Effectiveness of Inhalant Abuse Legislation.

BACKGROUND: Since peaking in the 1990s, inhalant abuse has steadily decreased over the past two decades. Concurrently, nearly every state has passed legislation aimed at minimizing inhalant abuse. While males have historically been more likely to abuse inhalants than females, there is no longer a sex effect in self-reported rates of inhalant abuse. OBJECTIVES: The objective of the present study is to evaluate the effect of anti-inhalant abuse legislation on self-reported rates of inhalant abuse, in high school age males and females. METHODS: Beginning in 1993, the CDC's biannual Youth Risk Behavior Surveillance Survey asked respondents if they have ever used inhalants to get high. Data from these surveys were collected, along with the date of passage of anti-inhalant abuse legislation in 46 of 50 states. ANOVAs were conducted to assess the effect of legislation on self-reported inhalant abuse rates. RESULTS: There were no significant main effects or interactions that demonstrated that inhalant abuse rates decreased in males or females following passage of legislation aimed at decreasing inhalant abuse. Conclusion/Importance: To date, 46 of 50 states have passed laws aimed at minimizing inhalant abuse, and while inhalant abuse rates have been decreasing for the past two decades, there is no evidence that this decline is related to enactment of these laws. Further research is needed to determine the cause of the decrease in inhalant abuse. The laws may benefit from amendments to include options for treatment.

Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans.

UNLABELLED: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain. METHODS: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. RESULTS: (123)I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test-retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. CONCLUSION: The data indicate that (123)I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of (123)I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.

Brain ß2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler.

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (ß2*-nAChRs). Previous studies examined ß2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of ß2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of ß2*-nAChRs 2-5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5-5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of ß2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

Quantification of smoking-induced occupancy of beta2-nicotinic acetylcholine receptors: estimation of nondisplaceable binding.

UNLABELLED: 5-(123)I-iodo-85380 ((123)I-5-IA) is used to quantitate high-affinity nicotinic acetylcholine receptors (beta(2)-nAChRs) on human SPECT scans. The primary outcome measure is V(T)/f(P), the ratio at equilibrium between total tissue concentration (free, nonspecifically bound, and specifically bound) and the free plasma concentration. Nondisplaceable uptake (free plus nonspecific) of (123)I-5-IA has not been measured in human subjects. Nicotine has high affinity for beta(2)*-nAChRs (nAChRs containing the beta(2)* subunit, for which * represents other subunits that may also be part of the receptor) and displaces specifically bound (123)I-5-IA. In this study, we measured nicotine occupancy and nondisplaceable binding in healthy smokers after they had smoked to satiety. METHODS: Eleven nicotine-dependent smokers (mean age +/- SD, 35.6 +/- 14.4 y) completed the study. One subject was excluded from subsequent analyses because of abnormal blood nicotine levels. Subjects abstained from tobacco smoke for 5.3 +/- 0.9 d and participated in a 15- to 17-h SPECT scanning day. (123)I-5-IA was administered by bolus plus constant infusion, with a total injected dose of 361 +/- 20 MBq. At approximately 6 h after the start of the infusion, three 30-min SPECT scans and a 15-min transmission-emission scan were acquired to obtain baseline beta(2)*-nAChR availability. Subjects then smoked to satiety (2.4 +/- 0.7 cigarettes), and arterial (first 40 min) and venous (until study completion) plasma nicotine and cotinine levels were collected. About 1 h after subjects had smoked to satiety, up to six 30-min SPECT scans were acquired. V(T)/f(P) data, computed from the tissue and plasma radioactivity measurements from the presmoking baseline and postsmoking scans, were analyzed using the Lassen plot method. RESULTS: Receptor occupancy after subjects had smoked to satiety was 67% +/- 9% (range, 55%-80%). Nondisplaceable uptake was estimated as 19.4 +/- 5.8 mL x cm(-3) (range, 15-28 mL x cm(-3)). Thus, in the thalamus, where mean V(T)/f(P) is 93 mL x cm(-3), nondisplaceable binding represents approximately 20% of the total binding. CONCLUSION: These results are in agreement with previous findings and suggest that when satiating doses of nicotine are administered to smokers, imaging of receptor availability can yield valuable data, such as quantifiable measures of nondisplaceable binding.

Differential effects of inhaled toluene on locomotor activity in adolescent and adult rats.

Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm "air" controls at both ages. These changes depended upon when activity was measured - during or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the "recovery" period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen prevalence of inhalant abuse.

GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression.

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State-Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES-D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = -0.47, P = 0.03), frontal (r = -0.46, P = 0.03), anterior cingulate (r = -0.47, P = 0.04), temporal (r = -0.47, P = 0.03), occipital (r = -0.43, P = 0.05) cortices, and cerebellum (r = -0.46, P = 0.04)], trait anxiety [parietal (r = -0.72, P = 0.02), frontal (r = -0.72, P = 0.02), and occipital (r = -0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = -0.68; P = 0.02), frontal (r = -0.65; P = 0.03), anterior cingulate (r = -0.61; P = 0.04), and temporal (r = -0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression.

Gestational toluene exposure effects on spontaneous and amphetamine-induced locomotor behavior in rats.

Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats. Bowen, S.E., Mohammadi, M.H., Batis, J.C., and Hannigan, J.H. Neurotoxicology and Teratology, XX, 2006. The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an "open-field" following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development.

The last decade of solvent research in animal models of abuse: mechanistic and behavioral studies.

The abuse of volatile organic solvents (inhalants) leads to diverse sequelae at levels ranging from the cell to the whole organism. This paper reviews findings from the last 10 years of animal models investigating the behavioral and mechanistic effects of solvent abuse. In research with animal models of inhalant abuse, NMDA, GABA(A), glycine, nicotine, and 5HT(3) receptors appear to be important targets of action for several abused solvents with emerging evidence suggesting that other receptor subtypes and nerve membrane ion channels may be involved as well. The behavioral effects vary in magnitude and duration among the solvents investigated. The behavioral effects of acute and chronic inhalant abuse include motor impairment, alterations in spontaneous motor activity, anticonvulsant effects, anxiolytic effects, sensory effects, and effects on learning, memory and operant behavior (e.g., response rates and discriminative stimulus effects). In addition, repeated exposure to these solvents may produce tolerance, dependence and/or sensitization to these effects.

Abuse pattern of gestational toluene exposure and early postnatal development in rats.

Inhalant abuse in the United States trails only alcohol, marijuana and nicotine abuse. Toluene, found in glues and cleaners, is among the most commonly abused inhalants. While teratogenicity due to occupational exposure to organic solvents (i.e., relatively long-term exposure to lower concentrations) has been studied, the teratogenic potential of organic solvent abuse (i.e., brief inhalation exposures to very high concentrations) has not been thoroughly examined. In a preclinical model of abuse patterns of fetal solvent exposure, timed-pregnant rats were exposed to 8000 parts per million (ppm) or 12,000 ppm of toluene, or to air (0 ppm), for 15 min twice daily from gestation day 8 (GD8) through GD20. After parturition, pups were tested from postnatal day 4 (PN4) to PN21 in a developmental test battery including measures of growth (i.e., body weight), maturational milestones (i.e., pinnae unfolding, incisor eruption and eye opening) and biobehavioral development (e.g., negative geotaxis, surface righting and grip strength). Pups exposed in utero to 12,000 ppm toluene weighed significantly less than the control pups at all ages before PN16. There were significant toluene-induced increases in an index of poor perinatal outcome (i.e., a combination of malformations, "runting" and neonatal death) and deficits in negative geotaxis. There were no significant delays in reaching maturational milestones. The results demonstrate that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth restriction, malformation and impairments of biobehavioral development in rats. A comparison of the present outcomes to previous studies of occupational exposure patterns suggests that for a given daily "dose" of toluene, a binge pattern of exposure may pose a greater risk for fetal development. Since the pattern of exposure in this experiment models binge exposure in human solvent abuse, the results imply that abuse of inhaled organic solvents, such as toluene, can cause similar teratogenic outcomes in humans.