The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.

Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence.

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment.

The first evidence for the modulation of dopamine (DA) synthesis by presynaptic dopamine receptors was presented in 1972 by Carlsson and coworkers, who observed that when impulse flow in nigrostriatal DA neurons is interrupted by axotomy the rate of tyrosine hydroxylation in striatal terminals is increased.’ This was interpreted as suggestive of the existence of a presynaptic site at which released DA can act to exert feedback inhibition on DA synthesis. At the time, the concept of autoregulation in the central nervous system (CNS) was novel. Since then, it has become clear that autoreceptors provide a means for many types of neurons to regulate cellular functions such as neurotransmitter release, synthesis, and impulse flow. Although the popularity of DA autoreceptors has waxed and waned over the years, autoreceptor reviews have been plentiful (see Reference 2 for a recent example). This paper will therefore be quite selective in its focus. First, it will concentrate on the autoreceptor regulation of DA synthesis, since release and impulse flow are being discussed by other authors in the volume. Second, the emphasis will be on new developments in this field.

Autoreceptor regulation of dopamine synthesis.

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled toadenylate cyclase do not induce stereotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral stereotypies. Partial D2 agonists (e.g. (—)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (—)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with α-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (—)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective. The behavioural stimulation induced by a particular DA agonist thus depends on relative D1/D2 receptor affinity and also on the intrinsic activity at D2 receptors, while intrinsic activity at D1 receptors appears to be less important. The relative importance of D1 and D2 receptors for expression of different stereotypy patterns is useful for in vivo evaluation of the selectivity ratios of DA agonists.

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats.

Dopamine receptors: Functions, subtypes and emerging concepts

B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.

Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain.

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Effects of B-HT 920 and B-HT 933 on dopamine and noradrenaline autoreceptors in the rat brain.