Dopamine (DA) autoreceptor efficacy of 3-PPP enantiomers after short-term synaptic DA deprivation

doi:10.1016/0014-2999(88)90715-7

European Journal of Pharmacology

Volume 152, Issue 3, 2 August 1988, Pages 207-215

https://doi.org/10.1016/0014-2999(88)90715-7 Get rights and content

Abstract

We have compared the central dopamine (DA) autoreceptor-stimulatory properties of the ‘atypical’ DA agonist, (-)-3-PPP, its (+)-antipode and the reference DA agonist, apomorphine, following a 5 or an 18 h interruption of synaptic dopaminergic transmission by means of reserpine. The results are consistent with the notion that even a relatively short period (18 h) of synaptic DA deprivation results in a functional ‘supersensitivity’ of central DA synthesis-modulating autoreceptors. Interestingly, the data demonstrate a clearcut and significant enhancement of the intrinsic agonist efficacy of (-)-3-PPP in limbic and striatal parts after an 18 h as compared to a 5 h reserpine-induced impairment of synaptic DA transmission. In addition, there was a tendency towards a reduction in the doses of apomorphine and the 3-PPP enantiomers needed to inhibit DA synthesis in 18 vs. 5 h reserpinised rats in both brain regions. The findings indicate that the adaptive state of the DA autoreceptors had been altered, tentatively as a result of the reduced (endogenous) agonist occupancy. This is consistent with the suggestion that DA autoreceptors are influenced by a certain, albeit presumably low, endogenous dopaminergic tone under in vivo physiological conditions. The data obtained provide further support for the contention that receptor responsiveness is a critical determinant of the intrinsic efficacy displayed by DA receptor agonists such as (-)-3-PPP.

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Pre- and postsynaptic actions of a partial D2 receptor agonist in reserpinized young rats: Longevity of agonistic effects
2006, Brain Research
Citation Excerpt :
The ability of partial D2 agonists to increase dopamine synthesis and reverse the quinpirole-induced inhibition of DOPA accumulation is evidence of their antagonistic effects at normosensitive D2 autoreceptors (Baldessarini et al., 1994; Clark et al., 1991a; Hjorth et al., 1983; Kehr, 1984; Svensson et al., 1991, 1993; Yoshida et al., 2006). That partial D2 agonists exhibit antagonistic effects at postsynaptic dopamine receptors is also well documented, because terguride and preclamol block cocaine-, amphetamine-, and apomorphine-induced behaviors of young (Arnt, 1983; McDougall et al., 2005; Sibole et al., 2003) and adult rodents (Arnt and Hyttel, 1990; Clark et al., 1991b; Hjorth et al., 1983, 1988; Izzo et al., 2001; Kohler and Herbster, 1987; Oshiro et al., 1998; Pulvirenti et al., 1998; Wachtel and Dorow, 1983). During states of low dopaminergic tone, partial D2 agonists induce agonist-like effects in preweanling and adult rats.
Partial D2 receptor agonists (e.g., terguride, preclamol, and aripiprazole) have antagonist-like effects at normosensitive D2 postsynaptic receptors and synthesis modulating autoreceptors. In reserpine-pretreated adult and young rats, however, partial D2 agonists function like high efficacy agonists at D2 postsynaptic receptors and autoreceptors (i.e., terguride increases locomotor activity and decreases dopamine synthesis). The purpose of the present study was to examine the time-course of these pharmacological effects. In all experiments, preweanling rats were given daily injections of reserpine (1 mg/kg, i.p.) or vehicle on postnatal day (PD) 16–PD 20. In the dopamine synthesis experiments, the ability of terguride (0.8 mg/kg) to reduce striatal DOPA accumulation (in NSD-1015 treated rats) was assessed either 5 h or 1, 2, 4, or 8 days (Experiment 1) or 4, 8, 12, 16, 20, or 24 days (Experiment 2) after reserpine pretreatment. In the behavioral experiments, locomotor activity of vehicle or terguride (0.8 mg/kg, i.p.) treated rats was assessed 5 h or 1, 2, 4, or 8 days after the 5-day reserpine regimen. Results from the dopamine synthesis experiments showed that terguride caused agonist-like effects (i.e., decreased DOPA accumulation) at only the 5 h and 1 day time points, although terguride did not induce its normal antagonist-like effects even 20 days after reserpine pretreatment. In the behavioral experiments, terguride stimulated locomotor activity for only the initial 2 days after reserpine pretreatment. The results of the present study show that the agonistic effects of terguride at pre- and postsynaptic receptors are short-lived, but terguride may not exhibit normal antagonistic effects, at least at synthesis modulating autoreceptors, until long after conclusion of reserpine pretreatment.
Effects of a partial D<inf>2</inf>-like receptor agonist on striatal dopamine autoreceptor functioning in preweanling rats
2006, Brain Research
Citation Excerpt :
Specifically, terguride reduced DOPA accumulation to levels similar to those produced by the D2-like agonist quinpirole. Similar effects have been reported in adult rats (Svensson et al., 1991), although full agonists are sometimes found to have greater intrinsic efficacy than partial agonists after reserpine treatment (Hjorth et al., 1988). Interestingly, reserpine treatment blunted the autoreceptor-mediated effects of haloperidol.
There is evidence that partial D₂-like dopamine agonists (e.g., terguride) may not affect D₂-like postsynaptic receptors in an adult-typical manner during the preweanling period. To determine whether synthesis modulating dopamine autoreceptors are also affected in an adult atypical manner by partial D₂-like agonists, preweanling rats were treated either acutely or repeatedly with reserpine (low dopaminergic tone) or vehicle (high dopaminergic tone). The ability of terguride, quinpirole (a full D₂-like agonist), or haloperidol (a D₂-like antagonist) to alter striatal DOPA accumulation was assessed after NSD-1015 treatment on postnatal day (PD) 21. In a separate set of experiments, terguride's ability to modulate dopamine synthesis was assessed in rats treated with the nerve impulse flow inhibitor γ-butyrolactone (GBL). Results showed that both terguride and quinpirole reduced striatal DOPA accumulation during a state of low dopaminergic tone (i.e., after reserpine pretreatment). During a state of high dopaminergic tone (i.e., after vehicle pretreatment), terguride had similar effects as haloperidol and increased DOPA accumulation. Terguride, like quinpirole, partially inhibited the GBL-induced increase in striatal DOPA accumulation. When considered together, these results indicate that synthesis modulating D₂-like autoreceptors are functional during the late preweanling period, and they respond in an adult-typical manner to a partial D₂-like agonist.
Motor effects of a dopamine stabilizer (GMC1111) in primate models of Parkinson and hemiparkinsonism
2003, European Journal of Pharmacology
The effects on motor behavior of a new potential dopamine stabilizer: 2-amino-6-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (GMC1111) were investigated in common marmosets with 6-hydroxydopamine lesions within the median forebrain bundle (12 unilateral, 6 bilateral). GMC1111 was administered orally or subcutaneously (s.c.) to unilaterally 6-hydroxydopamine lesioned monkeys, either alone or together with s.c. injections of apomorphine (0.2 mg/kg) and the effect on rotational behavior was examined. GMC1111 (0.03–3.0 mg/kg) alone, orally or s.c., did not induce rotational behavior. When apomorphine and GMC1111 were injected simultaneously, rotations were nearly abolished in three monkeys with a baseline apomorphine-induced rotation rate below 13/min, whereas GMC1111 did not modify the rotations in three high-rotating animals (>17/min). Oral administration of GMC1111 (1.0 and 3.0 mg/kg) abolished the apomorphine-induced rotations in another six unilaterally dopamine-denervated monkeys, indicating a good oral bioavailability. A low dose of GMC1111 (0.3 mg/kg) administered s.c. to marmosets with bilateral nigrostriatal lesions produced a reduction of Parkinson symptoms of approximately the same degree as with levodopa/benserazide (15/3.75 mg/kg), while higher doses of GMC1111 were less effective. When levodopa/benserazide was administered together with various doses of GMC1111 (0.3–3.0 mg/kg), the levodopa-induced peak-dose dyskinesias were reduced with the highest dose of GMC1111 (3 mg/kg). Taken together, GMC1111 modifies dopaminergic activity in a normalizing direction. Parkinson symptoms, as well as levodopa-induced dyskinesias are both reduced. This suggests the arrival of another member of the new dopamine stabilizer family.
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  1. Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.
- 2.
  2. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS.
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Brexpiprazole I: In vitro and in vivo characterization of a novel serotonin-dopamine activity modulator
2014, Journal of Pharmacology and Experimental Therapeutics
Cariprazine (RGH-188), a dopamine D<inf>3</inf> receptor-preferring, D <inf>3</inf>/D<inf>2</inf> dopamine receptor antagonist-partial agonist antipsychotic candidate: In vitro and neurochemical profile
2010, Journal of Pharmacology and Experimental Therapeutics

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¹: Present address: Neuropsychopharmacol. Lab., Dept. of Psychology, Univ. of Reading, Reading, England.

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Dopamine (DA) autoreceptor efficacy of 3-PPP enantiomers after short-term synaptic DA deprivation

Abstract

European J. Pharmacol.

J. Neural Transm.

Life Sci.

European J. Pharmacol.

European J. Pharmacol.

Brain Res.

J. Chromatogr.

Brain Res.

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

Psychopharmacology

Postsynaptic dopamine agonistic effects of 3-PPP enantiomers revealed by bilateral 6-hydroxy-dopamine lesions and by chronic reserpine treatment in rat

J. Neural Transm.

Presynaptic dopamine receptors: Insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol

Naunyn-Schmiedeb. Arch. Pharmacol.

Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain

Science

Dopamine agonists: Intrinsic activity vs. state of the receptor

J. Neural Transm.

Pharmacological properties of presynaptic dopamine receptor agonists

Effect of reserpine on monoamine synthesis and on apparent dopaminergic receptor sensitivity in rat brain