Differential electrophysiological effects of 3-PPP and its enantiomers on dopamine autoreceptors and postsynaptic receptors

The activities of substantia nigra pars compacta dopamine and globus pallidus neurons have been examined following the systemic administration of ( +/- )-3-PPP and the enantiomers of 3-PPP to investigate the relative effects of these putative dopamine agonists on dopamine autoreceptors and postsynaptic dopamine receptors. ( +/- )-3-PPP inhibited the firing rates of 7 out of 10 dopamine cells completely (ED50 = 0.18 +/- 0.06 mg/kg) but caused no consistent or significant alterations in the firing rates of globus pallidus neurons, exhibiting an apparent selectivity for the dopamine D-2 autoreceptors. However, (+)-3-PPP effectively inhibited the activity of all dopamine neurons studied (ED50 = 0.09 +/- 0.03 mg/kg) and, like d-amphetamine, apomorphine and other dopamine agonists, significantly stimulated pallidal activity. (-)-3-PPP was less effective at inhibiting dopamine cell activity; it had no effect on firing rates of pallidal cells when given alone, but it reversed the pallidal rate increases induced by (+)-3-PPP and also blocked the rate increases induced by systemically administered apomorphine. The results show that (-)-3-PPP, given systemically, acts as a partial agonist in the substantia nigra pars compacta and as an antagonist on postsynaptic dopamine receptors. These effects of (-)-3-PPP appear to account for the apparent dopamine autoreceptor selectivity demonstrated by racemic 3-PPP and further indicate that the autoreceptors and postsynaptic dopamine receptors may be differentially affected by a drug with mixed agonist/antagonist properties. These conclusions are consistent with those obtained from other techniques and support the idea that the effects of dopamine agonists on the activity of dopamine neurons and globus pallidus cells can provide an indication of the relative selectivity of these drugs for pre- or postsynaptic dopamine receptors.     

Effects of the enantiomers of 3-PPP on DA1 and DA2 dopamine receptors in the dog

The (+)- and (−)-enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) were studied for their effects on DA₁ and DA₂ dopamine receptors in pentobarbital anesthetized dogs. 3-PPP enantiomers were administered into the renal artery after phenoxybenzamine pretreatment to determine possible DA₁ activity; dopamine was also injected for comparison. DA₂ activity was determined by injection of the enantiomers into the femoral vascular bed with intact nerve supply and without phenoxybenzamine; dipropyl dopamine (DPDA) or apomorphine were used as standard DA₂ agonists. Antagonists activity of the enantiomers on DA₁ or DA₂ receptors was determined by simultaneous administration of the enantiomer with DA in the renal vascular bed and with DPDA or apomorphine in the femoral vascular bed. Neither enantiomer was active as a DA₁ agonist, but both exhibited antagonist activity. Both enantiomers were found to be agonists of the DA₂ receptor; in addition, both showed DA₂ antagonist activity. In all actions the (−)-enantiomer was approximately 4 times more potent than the (+)-enantiomer.     

Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptors agonist with greater autoreceptor selectivity than 3-PPP enantiomers

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.     

Differential effects of 3-PPP enantiomers on extracellular dopamine concentration in the caudate-putamen and nucleus accumbens of rats

The ability of the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine) to modify the extracellular concentration of dopamine (DA) in the caudate-putamen and the nucleus accumbens of awake rats was assessed using intracranial microdialysis. The enantiomers and the racemate were directly infused at 3 incremental concentrations (1–100 M) or systemically administered by subcutaneous injection (10 mg/kg). Both systemic administration and direct infusion of (–)3-PPP at the highest concentration (100 M) significantly increased extracellular DA in both brain regions. This increase was also seen in the presence of higher extracellular DA levels following reuptake inhibition by nomifensine (10 M). In contrast to the effects of (–)3-PPP, systemic administration of both (+)3-PPP and (±)3-PPP decreased DA levels. Infusion of (±)3-PPP led to slight increases in DA levels in both brain regions at the highest concentration (100 M), while (+)3-PPP at 100 M also produced a significant increase in the caudate-putamen, but not in the nucleus accumbens. However, in the presence of nomifensine-induced elevations in extracellular DA, (+)3-PPP produced a significant decrease in DA concentrations in both brain regions. These results support previous findings that the enantiomers of 3-PPP show unique profiles in their in vivo effects on DA terminal functions. Furthermore, these effects are dependent on the mode of 3-PPP administration, the brain region in which DA overflow is measured, and the level of basal extracellular DA. Correspondence to: R. E. See at the above address     

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D₂ blocker) or SCH 23390 (0.2 mg/kg i.p., D₁ blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D₁ or D₂ postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D₁ and D₂ receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.     

Differential effects of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) at dopamine receptor sites

The agonist actions of 3-PPP at central dopamine (DA) autoreceptors were found to reside mostly in its (+) enantiomer, (+)-3-PPP also reduced striatal content of DOPAC and HVA, whereas (-)-3-PPP elevated HVA levels. Only (-)-3-PPP antagonized DA stimulation of DA-receptor linked adenylate cyclase. It was more effective than (+)-3-PPP at inhibiting [3H]DA binding to striatal membranes. The results suggest that (+)-3-PPP may act predominantly at DA autoreceptors, while (-)-3-PPP exhibits weak affinity for presynaptic and postsynaptic DA receptors.     

Dopamine receptors involved in prolactin secretion pharmacologically characterized by means of 3-PPP enantiomers

3-(3-Hydroxyphenyl)-N-n-propylpiperidine (3-PPP) is a novel compound existing in two enantiomers which, as judged by recent biochemical and behavioural studies, both have clearcut though differential effects on central dopamine (DA) receptors. Thus, while both enantiomers act in low doses as agonists preferentially on autoreceptors, in higher doses the (+)-form is an agonist also postsynaptically while the (-)-form acts as an antagonist on postsynaptic DA receptors in the striatum and in the limbic system. In the present study both enantiomers were evaluated with respect to their effects on pituitary DA receptors involved in prolactin release. In previously untreated rats, no increase in prolactin release was observed after administration of either enantiomer in low or high doses. The lack of effect of high doses of the (-)-form indicates that DA receptors on the lactotrophs are pharmacologically different from postsynaptic DA receptors in nigrostriatal and mesolimbic systems. The finding that both enantiomers exerted a dose-dependent prolactin suppressive effect in reserpine-pretreated animals suggests instead that DA receptors on the lactotrophs are pharmacologically similar to DA autoreceptors in the brain. The effect of both 3-PPP enantiomers on prolactin release in reserpine-pretreated animals was antagonized by haloperidol, sulpiride and metoclopramide while pimozide and clozapine appeared less active. This finding is discussed with respect to possible selectivity on pre- vs. postsynaptic DA receptors for various antagonists.     

(+)- and (-)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis

Both enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP; 0.5-32 mg/kg s.c.) dose dependently reduced the increase in striatal dopamine (DA) synthesis rate produced by gamma-butyrolactone (GBL). Whereas (+)-3-PPP completely prevented the action of GBL, (-)-3-PPP was only partially effective. In addition, (-)-3-PPP partially antagonised the inhibitory action of apomorphine on the GBL-induced increase in DA synthesis rate. These findings suggest that (+)- and (-)-3-PPP act as full and partial agonists respectively, at striatal DA autoreceptors controlling DA synthesis.     

An electrophysiological analysis of the actions of the 3-PPP enantiomers on the nigrostriatal dopamine system

Summary Extracellular single unit recording and micro-iontophoretic studies were carried out in chloral hydrate-anesthetized and gallamine-paralyzed rats to investigate the actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, on the nigrostriatal DA system. Intravenously administered (+)-or (–)-3-PPP consistently inhibited nigral DA neuronal activity; these actions were readily antagonized by haloperidol but were not affected by a pretreatment of reserpine plus alpha-methyltyrosine. In contrast to (+)-3-PPP, the (–)-enantiomer produced only partial inhibition of the majority of cells studied and was also capable of partially reversing the inhibitory action of apomorphine. A prior hemitransection of the brain did not alter the inhibitory action of either enantiomer. Whereas iontophoretically ejected (+)-3-PPP consistently reduced DA cell firing rate, similarly applied (–)-3-PPP reduced the activity of only some DA cells, while the majority were not influenced. In addition, iontophoresis of (–)-3-PPP could reduce the inhibitory effect of similarly applied DA or (+)-3-PPP. The (+)-enantiomer reduced caudate neuronal activity both after intravenous administration and iontophoresis. Intravenously administered (–)-3-PPP failed to influence or increased the activity of these neurons and reversed the inhibitory action of apomorphine. However, iontophoretically ejected drug reduced caudate cell activity and did not influence the inhibitory action of DA. The activity of non-DA zona reticulata neurons was inconsistently influenced by the 3-PPP enantiomers. It is concluded that (+)-3-PPP is a directly acting DA agonist, stimulating both DA autoreceptors and postsynaptic DA receptors. In contrast, (–)-3-PPP appears to be a partial agonist at nigral DA autoreceptors, whereas the action of the drug at putative postsynaptic DA receptors in the caudate remains to clarified.     

The enantiomers of the D-2 dopamine receptor agonist N-0437 discriminate between pre- and postsynaptic dopamine receptors

The (+) and (-) enantiomers of the substituted 2-aminotetralin, N-0437 were evaluated in vivo for their dopaminergic activity, using biochemical as well as behavioural models. In presynaptic models, i.e. antagonism of gamma-butyrolactone-induced dihydroxyphenylalanine elevations and the induction of hypomotility, both enantiomers exhibited a similar high degree of potency. Following postsynaptic stimulation, (-)N-0437 was able to induce stereotypy in rats in a dose-dependent manner. Moreover this compound was able to produce rotation in 6-hydroxy-dopamine-lesioned rats. In contrast, at the doses tested (i.e. 1 and 10 mumol/kg, i.p.), (+)N-0437 displayed virtually no activity at all in either of these postsynaptic models. From in vitro evoked release studies of [3H]acetylcholine it became clear that (-)N-0437 is a postsynaptic dopamine agonist, while (+)N-0437 is a weak antagonist at these receptors. Taken together, the results indicate that (-)N-0437 is very selective for the stimulation of postsynaptic dopamine receptors, while (+)N-0437 stimulates presynaptic dopamine receptors and blocks postsynaptic receptors. These properties make (+)- and (-)N-0437 very promising candidates for psychotherapeutic use.     

Sexually differentiated actions of 3-PPP enantiomers on prolactin secretion

The ability of the enantiomers of the atypical dopamine receptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) to counteract gamma-butyrolactone-induced hyperprolactinemia was compared in male and female rats. Following gamma-butyrolactone (GBL) pretreatment serum prolactin concentrations were higher in female than in male rats. In males (-)-3-PPP tended to be somewhat less effective than (+)-3-PPP in decreasing serum prolactin concentrations (levels after (+)-3-PPP and (-)-3-PPP: 21% and 33%, respectively, of levels in GBL-pretreated control(s). In females the (-)-form induced a much weaker response than did the (+)-form (levels after (+)-3-PPP and (-)-3-PPP: 8% and 74%, respectively, of levels in GBL pretreated controls). Parallel experiments replacing GBL by reserpine yielded similar results. Data are discussed in terms of sex differences in responsiveness of pituitary dopamine receptors.     

Electrophysiological effects of the enantiomers of 3-PPP on neurons in the locus coeruleus of the rat

Extracellular single unit and microiontophoretic studies were carried out in rats, anesthetized with chloral hydrate, to investigate the actions of the enantiomers of the dopamine (DA) agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) on the firing rate of noradrenaline-containing neurons in the locus coeruleus (LC). Intravenously-administered (+)-3-PPP dose-dependently reduced firing of cells in the locus coeruleus with a 50% inhibition occurring after 2 mg/kg. This action was partially antagonized by the alpha 2-noradrenaline (NA) antagonist, yohimbine, but not by the DA antagonist haloperidol or the alpha 1-antagonist prazosin. Pretreatment with reserpine completely blocked the suppressant effect of (+)-3-PPP on firing rate. Iontophoretically-applied (+)-3-PPP did not influence the basal firing rate of cells in the locus coeruleus and failed to influence the inhibitory action of simultaneously-applied DA. Neither intravenously nor iontophoretically administered (-)-3-PPP influenced basal firing rate of neurones in the locus coeruleus. However, intravenously-administered drug weakly reversed the inhibitory action of the alpha 2-agonist clonidine (100 micrograms/kg) and iontophoretic ejection antagonized the inhibitory action of DA. These findings suggest that (-)-3-PPP possesses a weak antagonist action at alpha 2-adrenoceptors present in the locus coeruleus. In contrast, administration of (+)-3-PPP resulted in a weak activation of these receptors which was possibly the result of an enhanced release of NA.     

Agonist and antagonist interactions with D1 dopamine receptors: agonist-induced masking of D1 receptors depends on intrinsic activity.

The effects of agonist and antagonist compounds on the equilibrium binding of the D1 antagonist ligand [3H]SCH 23390 were examined in membranes from the striatum of the rat. The antagonist SK&F 83566 interacted with D1 receptors in the manner of a competitive antagonist, causing a decrease in the affinity of the binding of [3H]SCH 23390, without altering the maximum number of binding sites (Bmax). The interaction of agonist compounds with the D1 receptor appeared to be more complex. The drug SK&F 75670, a weak partial agonist, also acted competitively at D1 sites. However, agonists with moderate (SK&F 38393, CY 208-243) or full (dopamine) intrinsic activity to stimulate adenylate cyclase, interacted with D1 binding sites in a mixed competitive/non-competitive manner, causing both a decrease in ligand affinity and a decrease in Bmax. The benzazepine analogue, which also has full agonist activity, SK&F 82958, only caused a reduction in Bmax. Furthermore, there was a positive relationship between the intrinsic activity of agonists and the magnitude of the reductions in Bmax which they induced. In the presence of the GTP analogue, Gpp(NH)p, CY 208-243 no longer caused an apparent reduction in the number of receptors. These data suggests that the apparent loss of D1 receptors, induced by agonists, may result from an interaction with a guanine-nucleotide sensitive, high affinity agonist binding site and that the degree of interaction with this site depends on the intrinsic D1 activity of the agonist.     

Multiple postsynaptic dopamine receptors and behavioral manifestation

Previously we demonstrated the existence of non- and positive-cooperative dopamine receptors in rat striatum in [3H] apomorphine binding experiments. Non-cooperative sites were sensitive to the inhibition of sulpiride while cooperative sites were not. In the present study results dealing with the involvement of those two types of postsynaptic dopamine receptors in different behavior manifestations is shown employing lisuride hydrogen maleate (LHM). LHM elicited contralateral turnings in 6-hydroxydopamine lesioned rats unilaterally in the striatum whereas it caused ipsilateral turnings in kainic acid lesioned rats as was observed following the administration of apomorphine. Furthermore, the effect of LHM on rotating behavior was abolished by the pretreatment with sulpiride. On the other hand, LHM inhibited apomorphine induced stereotyped behavior whereas the sulpiride failed to block it. These results suggested the dual action of LHM on multiple postsynaptic dopamine receptors. The results also indicated that non-cooperative postsynaptic dopamine receptors are involved in rotating behavior while cooperative receptors participate in the elicitation of stereotypy.     

Dopaminergic agents including 3-PPP and its enantiomers on medial septal self-stimulation

The effects of several dopamine agonists were determined on medial septal self-stimulation in rats and compared with selected dopamine antagonists and with the psychostimulants, d-amphetamine and nomifensine. Apomorphine, 3-PPP, TL-99, N,N-dipropyl-5,6-ADTN and N,N-dipropyl-6,7-ADTN inhibited self-stimulation at dose ranges selective for the dopamine autoreceptor as indicated by biochemical studies. Haloperidol and molindone produced dose-related inhibition but sulpiride increased self-stimulation. D-amphetamine and nomifensine also increased responding. The agonist-induced inhibition differed from neuroleptic-induced inhibition of self-stimulation. Both (+) and (-) 3-PPP inhibited responding by a similar amount over the dose range 0.25-1.0 mg/kg. At higher doses, (-) 3-PPP further decreased responding whereas the effects of (+) 3-PPP plateaued at approximately 55% of controls. These studies show that dopamine agonists, like neuroleptics, inhibit medial septal self-stimulation. This effect appears to be mediated via autoreceptor activation. Differences between neuroleptic- and agonist-induced inhibition and the 3-PPP stereoisomer data accord with the hypothesis that behavioural inhibitory effects caused by autoreceptor activation are less severe than those caused by dopamine postsynaptic blockade.