The results suggested that NO/cGMP-dependent mechanism might be involved in toluene-induced locomotor activity in rats.

Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In this study, the effects of neonatal toluene exposure on NMDA receptors in primarily cultured cerebellar granule neurons were examined. Sprague-Dawley rats were treated with toluene (0, 200, 500, and 1000 mg/kg, i.p.) from postnatal day (PN) 4 to PN 7. Under toluene-free conditions, Ca2+ signals of cultured neurons in response to glutamate and NMDA were measured for up to 14 days. The expression of NMDA receptor subunits (NR1, NR2A, and NR2B) at 5-14 days in vitro (DIV) were also determined. Neonatal toluene exposure dose-dependently reduced intracellular Ca2+ signals in response to glutamate/glycine and NMDA/glycine in cultured cerebellar granule neurons, and these effects were gradually decreased with time. Such toluene exposure did not influence the inhibition of Mg2+ or MK801 on NMDA-evoked responses, but it decreased the potency of ifenprodil (an NR2B preferring antagonist). The protein levels of NMDA receptor subunit NR2B were consistently reduced by toluene exposure at 5 DIV, but not at 14 DIV. These results demonstrate that neonatal toluene exposure induces long-term but reversible changes in the function and composition of NMDA receptors. Such changes during developmental stages may contribute to the cerebellar dysfunction observed in fetal solvent syndrome.

These results indicate that neonatal but not adolescent toluene exposure produces long-term effects on selective behaviors induced by NMDA antagonists. Theses findings further support the hypothesis that functional changes in NMDA receptors may be related to the neurobehavioral dysfunction associated with fetal solvent syndrome.

Toluene, an industrial organic solvent, is voluntarily inhaled as drug of abuse. Toluene has been shown to inhibit the nicotinic acetylcholine receptors. Nicotinic receptors play an important role in brain development during brain growth spurt and early adolescence. The long-term effects of neonatal and adolescent toluene exposure on behavioral responses to nicotine in early adulthood were compared. Sprague-Dawley male and female rats were treated with toluene (500 mg/kg, ip) or corn oil daily over postnatal day (PN) 4-9 or 25-30. Nicotine-induced hypothermia, antinociception, and seizure activity were examined during PN 56-60. Toluene exposure during the brain growth spurt, but not adolescence, reduced the behavioral responses to nicotine in young adult rats. However, the levels of alpha4, alpha7, and beta2 nicotinic receptors were not altered in the frontal cortex, striatum, thalamus, hippocampus, and cerebellum by neonatal toluene exposure. These results indicate that toluene exposure during the brain growth spurt produces long-term changes in nicotine sensitivity, which may be unrelated to the total expression levels of alpha4, alpha7, and beta2 nicotinic receptors. The alterations in nicotine sensitivity may be related to the neurobehavioral disturbance associated with fetal solvent syndrome.