Different Neural Mechanisms Underlie Dizocilpine Maleate- and Dopamine Agonist-induced Locomotor Activity

This study evaluated and compared the role of mesoaccumbens dopamine and the ventral pallidal region in the locomotor stimulatory action of the non-competitive N-methyl-D-aspartate antagonist dizocilpine maleate and dopamine agonists. Intra-accumbens injections of both amphetamine (1, 5 and 25 nmol) and dizocilpine maleate (1, 5, 25 and 50 nmol) induced a dose-dependent increase in locomotor activity. The N-methyl-D-aspartate antagonist was somewhat less effective than amphetamine. 6-Hydroxydopamine dopamine-depleting lesions of the nucleus accumbens completely blocked locomotor stimulation induced by focal administrations of amphetamine (5 nmol), but were ineffective in altering the actions of dizocilpine maleate (50 nmol). Ibotenic acid lesions of the ventral pallidal region and muscimol injections into this area also prevented the stimulatory effects of systemic amphetamine (1 mg/kg), while having no effect on the locomotor-activating actions of systemic dizocilpine maleate (0.3 mg/kg). Microdialysis studies revealed that systemically administered apomorphine (2 mg/kg) significantly decreased extracellular GABA in the pallidum, which was accompanied by substantial increases in locomotor output. Systemically administered dizocilpine maleate (0.3 mg/kg), on the other hand, also increased locomotor activity without having any effect on pallidal GABA. These data, taken together, indicate that while the locomotor effects of dopamine agonists are dependent upon intact mesoaccumbens dopamine and involve GABAergic efferents from the nucleus accumbens to the ventral pallidum, dizocilpine maleate's stimulatory actions are independent of such mechanisms.