Dopamine D1 receptor-stimulated release of acetylcholine in rat striatum is mediated indirectly by activation of striatal neurokinin1 receptors

Abstract

Activation of dopamine D1 receptors is thought to stimulate release of striatal acetylcholine (ACh) indirectly, possibly through local release of substance P which, in turn, may enhance release of ACh. To test this hypothesis, in vivo microdialysis was used to assess the effect of neurokinin1 (NK1) receptor blockade on D1 agonist-induced increases in ACh release in the striatum of awake, freely moving rats with and without a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway. Local perfusion with the D1 agonist (+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 microM for 20 min) increased striatal ACh release in both intact rats and rats with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the NK1 antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N- [(methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345; 10 and 25 microM), but not its less active enantiomer (2R,3R)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 microM), decreased the elevation in ACh induced by SKF 38393 in both intact rats and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist 17-beta-hydroxy-17-a-androstanol[3.2- b]pyrimidol[1,2-a]benzimidazole hydrochloride (WIN 51,708; 20 mg/kg i.p.) also reduced the increase in ACh release induced by local perfusion of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)