Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in rats

Convergent evidence suggests that the locomotor stimulant effect of nicotine is mediated by nicotinic receptors located on mesolimbic dopaminergic neurons. However, 6-hydroxydopamine lesions of the ventral tegmental area, resulting in substantial depletion of nucleus accumbens dopamine, were recently reported to have no effect on nicotine-induced locomotion. The present study sought to re-examine this issue. Rats received bilateral infusions of 6-hydroxydopamine or vehicle into the ventral tegmental area. Starting 3 weeks later, locomotor activity was tested after subcutaneous injection of saline, nicotine (0.4 mg/kg base), amphetamine (0.5 mg/kg) or scopolamine (0.5 mg/kg). In lesioned animals, the locomotor stimulant effects of nicotine and amphetamine were greatly reduced, whereas saline and scopolamine-induced activity was scarcely affected. Dopamine denervation was assessed by autoradiography, using [ 125I]RTI-55 to label plasmalemmal dopamine transporters. Labelling was reduced in nucleus accumbens core and shell and in the ventral tegmental area (by 87, 81 and 70%, respectively), and in nigrostriatal areas (52–77%). The locomotor stimulant effects of nicotine and amphetamine were correlated with residual [ 125I]RTI-55 labelling in mesolimbic and nigrostriatal regions ( r=0.6–0.8). The present results provide further evidence that the locomotor stimulant effect of nicotine is dependent on the integrity of ascending dopamine neurons.