Effects of putative dopamine autoreceptor agonists in pharmacological models related to dopaminergic and neuroleptic activity

Abstract

The pharmacological profile of 2 proposed selective dopamine (DA) autoreceptor agonists 3-PPP and 3-phenethyl-PP was compared with that of apomorphine in test systems for detection of dopaminergic and antidopaminergic activity. In vitro 3-PPP and 3-phenethyl-PP showed preferential affinity for D-2 DA receptors and only very low affinity for D-1 DA receptors. Accordingly, and in contrast to apomorphine, no stimulation of DA-sensitive adenylate cyclase was observed. A weak to moderate inhibitory activity of all 3 compounds was shown in uptake systems for DA, NA and 5-HT. A weak or no effect on α 1-or α 2-adrenergic receptors was observed. 3-PPP, 3-phenethyl-PP and apomorphine inhibited spontaneous locomotor activity in mice and rats, induced contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and induced emesis in dogs. The DA involvement in these effects was confirmed by antagonistic effects of neuroleptics in all three test systems. Apomorphine was the only compound inducing stereotyped behaviour in normal rats and neuroleptically induced supersensitive mice and inducing ipsilateral circling behaviour in hemitransected rats. 3-PPP did not show activity in several tests for neuroleptic effects in vivo, including inhibition of apomorphine- and methylphenidate-induced stereotyped gnawing, cataleptogenic effect, inhibition of conditioned avoidance response and inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. In contrast 3-PPP and 3-phenethyl-PP antagonized d-amphetamine-induced stereotyped licking/gnawing and hyperactivity. 3-PPP did not influence the cateleptogenic or methylphenidate antagonistic effect of cis-(Z)-flupentixol or haloperidol. 3-PPP increased the methylphenidate antagonistic effect of spiroperidol and the apomorphine antagonistic effect of cis-(Z)-flupentixol, cis-(Z)-clopenthixol and spiroperidol. It is concluded that 3-PPP and its more potent derivative 3-phenethyl-PP show high selectivity for DA receptors mediating sedation in rodents but that these compounds activate DA receptors mediating emesis and activate denervation supersensitive DA receptors, while not affecting neuroleptic supersensitive DA receptors. The neuroleptic-like activity of 3-PPP and 3-phenethyl-PP is only shown as a d-amphetamine antagonistic effect, indicating a presynaptic site of action. The increase of some neuroleptic effects may have clinical relevance for treatment of diseases associated with DA hyperactivity.