Sex and strain differences in dynamic and static properties of the mesolimbic dopamine system.

Sex is a biological variable that contributes to the incidence, clinical course, and treatment outcome of brain disorders. Chief among these are disorders associated with the dopamine system. These include Parkinson's disease, ADHD, schizophrenia, and mood disorders, which show stark differences in prevalence and outcome between men and women. In order to reveal the influence of biological sex as a risk factor in these disorders, there is a critical need to collect fundamental information about basic properties of the dopamine system in males and females. In Long Evans rats, we measured dynamic and static properties related to the mesolimbic dopamine system. Static measures included assessing ventral tegmental area (VTA) dopamine cell number and volume and expression of tyrosine hydroxylase and dopamine transporter. Dynamic measures in behaving animals included assessing (1) VTA neuronal encoding during learning of a cue-action-reward instrumental task and (2) dopamine release in the nucleus accumbens in response to electrical stimulation of the VTA, vesicular depletion of dopamine, and amphetamine. We found little or no sex difference in these measures, suggesting sexual congruency in fundamental static and dynamic properties of dopamine neurons. Thus, dopamine related sex-differences are likely mediated by secondary mechanisms that flexibly influence the function of the dopamine cells and circuits. Finally, we noted that most behavioral sex differences had been reported in Sprague-Dawley rats and repeated some of the above measures in that strain. We found some sex differences in those animals highlighting the importance of considering strain differences in experimental design and result interpretation.

Structure-activity study of acute neurobehavioral effects of cyclohexane, benzene, m-xylene, and toluene in rats.

Toluene is a widely misused solvent that causes a variety of behavioral effects in both humans and animals. Preclinical and clinical research has provided evidence that toluene inhalation produces psychoactive effects similar to those caused by other Central Nervous System depressant drugs, but little is known about the consequences of inhaling solvents other than toluene that are also present in commercial products. As part of this research project, we studied the effects of hydrocarbon solvents chemically related to toluene on anxiety-like behavior, passive-avoidance learning, nociception, motor coordination and social interaction. We tested independent groups of adolescent male Wistar rats in the burying behavior task, step through avoidance learning task, hot plate test, shock threshold test, social interaction or rotarod tests after a 30 min exposure to either cyclohexane, benzene, toluene or m-xylene (2000 to 8000 ppm). Control animals breathed only air. Benzene, toluene and m-xylene produced anxiolytic-like actions, impaired learning, caused antinociception and decreased social interaction in a concentration-dependent manner. Locomotor coordination was impaired only with 8000 ppm m-xylene and 8000 ppm toluene. Cyclohexane had no effect on any of the behavioral tasks. Our data suggest that the aromatic ring is critical for solvents to produce a wide variety of behavioral effects.

Structure-activity relationship for the anticonvulsant effects of organic solvents.

Several organic solvents have anticonvulsant or convulsant actions depending on the dose and exposure time. To study if there is a structure-activity relationship for organic solvents as anticonvulsant agents we subjected independent groups of mice to a single 30-min exposure session to inhale n-hexane, cyclohexane, benzene (8000ppm each), toluene (500-6000ppm), m-xylene (1000-6000ppm), ethylbenzene (500-4000ppm) or propylbenzene (500-4000ppm). Immediately after, animals were injected i.p. with 90mg/kg pentylenetetrazol (PTZ) and re-exposed to the same solvent for another 30min. During this time, the occurrence of seizures and death was recorded. n-Hexane and cyclohexane had no anticonvulsant effect. Benzene and alkylbenzenes delayed the onset of PTZ-induced seizures. In addition, all four alkylbenzenes decreased the number of animals that seized. Propylbenzene and ethylbenzene were equally effective, but more potent than toluene and m-xylene to block PTZ actions. In the second part of the study we exposed independent groups of mice to 8000ppm n-hexane, cyclohexane (solvents without effect in the PTZ experiment), 8000ppm benzene or 6000ppm toluene, m-xylene, ethylbenzene or propylbenzene following the same experimental protocol (i.e. 30-min exposure, injection, 30-min re-exposure), but using 120mg/kg NMDA as the convulsant agent. All aromatic compounds prevented NMDA lethal effects, but only benzene and toluene decreased the percentage of animals that seized. Taken together, our data suggest that the benzene ring alone or substituted with alkyl groups is necessary for the anticonvulsant effect of acute solvent exposure against seizures and/or death produced by PTZ or NMDA.

Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems.

RATIONALE: Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized. OBJECTIVES: This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs. METHODS: Independent groups of rats inhaled toluene (500-12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC. RESULTS: Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT2A/2C receptor antagonist), M100907 (selective 5-HT2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D2 receptor antagonist) significantly decreased toluene's and ketamine's actions. The 5HT1A receptor antagonist WAY100635 had no effect. CONCLUSION: Toluene stimulates 5HT2A and 5HT2C receptors, and increases 5-HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism.

Review of toluene action: clinical evidence, animal studies and molecular targets.

It has long been known that individuals will engage in voluntary inhalation of volatile solvents for their rewarding effects. However, research into the neurobiology of these agents has lagged behind that of more commonly used drugs of abuse such as psychostimulants, alcohol and nicotine. This imbalance has begun to shift in recent years as the serious effects of abused inhalants, especially among children and adolescents, on brain function and behavior have become appreciated and scientifically documented. In this review, we discuss the physicochemical and pharmacological properties of toluene, a representative member of a large class of organic solvents commonly used as inhalants. This is followed by a brief summary of the clinical and pre-clinical evidence showing that toluene and related solvents produce significant effects on brain structures and processes involved in the rewarding aspects of drugs. This is highlighted by tables highlighting toluene's effect on behaviors (reward, motor effects, learning, etc.) and cellular proteins (e.g. voltage and ligand-gated ion channels) closely associated the actions of abused substances. These sections demonstrate not only the significant progress that has been made in understanding the neurobiological basis for solvent abuse but also reveal the challenges that remain in developing a coherent understanding of this often overlooked class of drugs of abuse.