Antagonism of l-stepholidine on D2 receptor-mediated inhibition of synaptosomal adenylate cyclase in rat corpus striatum

In the presence of Sch 23390 0.1 mumol.L-1, dopamine (DA) inhibited the activity of synaptosomal adenylate cyclase (AC) isolated from rat striatum in a concentration-dependent manner with IC50 value of 2.2 mumol.L-1. The maximal inhibition corresponded to a 51% decrease of basal enzyme activity and was obtained at DA 100 mumol.L-1. The inhibitory effect of DA was reversed by selective D2 receptor antagonist spiperone 10 mumol.L-1. N-0437, a selective D2 DA receptor agonist also inhibited the activity of AC in the manner similar to that of DA. Both the inhibitions induced by DA and N-0437 were antagonized by l-stepholidine (l-SPD). However, in the presence of Sch 23390, l-SPD alone also inhibited the activity of AC by 29% and 33% at the concentrations of 10 and 100 mumol.L-1, respectively. The inhibition of l-SPD on AC activity was significantly antagonized by spiperone. In the presence of Sch 23390, both DA and N-0437 increased the activity of high affinity GTP phosphohydrolase in striatal synaptosomes. The increases of GTP phosphohydrolase activity stimulated by DA and N-0437 were completely reversed by l-SPD 100 mumol.L-1. These results suggest that l-SPD antagonizes or reverses the D2 receptor-mediated inhibition of AC activity through affecting the regulation of Gi (inhibitory guanine nucleotide-dependent protein) on D2 receptor-coupled AC and therefore affects the negative feedback of presynaptic DA receptors. Moreover, the inhibition of AC activity induced by l-SPD alone may provide a useful biochemical index for dual action of l-SPD.