The effects of central aromatic amino acid DOPA decarboxylase inhibition on the motor actions of L‐DOPA and dopamine agonists in MPTP‐treated primates

Endogenous L-DOPA may act as a neuromodulator contributing to the production of motor activity. We now investigate the effects of the centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor NSD-1015 (3-hydroxybenzyl hydrazine) on the motor actions of L-DOPA and dopamine agonist drugs in MPTP treated common marmosets. Pretreatment with NSD-1015 (10–50 mg kg−1; i.p.) worsened baseline motor deficits in MPTP-treated common marmosets. Similarly, it abolished L-DOPA (5–18 mg kg−1 s.c.) induced locomotor activity and reversal of disability. NSD-1015 pretreatment inhibited dopamine formation and elevated L-DOPA levels in plasma. The increase in locomotor activity and improvement in disability produced by the administration of the D-1 agonist A-86929 (0.03–0.04 mg kg−1 s.c.) or the D-2 agonist quinpirole (0.05–0.3 mg kg−1 i.p.) was abolished by NSD-1015 (25 mg kg−1 i.p.) pretreatment. While the effects of a low dose combination of A-86929 (0.04 mg kg−1 s.c.) and quinpirole (0.05 mg kg−1 i.p.) were inhibited by NSD-1015 (25 mg kg−1 i.p.), there was little effect on the action of a high dose combination of these drugs (0.08 mg kg−1 A-86929 and 0.1 mg kg−1 quinpirole). Following central AADC inhibition with NSD-1015 (25 mg kg−1 i.p.), locomotor behaviour induced by administration of high dose combinations of A-86929 (0.08 mg kg−1 s.c.) and quinpirole (0.1 mg kg−1 i.p.) was unaffected by L-DOPA (5 mg kg−1 s.c.) pretreatment. These results do not support a role for endogenous L-DOPA in spontaneous or drug induced locomotor activity. Rather, they strengthen the argument for the importance of endogenous dopaminergic tone in the motor actions of dopamine agonists. British Journal of Pharmacology (2000) 129, 1355–1364; doi:10.1038/sj.bjp.0703189