The regulation of striatal cholinergic function by dopamine D1 receptor activation was examined in vivo in urethane-anaesthetized rats with microdialysis probes. Extracellular acetylcholine levels were enhanced by activation of D1 receptors either directly by a striatal application of the D1 receptor agonist (+)-SKF-38393 (3 microM) or indirectly by the release of dopamine evoked by striatal application of neurotensin (0.1 microM) under D2 receptor blockade. SR 144190, a new potent and selective non-peptide neurokinin-2 receptor antagonist (0.03-1 mg/kg, i.p.), dose-dependently reduced the acetylcholine release induced by (+)-SKF-38393 or neurotensin. Furthermore, intrastriatal application of SR 144190 (1 nM) blocked the increase in acetylcholine release induced by the local application of (+)-SKF-38393 (3 microM), neurokinin A (1 microM) or substance P (1 microM). Finally, a role for nitric oxide in mediating the effects of D1 neurokinin-2 receptor activation on acetylcholine release is proposed since local infusion of the competitive inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (0.01-10 microM), blocked the increase in acetylcholine release induced by (+)-SKF-38393 (3 microM), neurotensin (0.1 microM) or neurokinin A (1 microM) without affecting the enhancing effect of the neurokinin-1 agonist septide (0.1 microM).