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Abstract: Toluene, a psychoactive volatile solvent found in adhesives and other products, is inhaled for its euphoric and intoxicating effects. Toluene inhalation additionally results in cognitive disturbances including impairments in select types of spatial and non-spatial memory, which converging evidence suggests may involve neurons of the dentate gyrus. In the present study we examined the effects of acute binge-like (~5000ppm) toluene inhalation on dentate gyrus granule cell output and perforant path synaptic transmission, using extracellular field potential recordings in anesthetized adult rats in vivo. We found that toluene rapidly and reversibly increased or decreased the amplitudes of evoked population spikes from granule cells over a wide range of stimulation intensities. These changes in granule cell output could not be accounted for by changes in perforant path action potential discharge or presynaptic neurotransmitter release. A marked decrease in the power of the theta rhythm measured within the dentate gyrus was additionally noted. Overall our results suggest that inhalation of abuse-relevant concentrations of toluene changes the readout of perforant path inputs by dentate gyrus granule cells, putatively through a postsynaptic mechanism, and may contribute to explanations for specific learning and memory deficits associated with toluene inhalation. [Copyright &y& Elsevier]

Introduction Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Δ9-tetrahydrocannabinol (Δ9-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Δ9-THC and directly compared to parenteral (intraperitoneal, IP) administration of Δ9-THC. Methods: Sprague–Dawley rats were exposed to pure Δ9-THC vapour (1, 2, 5, 10, and 20 mg/pad), using a Volcano® vapourizing device (Storz and Bickel, Germany) or IP-administered Δ9-THC (0.1, 0.3, 0.5, 1.0 mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5 mg/kg) were measured. Results: Vapourized Δ9-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Δ9-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10 mg of vapourized Δ9-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7 days of repeated exposure; this chronic exposure to 10 mg of vapourized Δ9-THC did not induce behavioural sensitization to morphine. Discussion: These results suggest vapourized Δ9-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Δ9-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal and human cannabinoid studies may be related to pharmacokinetic differences associated with route of administration. [ABSTRACT FROM AUTHOR]

Introduction Most studies evaluating the effects of Δ9-tetrahydrocannabinol (Δ9-THC) in animal models administer it via a parenteral route (e.g., intraperitoneal (IP) or intravenous injection (IV)), however, the common route of administration for human users is pulmonary (e.g., smoking or vapourizing marijuana). A vapourized Δ9-THC delivery system for rodents was developed and used to compare the effects of pulmonary and parenteral Δ9-THC administration on blood cannabinoid levels and behaviour. Methods Sprague–Dawley rats were exposed to pulmonary Δ9-THC (1, 5, and 10 mg of inhaled vapour) delivered via a Volcano® vapourizing device (Storz and Bickel, Germany) or to parenteral Δ9-THC (0.25, 0.5, 1.0, and 1.5 mg/kg injected IP). Quantification of Δ9-THC and its psychoactive metabolite, 11-hydroxy-Δ9-THC (11-OH-Δ9-THC), in blood was determined by liquid chromatography/mass spectrometry (LC/MS). In order to verify the potential for the vapourization procedure to produce a robust conditioned place preference (CPP) or conditioned place avoidance CPA, classical conditioning procedures were systematically varied by altering the exposure time (10 or 20 min) and number of exposed rats (1 or 2) while maintaining the same vapourization dose (10 mg). Results Blood collected at 20 min intervals showed similar dose-dependent and time-dependent changes in Δ9-THC and 11-OH-Δ9-THC for both pulmonary and parenteral administration of Δ9-THC. However, vapourized Δ9-THC induced CPP under certain conditions whereas IP-administered Δ9-THC induced CPA. Discussion These results support and extend the limited evidence (e.g., in humans, Naef et al., 2004; in rodents, Niyuhire et al., 2007) that Δ9-THC produces qualitatively different effects on behaviour depending upon the route of administration. [ABSTRACT FROM AUTHOR]

Abstract: Inhalation of vapors from toluene-containing products results in euphoria accompanied by a variety of cognitive impairments and motor dysfunctions. The profound behavioral changes observed during and following toluene inhalation suggest changes in the activity of cells in potentially many brain regions; however, a comprehensive assessment of the neuroanatomical structures activated by toluene vapor has not been completed. Thus in the present study we systematically mapped in over 140 brain structures the distribution of c-Fos immunoreactivity (c-Fos IR), a proxy for neural activation, following exposure to an abuse-like concentration (~5000ppm) of toluene vapor for 0, 5, 10 or 30min. Quantitative analyses revealed increases in c-Fos IR in about one-third of the brain structures examined, with most of these structures significantly activated only after prolonged toluene exposure. The majority of brain structures activated by toluene were found in the forebrain and midbrain, with particularly pronounced activation in nuclei implicated in the processing of rewarding, emotional, and olfactory stimuli, and those controlling motor output. These structures included the ventral tegmental area, nucleus accumbens, select regions of the amygdala and hypothalamus, cingulate cortex, olfactory nuclei, piriform cortex, secondary motor cortex and caudate-putamen. In contrast, all subregions of the hippocampus and most thalamic nuclei were not significantly activated by toluene vapor. In the brainstem, effects of toluene vapor were restricted to select nuclei in the pons. The pattern of c-Fos IR evoked by inhalation of toluene vapor appears distinct from other psychoactive substances, consistent with the unique and complex behavioral outcomes associated with acute toluene inhalation. [Copyright &y& Elsevier]