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 nicotin e is mediated by nicotinic receptors located on mesolimbic dopaminergic neu rons. However. 6-hydroxydopamine lesions of the ventral tegmental area, res ulting in substantial depletion of nucleus accumbens dopamine, were recentl y reported to have no effect on nicotine-induced locomotion. The present st udy sought to re-examine this issue. Rats received bilateral infusions of 6 -hydroxydopamine or vehicle into the ventral tegmental area. Starting 3 wee ks later, locomotor activity was tested after subcutaneous injection of sal ine, 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 an d amphetamine were greatly reduced, whereas saline and scopolamine-induced activity was scarcely; affected. Dopamine denervation was assessed by autor adiography, using [I-125]RTI-55 to label plasmalemmal dopamine transporters . Labelling was reduced in nucleus accumbens core and shell and in the vent ral 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 [I-125]RTI-55 labelling in mesolimbic and ni grostriatal regions (r = 0.6-0.8). The present results provide further evid ence that the locomotor stimulant effect of nicotine is dependent on the in tegrity of ascending dopamine neurons, (C) 1998 Elsevier Science Ltd. All r ights reserved.