depressant drugs. In an effort to provide information relevant to potential mechanisms involved in the behavioral effects and abuse potential of TRI, the present study evaluated the acute effects of this agent on the activity of the hypothalamo-pituitary-adrenal (HPA) axis . Male Sprague-Dawley rats were exposed to 3500 or 5000 ppm TRI by inhalation for 10 or 30 min. Following exposure, plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone and levels of ACTH and corticotropin-releasing factor (CRF) in three brain regions--hypothalamus, hippocampus, and frontal cortex--were determined by selective radioimmunoassays. Levels of TRI in the three brain regions as well as blood were measured by headspace gas chromatography to determine the target tissue concentrations responsible for neuroendocrine changes. Uptake of TRI in blood and all brain regions was very rapid, with stable concentrations apparently achieved within 10 min and maintained for 30 min. During this time course, a significant decrease in plasma corticosterone was produced at 30 min but no significant change in plasma ACTH was observed with 3500 ppm TRI. However, after exposure to 5000 ppm, both plasma ACTH and plasma corticosterone were significantly reduced at 10 and 30 min. ACTH levels in the three brain regions were not significantly changed by TRI, while hypothalamic CRF was significantly increased during exposure to 3500 ppm. However, hypothalamic concentrations of CRF declined following 30 min at 3500 ppm and were not significantly changed by 5000 ppm. This complexity of effects on the regulation of HPA axis activity likely precluded the establishment of consistent relationships between changes in hormonal levels and blood or regional brain concentrations of the inhalant. However, these actions of TRI were strikingly similar to those previously reported for the benzodiazepines.

Administration, Inhalation↗
PubMed2001

Diagnostic concordance of DSM-III-R, DSM-IV, and ICD-10 inhalant use disorders.

The diagnostic concordance of DSM-III-R, DSM-IV, and ICD-10 inhalant use disorders was assessed using the sample of lifetime inhalant users (n=76) participating in the DSM-IV Field Trial for Substance Use Disorders. Substantially smaller proportions of lifetime inhalant users met DSM-IV inhalant abuse or dependence criteria than met comparable DSM-III-R or ICD-10 criteria. DSM-III-R and ICD-10 performed similarly, although DSM-III-R tended to be more inclusive vis-à-vis diagnoses of inhalant dependence. Kappa coefficients indicated a moderate degree of concordance between the three nosologies for inhalant use disorder diagnosis rates. Inclusion of possible withdrawal symptomatology criteria (that are not normally included) in the DSM-IV and ICD-10 criteria sets for inhalant dependence exerted little effect on diagnosis rates.

Adolescent↗
PubMed2004

Epidemiology of volatile substance abuse (VSA) cases reported to US poison centers.

Volatile substance abuse (VSA) is believed to be widespread. The Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Systems offers an opportunity to evaluate the epidemiology of volatile substance abuse using a data set that captures data from a large geographic area covering a wide-ranging group of socioeconomic strata, ethnic groups, and demographics. To utilize this potential we analyzed a data set of TESS for the 6-year period of 1996 through 2001 involving all cases of intentional inhalational abuse of nonpharmaceutical substances. Over the study period there was a mean annual decline of 9% of reported VSA with an overall decline of 37% from 1996 to 2001. Volatile substance abuse was reported primarily in children, with 6358 cases (54%) in children 13-19 yr and 1803 (15%) cases in children 6-12 yr. Fifty-two cases were reported in children < 5 or = 5 yr. A total of 2330 (20%) VSA cases had a serious outcome, defined as either moderate effect (n = 2000), major effect (n = 267), or death (n = 63). The top five categories of substances abused were gasoline (41%), paint (13%), propane/butane (6%), air fresheners (6%), and formalin (5%). Three categories were responsible for the majority of deaths: gasoline (45%), air fresheners (26%), and propane/butane (11%). While there was a decline in reported cases, there was no decline in major outcomes or fatalities. Volatile substance abuse was reported in all 50 states, with case distribution similar to population distribution. However, seven states had > 2 times the expected rate based on their population; three western states, two midwestern states, and two Appalachian states. The role of urban vs. rural population may possibly explain the difference in numbers, with a greater incidence of VSA cases reported in states with large rural populations. The mean monthly occurrence rate was 162 VSA cases/month (S.D. +/- 10.85). There were 4 months that were > 2 standard deviations from the mean, with two peak months (May, 192/month and March, 187/month) and two trough months (December, 126/month and January, 137/month). This report presents a broad picture of VSA in the United States. Volatile substance abuse, as reported to U.S. poison centers, appears to be on the decline, but continues to be an ongoing problem. Volatile substance abuse is reported throughout the U.S. in all areas of the country, with a higher incidence in states with large rural populations. A small group of substances appears responsible for the majority of deaths. It is imperative that we continue to educate the public and healthcare professionals regarding the risks of VSA and hopefully impact the incidence of VSA.

Administration, Inhalation↗
PubMed1998

Effects of acute inhalation exposure to isoamyl nitrite on the hypothalamo-pituitary-adrenal axis in male Sprague-Dawley rats.

Isoamyl nitrite (IAN) is a member of the family of volatile organic nitrites that exert vasodilatory effects and have recently exhibited a considerable potential for inhalation abuse. In an effort to provide mechanistic insight into the neurotoxic effects and abuse potential of these agents, the present study was designed to evaluate the acute effects of IAN on the hypothalamo-pituitary-adrenal (HPA) axis. Attempts were also made to correlate the neuroendocrine effects of IAN with its pharmacokinetic profile. Male Sprague-Dawley rats were exposed to 600 or 1200 ppm IAN by inhalation for 10 or 30 min. Following exposure, adrenocorticotropic hormone (ACTH) and corticosterone in plasma and corticotropin-releasing factor (CRF) in three brain regions (hypothalamus, hippocampus, and frontal cortex) were determined by radioimmunoassay. Levels of IAN in the three brain regions as well as in blood were measured by gas chromatography to determine the target tissue concentrations responsible for neuroendocrine changes. Uptake of IAN into blood and all brain regions was very rapid, as stable concentrations were achieved within 10 min of exposure and maintained for 30 min of continuous inhalation. Plasma corticosterone decreased significantly after 10 min inhalation of both IAN doses, and returned to control levels after 30 min. Moreover, plasma ACTH was significantly increased by 10 and 30 min of exposure to 600 and 1200 ppm IAN, while hypothalamic CRF increased significantly after 30 min of exposure to the 600 ppm dose. These latter findings suggest activation of the hypothalamus and pituitary due to a reduction in negative feedback resulting from the initial decrease in corticosterone. Although plasma ACTH was greatly increased after 30 min, plasma corticosterone levels were unchanged, indicating that IAN primarily acts to inhibit the synthesis or secretion of adrenal steroids and that activation of the HPA axis is not involved in the behavioral manifestations of IAN inhalation. These compensatory effects of HPA axis regulation, and possibly the vasodilatory properties of IAN, also likely precluded the establishment of definitive relationships between observed changes in hormone levels and blood or regional brain concentrations of the inhalant.

Administration, Inhalation↗
PubMed2003

Inhalational methanol toxicity in pregnancy treated twice with fomepizole.

We describe a pregnant patient with a long history of inhalant abuse who came to our hospital twice during her pregnancy. In both admissions, she was treated with fomepizol (4-MP), a newly available alcohol dehydrogenase antagonist for treatment of ethylene glycol poisoning.

Administration, Inhalation↗
PubMed2003

Conditioned place aversion and self-administration of nitrous oxide in rats.

The rewarding/aversive effects of nitrous oxide (N(2)O) were evaluated using the place conditioning paradigm. Male Long-Evans rats (N=103) received a daily 40-min gas exposure for 8 consecutive days that alternated between two distinct chambers. A control group received placebo gas in both chamber types, while the N(2)O groups (8%, 15%, 30%, and 60% N(2)O) received four consistent pairings of N(2)O with one chamber type and four pairings of placebo gas with the other. A conditioned place aversion was found for the chambers that had been paired with 30% and 60% N(2)O. Place aversions were demonstrated during a 20-min test session on Day 9 when placebo gas was delivered to both chambers, and also during a 20-min test session on Day 10 when N(2)O was delivered to both chambers. A second study evaluated two novel methods of inhalant self-administration, one that used a forced-choice alternating gas environment and one that used a free-choice paradigm. Of four rats tested, two self-administered N(2)O, one rat avoided N(2)O, and one rat's behavior was consistent with neither self-administration nor avoidance. Availability of these methods will facilitate research on the neurobiological mechanisms underlying the rewarding and reinforcing effects of N(2)O and other abused inhalants.

Administration, Inhalation↗
PubMed2006

Effects of toluene exposure during brain growth spurt on GABA(A) receptor-mediated functions in juvenile rats.

Toluene is a commonly abused inhalant. Its neurobiological effects are, at least in part, mediated by gamma-aminobutyric acid (GABA(A)) receptors. Since GABA(A) receptor function is critical during brain development, the long-term effects of toluene exposure during brain growth spurt were investigated. Spargue-Dawley male rats were administered with toluene (500 mg/kg, i.p.) on postnatal day (PN) 4-9. Behavioral and electrophysiological measures and the levels of messenger RNA (mRNA) expression of GABA(A) receptor subunits were examined on PN 28-32. The seizure sensitivity induced by bicuculline (a GABA(A) receptor antagonist), methyl beta-carboline-3-carboxylate (inverse agonists of the GABA(A)/benzodiazepine receptor) but not 3-mercaptopropionic acid (a glutamate decarboxylase inhibitor) was enhanced by toluene exposure. Toluene exposure had no effect on the performance in the elevated plus-maze and rotarod test but reduced the responses to diazepam in these two tests. In vitro intracellular electrophysiological recordings employing brain slices from rats treated with toluene demonstrated a significant decrease in GABA(A) receptor-mediated inhibitory postsynaptic currents in CA1 neurons but an increased response to GABA perfusion. The relative abundance of the mRNAs encoding various subunits of GABA(A) receptor (alpha1, alpha2, alpha4, alpha5, alpha6, beta2, beta3, gamma2S, gamma2L) was examined in four brain regions (hippocampus, striatum, cortex, and cerebellum) by semiquantitative reverse transcription-PCR. These results demonstrated that subunit- and brain area-selective alterations in GABA(A) receptors after toluene exposure during brain growth spurt. The alterations in GABA(A) receptors might be associated with the neurobehavioral disturbance in offspring of toluene-abusing women.

Animals↗
PubMed1985

Acute nonlymphocytic leukemia in a glue sniffer.

A 17-year-old white male with a past history of chronic inhalational abuse of plastic glue was referred to our institution for sore throat, cervical adenopathy, and an abnormal peripheral blood smear. A diagnosis of acute myelomonocytic leukemia was made and abnormalities in cytogenetic studies were demonstrated. Specific inquiry regarding this form of drug exposure should be pursued when searching for possible etiologies of malignant disease.

Adhesives↗
PubMed2004

Intravenous self-administration of abused solvents and anesthetics in mice.

Volatile organic solvents, fuels and anesthetics are subject to abuse. The aim of the present study was to evaluate i.v. self-administration of several of these chemicals in drug- and experiment-naive mice using a commercially available vehicle, intralipid. Two strains of mice (DBA/2 and Swiss) were allowed to self-administer toluene (0.0017-0.17 micromol/infusion), 1,1,1-trichloroethane (0.006-0.19 micromol/infusion), ethanol (0.32-1.6 micromol/infusion), cyclohexane (0.0017-0.052 micromol/infusion), propofol (0.01-0.53 micromol/infusion) and flurothyl (0.00042-0.072 micromol/infusion) or their vehicles during 30-min tests. During the test, each nose-poke of the master mouse resulted in a 1.88-microl i.v. infusion to the master mouse and a yoked control mouse. When the delivery line was loaded with a reinforcing drug solution, the number of nose-pokes of the master mice significantly exceeded that for yoked control mice. In the present experiments, significant differences in rates of nose-poking were observed between mice receiving response-contingent and response-noncontingent deliveries of ethanol and toluene in both strains of mice and of 1,1,1-trichloroethane in Swiss mice. These data suggest that the reinforcing effects of abused inhalants can be studied using i.v. self-administration procedures.

Anesthetics↗
PubMed2005

Behavioral effects of toluene in rats selectively bred for infantile vocalization rate.

Glue sniffing is epidemic among children living in poverty in Latin America. Previous research has shown that abused inhalants such as toluene share pharmacological properties with anxiolytic drugs, and that personality factors such as degree of anxiety have been proposed to modulate the effects of these drugs. To study this interaction in an animal model, rats selectively bred for high (High) or low (Low) rates of distress calls after maternal separation (ultrasonic vocalizations, USVs) were used to investigate toluene's acute and long-term effects on two measures of anxiety behavior. At ten days of age, neonatal subjects were administered toluene (1 g/kg i.p.) and USVs were recorded. The subjects were retested as juveniles on an elevated plus maze to examine sequela of earlier toluene exposure. Acute toluene administration reduced USVs relative to control groups in neonates of both lines, indicating anxiolysis. As expected, Lows had reduced USVs relative to Highs. At 28 days of age, Highs spent more time in the open arms of the elevated plus maze than Lows. However, prior neonatal toluene exposure blocked this reversal of behavioral phenotype. This suggests that early toluene exposure compromised a compensatory process occurring during this developmental period, which may have been maternally mediated. These results have implications for the effects of early drug exposure on plasticity in the developing nervous system.

Animals↗
PubMed2006

[Spontaneous pneumomediastinum in asthma].

A pneumomediastinum is characterized by free air within the mediastinum. In most cases it is caused by an injury of the thorax. A spontaneous pneumomediastinum (sPM) occurred without any recognizable cause. By a sudden intraalveolar hypertension (caused by cough or physical exertion) a damage of alveoli is followed by diffusion of air along the bronchovascular sheats to the mediastinal soft tissue. sPM is a rare complication of asthma especially in young men. We demonstrate a young asthmatic patient with sPM first diagnosed as an allergic reaction to draw the attention to this rare but differential diagnostic important entity. sPM is reported in connection with drug inhalation abuse as a more frequent problem within the last years.

Adult↗
PubMed2003

Ether: a forgotten addiction.

Among abused inhalants, ether has recently received little attention. The case of a patient suffering from ether dependence is reported. Whereas several features of DSM-IV dependence were fulfilled, no physical withdrawal signs were observed.

Anesthetics, Inhalation↗
PubMed2000

Prenatal exposure to toluene results in abnormal neurogenesis and migration in rat somatosensory cortex.

Toluene inhalant abuse during pregnancy may result in growth-retarded microcephalic newborns who subsequently demonstrate developmental impairment. By using a rat model of toluene-abuse embryopathy, we studied the effects of prenatal toluene exposure on the generation and migration of cortical neurons. Dams were exposed by gavage to either corn oil or toluene diluted in corn oil on d 6-21 of gestation. The time of origin of cortical neurons was determined in the mature pups of dams injected with the thymidine analogue 5'-bromodeoxyuridine on 1 d during the period from d 13-21 of gestation. 5'-Bromodeoxyuridine-labeled neurons were identified by immunohistochemistry in a 400-microm-wide column of somatosensory cortex. The brains of the toluene-exposed pups had a significant reduction in the number of neurons within each cortical layer (p < 0.001). Depending on the cortical layer, the generation of neurons in the toluene-exposed pups was delayed by 1 or 2 d. In addition, the brains of the toluene-exposed pups also showed evidence of abnormal neuronal migration. However, there were no differences in either brain weight or body weight between the control and toluene-exposed pups. These observations suggest that although prenatal toluene exposure results in abnormal neuronal proliferation and migration, brain weight in the toluene-exposed pups may be preserved by enhanced development of glia or the neuropil.

Animals↗