In vivo comparisons of the effects of quinpirole and the putative presynaptic dopaminergic agonists B-HT 920 and SND 919 on striatal dopamine and acetylcholine release

The extent to which the putative dopamine (DA) autoreceptor agonists B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5d]azepine dihydrochloride) and SND 919 (2-amino-4,5,6,7-tetrahydro-6-propylamino- benzthiazol dihydrochloride) and the potent D2 receptor agonist quinpirole have differential effects on pre- and postsynaptic DA receptors was determined by using in vivo microdialysis to monitor the effects of these compounds on extracellular concentrations of DA and acetylcholine (ACh) in the striata of freely moving rats. B-HT 920 and SND 919 reduced interstitial concentrations of DA, but not ACh, when administered s.c. at doses of 0.05 and 0.1 mg/kg. Quinpirole (0.05 and 0.2 mg/kg) decreased extracellular concentrations of both DA and ACh. Hence, relative to its effects on DA, quinpirole was more potent than the other drugs at DA receptors controlling ACh release. These results are consistent with the hypothesis that B-HT 920 and SND 919 have preferential actions on DA autoreceptors. Local application of the selective D2 receptor antagonist raclopride produced similar dose- dependent increases in DA and ACh release. It is unlikely therefore that differences in the degree to which endogenous DA inhibits transmitter release from nigrostriatal terminals and cholinergic neurons can account for the greater sensitivity of the former to the depressant actions of systematically administered B-HT 920 and SND 919. As was the case with systemic administration, local striatal application of B-HT 920 produced larger decreases in extracellular DA than ACh. This suggests that the potent reduction in striatal DA release produced by systemic administration of B-HT 920 is mediated, at least in part, by autoreceptors on the terminals of nigrostriatal neurons. However, that difference between the average reductions in extracellular DA and ACh concentrations produced by local application of B-HT 920 was small compared to that elicited by peripheral administration. This suggests that actions at somatodendritic DA autoreceptors may also contribute to the inhibitory effects of systemically administered B-HT 920 on extracellular concentrations of DA in the striatum. In the final series of experiments, the effects of B-HT 920 (0.05 and 0.2 mg/kg) on interstitial concentrations of ACh were examined in the striatum ipsilateral to a unilateral 6-hydroxydopamine lesion of the mesotelencephalic DA system. These lesions significantly reduced basal extracellular concentrations of ACh in the striatum. In addition, the inhibitory effect of B-HT 920 (0.2 mg/kg s.c.) was potentiated in the denervated striatum. The enhanced ability of B-HT 920 to inhibit ACh release is discussed in the context of lesion-induced increases in DA receptor reserve.