DOPAMINE D-1 RECEPTOR-STIMULATED RELEASE OF ACETYLCHOLINE IN RAT STRIATUM IS MEDIATED INDIRECTLY BY ACTIVATION OF STRIATAL NEUROKININ(1) RECEPTORS

Activation of dopamine D-1 receptors is thought to stimulate release o f striatal acetylcholine (ACh) indirectly, possibly through local rele ase 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 neurokinin(1) (NK1) receptor blockade on D-1 agonist-induced increa ses in ACh release in the striatum of awake, freely moving rats with a nd without a unilateral 6-hydroxydopamine-induced lesion of the nigros triatal pathway. Local perfusion with the D-1 agonist nyl-2,3,4,5-tetr ahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 mu M for 20 min) increased striatal ACh release in both intact rats and ra ts with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the N K1 antagonist, oxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP- 96,345; 10 and 25 mu M), but not its less active enantiomer oxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 mu M), decreased the elevation in ACh induced by SKF 38393 in both intact rat s and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist -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. These results in dicate that antagonism of striatal NK1 receptors reduces D-1 receptor- stimulated release of striatal ACh and suggest that increases in ACh r elease induced by D-1 agonists may be mediated indirectly through loca l release of substance P acting at NK1 receptors on striatal cholinerg ic neurons.