The contribution of mesolimbic dopamine to the locomotor stimulant effect of nicotine /

In drug-tolerant rats, acute administration of systemic nicotine stimulates locomotor activity. Several lines of evidence suggest that this effect is mediated by nicotinic acetylcholine receptors located on the neurons of the mesolimbic dopaminergic (MLDA) pathway. However, a report published recently has challenged this idea, finding that destruction of the MLDA with 6-hydroxydopamine (6-OHDA), a catecholamine specific neurotoxin, had no effect on nicotine-induced hyperlocomotion. The objective of this thesis was therefore to re-examine the role of the MLDA in mediating the locomotor stimulant effect of nicotine in rats. Vehicle or 6-OHDA was bilaterally infused into the ventral tegmental area, the somatodendritic region of the MLDA pathway, of rats that had been pre-treated with nicotine. Drug-induced locomotor activity was then assessed. The locomotor activity of lesioned animals in response to nicotine (0.4 mg/kg base sc) and amphetamine (0.5 mg/kg salt sc) decreased by 75% and 87% respectively in comparison to non-lesioned rats, while the saline and scopolamine-induced (0.5 mg/kg salt sc) locomotor activity was not significantly altered. Autoradiographic examination of rat brains using 125[I]-RTI 55, a dopamine transporter ligand, revealed that binding within the cell body and terminal region of the MLDA pathway was decreased by 70% and 85% respectively in lesioned animals. A significant correlation (r = 0.68) was found between 125[I]-RTI 55 binding in the nucleus accumbens, the main projection of the MLDA system, and nicotine-induced locomotor activity. These findings strongly implicate the MLDA pathway in mediating the locomotor stimulant effect of nicotine in rats