Excitation by dopamine D-2 receptor agonists, bromocriptine and LY 171555, in caudate nucleus neurons activated by nigral stimulation

Electrophysiological studies using cats anesthetized with alpha-chloralose were carried out to determine whether or not the dopamine D-2 receptor mediates the excitation of the caudate nucleus (CN) neurons activated by stimulation of the substantia nigra (SN). Microiontophoretic application of domperidone (D-2 antagonist) produced a significant inhibition of spikes elicited by SN stimulation in 20 of 27 CN neurons. When bromocriptine and LY 171555 (D-2 agonists) were iontophoretically applied to the CN neurons in which the SN-induced spikes were inhibited by domperidone, an increase in spontaneous firing rate was observed in 18 of 20 neurons and all of 10 neurons tested, respectively. However, no alterations of firing occurred with bromocriptine or LY 171555 in any 7 neurons in which the SN-induced spikes were not affected by domperidone. The increase in firing rate by the D-2 agonists was apparently antagonized during simultaneous application of domperidone and haloperidol, but not affected during application of SCH 23390 (D-1 antagonist). These results strongly suggest that the spike generation of the CN neurons upon SN stimulation is mediated by the dopamine D-2 receptor.     

Dopamine D-2 receptor-mediated excitation of caudate nucleus neurons from the substantia nigra

Microiontophoretic studies using cats anesthetized with alpha-chloralose were performed to elucidate whether the excitatory response of caudate nucleus (CN) neurons upon stimulation of the pars compacta of the substantia nigra (SN) is mediated by the dopamine D-1 or D-2 receptor. There were rare convergent inputs from the SN and motor cortex (MC) in the CN neurons. Iontophoretic application of haloperidol and domperidone (dopamine D-2 receptor antagonist) produced dose-dependent inhibition of spikes elicited by SN stimulation in 25 of 42 and 50 of 82 CN neurons, respectively, however, no alterations of spikes elicited by MC stimulation occurred in any 11 neurons tested. Iontophoretically applied SCH 23390 (D-1 antagonist) did not inhibit the SN-induced spikes in any CN neurons, of which spikes were inhibited by domperidone. These results suggest that the SN-induced spikes are mediated by dopamine, which acts on postsynaptic D-2 receptors.     

The discriminative stimulus properties of the D-1 agonist SK&F 38393 and the D-2 agonist (-)-NPA are mediated by separate mechanisms

The dopamine D-1 agonist SK&F 38393 (10 mg/kg) the D-2 agonist (-)-NPA (0.04 mg/kg) and d-amphetamine (1.0 mg/kg) were established as discriminative stimuli versus saline in rats. The stimulus induced by SK&F 38393 was stereoselective, since the R-(+)-, but not the S-(-)-enantiomer was effective. It was mimicked by two partial D-1 agonists with central effects, SK&F 75670 and Lu 24-040, but not by the peripheral agonist fenoldopam. D-2 agonists and d-amphetamine were ineffective. The effect of SK&F 38393 was antagonized by SCH 23390, but not by its inactive enantiomer SCH 23388 or by the D-2 antagonist YM 09151-2. The (-)-NPA stimulus was dependent on postsynaptic D-2 receptors: It was mimicked by quinpirole and pergolide in stimulant dosages, whereas the partial D-2 agonist (-)-3-PPP inhibited the effect of (-)-NPA. The dopamine synthesis inhibitor alpha-methyl-p-tyrosine did not antagonize the effect of (-)-NPA. Likewise, the above-mentioned D-1 agonists produced saline responding. D-amphetamine produced partial substitution to (-)-NPA. The (-)-NPA stimulus was blocked by YM 09151-2, but not by SCH 23390. In d-amphetamine-trained rats, quinpirole, (-)-NPA and pergolide produced generalization, whereas SK&F 38393 was ineffective. Both SCH 23390 and YM 09151-2 antagonized the effect of d-amphetamine. It is concluded that the cues induced by SK&F 38393 and (-)-NPA are mediated by separate D-1 and D-2 sites, whereas both sites contribute to the effect of d-amphetamine.     

Functional antagonism of D-1 and D-2 dopaminergic mechanisms affecting striatal acetylcholine release

Rat striatal slices prelabelled with [3H]choline were superfused with dopamine D-1 and D-2 agonists and antagonists, separately and in combination, during measurement of [3H]acetylcholine (ACh) release. SKF38393 (D-1 agonist), 10(-7)-10(-4) M, and SCH23390 (D-1 antagonist), 10(-7)-10(-5) M, produced a dose-dependent increase in [3H]ACh release when given separately. The increased [3H]ACh release induced by either drug could not be attenuated by sufficient L-sulpiride to block D-2 receptors. Yet both SKF38393, 10(-6)-10(-5) M, and SCH23390, 10(-6)-10(-5) M, were able to partially or fully overcome the [3H]ACh release-depressant effect of cosuperfused LY171555 (D-2 agonist), 10(-6) M. This suggests that a functional antagonism regarding striatal ACh release exists between D-1 and D-2 dopaminergic receptor-mediated mechanisms, but that D-1 modulation of local ACh release does not occur at the level of the recognition site of the striatal D-2 receptor. Finally, although attenuation of the increased release of striatal [3H]ACh induced by 10(-5) M SCH23390 by SKF38393 was seen, it is possible that such functional antagonism is not mediated by exclusively D-1 dopaminergic means.     

Behavioural expression of D-1 receptor supersensitivity depends on previous stimulation of D-2 receptors

SKF 38393 (2 mg/kg s.c.), a reportedly selective D-1 agonist, failed to induce contralateral turning behaviour in naive rats bearing 12 days old unilateral 6-hydroxydopamine lesions. On the other hand strong contraversive turning in response to SKF 38393 was obtained if rats had been tested 2 or 7 days before with apomorphine (0.1 mg/kg s.c.) or with LY 171555 (0.2 mg/kg s.c.), a selective D-2 receptor agonist. Contraversive turning in response to SKF 38393 was blocked by a low dose (0.05 mg/kg s.c.) of the specific D-1 antagonist SCH 23390. The results indicate that the behavioural expression of D-1 receptor supersensitivity following lesion of dopaminergic neurons depends on previous exposure to a stimulation of D-2 receptors.     

Influence of D-1 receptor system on the D-2 receptor-mediated hypothermic response in mice

The hypothermia induced by apomorphine, a mixed dopamine (DA) agonist in male Swiss-Webster mice, was not blocked by the selective D-1 antagonist SCH 23390 but was completely blocked by the selective D-2 antagonists haloperidol, sulpiride and YM-09151-2. The selective D-1 agonist SKF 38393 did not elicit hypothermic response but the selective D-2 agonist quinpirole caused a marked lowering of rectal temperature. D-2 antagonists blocked this response to quinpirole. SCH 23390 enhanced and SKF 38393 attenuated the hypothermia induced by quinpirole. Ineffective doses of haloperidol and SKF 38393, when given together, completely blocked the effect of quinpirole. It was concluded that hypothermia is a D-2 receptor mediated response but modulated by the D-1 receptor system. In another series of experiments the influence of neuroleptics and antidepressants on the hypothermic effect of apomorphine and quinpirole was investigated. The hypothermic effect of a low dose (1 mg/kg) of apomorphine was blocked by the D-2 receptor antagonists, but not by classical antidepressants. However, the response to a high dose (10 mg/kg) of apomorphine was blocked by both classical antidepressants and D-2 antagonists (except haloperidol). These drugs did not show similar effect on quinpirole-induced hypothermia. It is clear that the hypothermic response, especially that of quinpirole, is not a suitable model for testing either neuroleptics or antidepressants.     

Stimulation of dopamine D-1 receptors by SKF 38393 induces EEG desynchronization and behavioral arousal

The dopamine D-1 receptor agonist SKF 38393 dose-dependently (2.5-10 mg/kg) induced desynchronization of the electroencephalographic (EEG) activity and behavioral arousal in both rabbits and rats. Unlike apomorphine, SKF 38393 elicited no signs of stereotyped behavior in rabbits and minimal effects, such as episodes of grooming, in rats. The effects of SKF 38393 10 mg/kg on the EEG were prevented by the selective D-1 receptor antagonist SCH 23390 at a dose as low as 0.003 mg/kg, but not by the D-2 antagonist (-)-sulpiride (25-50 mg/kg). These data provide evidence of a role of D-1 receptors in the generation of EEG activity related to behavioral arousal. In addition, this model is a valuable tool to functionally evaluate the D-1 antagonistic properties of neuroleptics.     

Presynaptic inhibition of excitatory input from the substantia nigra to caudate nucleus neurons by a substituted quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392)

The effects of a newly synthesized quinolinone derivative, 7-[3-(4-(2,3-dimethylphenyl)piperazinyl) propoxy]-2(1H)-quinolinone (OPC-4392) on neuronal activities of the caudate nucleus (CN) were investigated in cats anesthetized with alpha-chloralose using a microiontophoretic method. In the CN neurons of which spikes elicited by stimulation of the pars compacta of substantia nigra (SN) were suppressed by iontophoretically applied domperidone, a dopamine D-2 receptor antagonist, application of OPC-4392 (100-200 nA) inhibited the spike generation induced by SN stimulation. Conversely, the CN neurons insensitive to domperidone were unaffected by OPC-4392. Iontophoretic application of CPC-4392 up to 200 nA did not affect glutamate-induced firing of the CN neurons, of which the firing was blocked by dopamine less than 100 nA. In addition, OPC-4392 did not inhibit firing induced by bromocriptine, a dopamine D-2 agonist; while domperidone suppressed the bromocriptine-induced firing without affecting the glutamate-induced firing. These results suggest that OPC-4392 acts on the dopaminergic nerve terminals and inhibits excitatory transmission from the SN to the CN.     

Pharmacologic evidence for direct dopaminergic regulation of striatal acetylcholine release

This study was done to provide pharmacologic evidence for the location of those striatal dopamine D-1 and D-2 receptors that participate in the regulation of local acetylcholine (ACh) release. Striatal tissue slices from adult male Sprague-Dawley rats were preloaded with [3H]choline and superfused in separate experiments with buffer containing either: a D-2-specific agonist (LY141865 or LY171555), a D-2 specific antagonist (L-sulpiride), a D-1 specific agonist (SKF38393), or a D-1 antagonist (SCH23390), in the presence or absence of tetrodotoxin (TTX), used to block interneuronal activity. With either D-2 agonist there was a dose-dependent decrease in K+-stimulated [3H]ACh release, maximally at 5 X 10(-7)-10(-6) M [agonist] and to the same extent with each drug. Both SKF38393 and SCH23390 increased [3H]ACh release at tested concentrations of these agents. Results were unchanged when any of the drugs used was superfused in the presence of TTX, 5 X 10(-7) M. These data are consistent with the hypothesis that populations of striatal D-1 and D-2 receptors exist on local cholinergic neurons, where they regulate ACh release. Alternative interpretations are discussed.     

D-1 dopamine agonist administration reduces the threshold for convulsions produced by pilocarpine

Focal, limbic seizures were produced by systemically administered pilocarpine (200 mg/kg, i.p.); as previously described this dose produces limbic stereotypies but neither convulsions nor seizure-related brain damage. The pretreatment, 5 minutes prior pilocarpine, with the D-1 agonist SKF 38393 (-ED50 = 1 mg/kg; i.p.) induced convulsions similar to those produced by a higher, convulsant dose of pilocarpine. On the other hand, the pretreatment with the D-2 agonist LY 171555 failed to induce convulsions. The D-1 receptor antagonist SCH 23390 prevented the convulsions induced by SKF 38393 plus pilocarpine (200 mg/kg). This study indicates that D-1, but not D-2, receptor stimulation converts subconvulsant doses of pilocarpine into convulsant ones.     

μ-Opioid Receptors Mediate the Inhibitory Effect of Opioids on Dopamine-Sensitive Adenylate Cyclase in Primary Cultures of Rat Neostriatal Neurons

The receptors mediating the inhibition of D1 dopamine receptor-stimulated adenylate cyclase by opioids were examined in primary cultures of rat neostriatal neurons. Adenylate cyclase activity was dose-dependently increased by the selective D1 dopamine receptor agonist SKF 38393 (EC50 = 0.05 microM). This stimulation was fully antagonized by the selective D1 dopamine receptor antagonist SCH 23390 (1 microM). SKF 38393 (1 microM)-stimulated adenylate cyclase activity was strongly reduced (by almost 60%) by the highly selective mu-agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO; EC50 = 0.006 microM) and high concentrations of the selective delta-agonist [D-Ser2(O-tert-butyl), Leu5]-enkephalyl-Thr6 (DSTBU-LET; EC50 = 0.13 microM) but not by the selective delta-agonist [D-penicillamine2, D-penicillamine5]enkephalin (DPDPE). D1 dopamine receptor-stimulated adenylate cyclase activity was also slightly reduced (by approximately 20%) by high concentrations of the kappa-agonist U50,488 (EC50 = 0.63 microM). The inhibitory effects of submaximally effective concentrations of DAGO, DSTBULET, and U50,488 were equally well antagonized by the mu-opioid receptor-selective antagonist naloxone (EC50 of approximately 0.1 microM). Neither the irreversible delta-ligand fentanyl isothiocyanate (1 microM) nor the reversible delta-antagonist ICI 174864 (1 microM) reversed the inhibitory effects of DSTBULET. The inhibitory effects of DAGO and U50,488 were equally well reversed by high concentrations (greater than 0.1 microM) of the kappa-opioid receptor-selective antagonist norbinaltorphimine. The effect of DAGO (1 microM) was already detectable after 1 day in culture, whereas DPDPE (1 microM) had no effect even after 28 days in culture. These data indicate that an homogeneous population of mu-opioid receptors coupled as inhibitors to D1 dopamine receptor-stimulated adenylate cyclase is expressed in rat neostriatal neurons in primary culture.     

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.     

SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models

SCH 23390 induced only a negligible incidence of the acute dyskinetic syndrome, a predictor of neuroleptic-induced extrapyramidal liability, in squirrel monkeys. However, haloperidol-induced dyskinesias were potentiated by SCH 23390 and were blocked by the D-1 agonist, SKF 38393. When administered orally or intraperitoneally to mice, SCH 23390 showed a considerably wider dose separation than did conventional neuroleptics between antagonism of apomorphine climbing and antagonism of stereotyped sniffing. Clinically relevant distinctions may exist between D-1 and D-2 antagonists, with D-1 antagonists (exemplified by SCH 23390) showing lower, although possibly not negligible, potential to cause extrapyramidal side effects.     

Binding of [3H]SKF 38393 to Dopamine D-l Receptors in Rat Striatum In Vitro; Estimation of Receptor Molecular Size by Radiation Inactivation

[3H]SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) binds with high affinity to 3,4-dihydroxyphenylethylamine (dopamine) D-1 receptors in rat striatum in vitro (KD = 7 and 14 nM in nonfrozen and frozen striatum, respectively). The number of binding sites (Bmax) was approximately 80.0 pmol/g of original tissue, a value similar to the Bmax for the dopamine D-1 antagonist SCH 23390. Nondisplaceable [3H]SKF 38393 binding was approximately 45% of total binding. Irradiation (0-4 Mrad) of frozen whole striata decreased the number of [3H]SKF 38393 binding sites monoexponentially without changing the binding affinity. The functional molecular mass for the agonist dopamine D-1 binding site was 132,800 daltons, which is higher than the functional molecular mass of the antagonist dopamine D-1 binding site (approximately 80,000 daltons).     

Interactions of novel dopaminergic ligands with D-1 and D-2 dopamine receptors

The interactions of three novel dopaminergic ligands, SKF38393, SKF82526 and SKF83742, with D-1 and D-2 dopamine (DA) receptors have been investigated using radioligand binding techniques and computer modeling procedures. Using the bovine anterior pituitary D-2 DA receptor system, SKF38393 and SKF82526 behave as agonists demonstrating biphasic agonist/3H-antagonist competition curves. For both drugs, the high affinity phase comprised 30% of the total displacement curve. Such findings are atypical as previously tested classical dopamine agonists demonstrated high and low affinity displacement phases in equal proportions. Such behavior exhibited by the SKF agonists may be related to their activity as partial agonists. In contrast, SKF83742 behaves as an antagonist exhibiting homogeneous monophasic competition curves. Similar results are obtained in the rat striatal membrane D-2 DA receptor system. Both SKF38393 and SKF82526 also demonstrate shallow biphasic displacement curves on rat striatal D-1 receptors labeled with 3H-flupentixol whereas SKF83742/3H-flupentixol curves are uniphasic. Of all the ligands, only SKF38393 clearly demonstrates higher affinity for 3H-flupentixol labeled D-1 receptors.     

Forskolin Potentiates the Stimulation of Rat Striatal Adenylate Cyclase Mediated by D-1 Dopamine Receptors, Guanine Nucleotides, and Sodium Fluoride

We report here that forskolin acts in a synergistic manner with dopaminergic agonists, guanine nucleotides, or sodium fluoride to potentiate the stimulation of rat striatal adenylate cyclase mediated by these reagents. In the presence of 100 microM GTP, 100 microM guanyl-5'-yl imidodiphosphate [Gpp(NH)p], or 10 mM NaF, there is a greater than additive increase in forskolin-stimulated enzyme activity as well as a concomitant decrease (two- to fourfold) in the EC50 value for forskolin stimulation of striatal enzyme activity. In the presence of various concentrations of forskolin (10 nM-100 microM), the stimulation of adenylate cyclase elicited by GTP, Gpp(NH)p, and NaF is potentiated 194-1,825%, 122-1,141%, and 208-938%, respectively, compared with the stimulation by these agents above basal activity in the absence of forskolin. With respect to 3,4-dihydroxyphenylethylamine (dopamine) receptor-mediated stimulation of striatal enzyme activity, the stimulation of enzyme activity by dopaminergic agonists, in the absence or presence of forskolin, was GTP-dependent and could be antagonized by the selective D-1 antagonist SCH23390 (100 nM), indicating that these effects are mediated by D-1 dopamine receptors. In the presence of 100 microM GTP, forskolin at various concentrations markedly potentiates the stimulation elicited by submaximal as well as a maximally effective concentrations of dopamine (100 microM) and SKF38393 (1 microM). At higher concentrations of forskolin (10-100 microM) the stimulation elicited by the partial agonist SKF38393 is comparable to that of the full agonist dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack or Inhibition of Dopaminergic Stimulation Induces a Development Increase of Striatal Tyrosine Hydroxylase-Positive Interneurons

We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH⁺) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl-p-tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH⁺ neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH⁺ neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH⁺ neurons. A single i.p. injection of the D1 receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH⁺ neurons after 4 days. Treatment with the D1-like receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH⁺ neurons. At least the effects of {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 were prevented by a combined treatment with {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393. Immunohistochemical analysis indicated that striatal TH⁺ neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH⁺ neurons. The evidence that DHβE mimicked the action of {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 in increasing the number of TH⁺ neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH⁺ neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH⁺ neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.     

Attenuation of D-1 antagonist-induced D-1 receptor upregulation by concomitant D-2 receptor blockade

The effect of chronic selective D-1 and/or D-2 dopamine receptor blockade on regional D-1 receptor binding was studied in rat brain following chronic treatment with the specific D-1 antagonist SCH 23390 and/or the predominantly D-2 antagonist haloperidol. D-1 receptor density and affinity were evaluated by quantitative autoradiography using 125I-SCH 23982. Chronic SCH 23390 treatment increased D-1 receptor density by 30 to 40% in the striatum, accumbens and tuberculum olfactorium; receptor affinity remained unchanged. Haloperidol had no effect on D-1 receptor Bmax or Kd values, although, when administered with SCH 23390, reduced the D-1 receptor upregulation induced by the D-1 antagonist in striatum and tuberculum olfactorium, but not in nucleus accumbens. These results may be attributable to D-1/D-2 dopamine receptor interactions occurring in the striatum and tuberculum olfactorium and may have implications for the prevention and treatment of drug-induced extrapyramidal disorders.     

Identification of D1-like dopamine receptors on human blood platelets

Dopamine is able to inhibit the epinephrine-induced aggregation of human blood platelets, but the mechanism of action has not been elucidated. In this study we report that membranes from human blood platelets possess high affinity, saturable and stereoselective binding sites for the D1 dopamine receptor antagonist (3H) SCH 23390. (3H) SCH 23390 appeared to label a single class of binding sites with a Bmax of 18.6 +/- 1.6 fmol/mg protein and a KD of 0.8 nM. The potencies of different dopaminergic antagonists and agonists in displacing (3H) SCH 23390 from blood platelet membranes were similar to those obtained for striatal membranes. Unlike the classically defined D1 receptors, e.g. those in striatum, the D1 receptor sites on platelets appeared not to be coupled to the adenylate cyclase system, hence the term "D1-like". The D1 agonist SKF 38393 was more potent than dopamine in inhibiting platelet aggregation induced by epinephrine, and the effects of dopamine and SKF 38393 were prevented by SCH 23390. These results suggest that the inhibitory action of dopamine on the epinephrine-induced platelet aggregation is mediated through these D1-like receptors.     

Selective depletion of dopamine in the goldfish pituitary caused by domperidone.

The effects of the dopamine type-2 receptor (D-2) antagonist domperidone on pituitary and brain amine concentrations and serum gonadotropin levels in the goldfish were investigated. Domperidone caused a long-lasting, dose-dependent depletion of dopamine in the goldfish pituitary. Pituitary concentrations of 5-hydroxytryptamine (5HT) were unaffected by domperidone treatment. Concentrations of noradenaline, dopamine, and 5HT in the hypothalamus and telencephalon were also unaffected by domperidone treatment. In contrast to the goldfish, dopamine levels in both mouse pituitary and hypothalamus were unaffected by domperidone treatment. The depletion of dopamine was observed in both sexually regressed and recrudescent, male and female fish, but elevation of serum gonadotropin levels in response to domperidone treatment occurred only in sexually recrudescent fish. Treatment of sexually recrudescent fish with the D-2 antagonists pimozide, (-)-sulpiride and eticlopride and the dopamine type-1 (D-1) antagonists SKF 83566 and SCH 23390 failed to elicit a depletion of pituitary dopamine or elevation of serum gonadotropin. Treatment of sexually recrudescent fish with domperidone, alpha-methyl-p-tyrosine or carbidopa elicited comparable depletions of pituitary dopamine and elevations of serum gonadotropin. The results suggest that in addition to D-2 receptor antagonist activity, domperidone has some other neuropharmacological action on dopaminergic neurones in the goldfish pituitary.