Classical Dopamine Receptor Research Articles

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

The loss of dopamine (DA) in Parkinson’s is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

Dopamine inhibition of glycine release in the rat trigeminal nucleus pars caudalis: possible involvement of trace amine receptors

Dopamine (DA)-induced pre-synaptic inhibition of glycinergic transmission was studied from substantia gelatinosa (SG) neurons of the trigeminal nucleus pars caudalis using a conventional whole-cell patch clamp technique. The action potential-dependent glycinergic inhibitory post-synaptic currents (IPSCs) were recorded from SG neurons in the presence of 3 mM kynurenic acid and 10 μM 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid HBr (SR95531). In these conditions, bath applied DA (100 μM) reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio, suggesting that DA acts pre-synaptically to reduce the probability of glycine release. However, the inhibitory action of DA on glycinergic IPSCs was not blocked by SCH23390 (10 μM) and spiperone (1 μM), selective D(1) - and D(2) -like receptor antagonists, respectively. In addition, either SKF38393 (100 μM), a selective D(1) -like receptor agonist, or quinpirole (100 μM), a selective D(2) -like receptor agonist, had no pre-synaptic effect on glycinergic IPSCs. The results suggest that both D(1) - and D(2) -like receptors are not involved in the DA-induced decrease in glycinergic IPSCs. On the other hand, tyramine (100 μM), one of representative trace amines, reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio, suggesting that tyramine acts pre-synaptically to reduce the probability of glycine release. Considering that DA can activate trace amine (TA) receptors and that TA receptors are exclusively expressed on the trigeminal nucleus pars caudalis, DA might act on putative pre-synaptic TA receptors, rather than classical DA receptors, to inhibit glycinergic transmission onto SG neurons of the trigeminal nucleus pars caudalis.

Activation of Phosphatidylinositol-Linked D1-Like Receptor Modulates FGF-2 Expression in Astrocytes via IP3-Dependent Ca2+ Signaling

Fibroblast growth factor-2 (FGF-2) is predominantly synthesized and secreted by astrocytes in adult brain. Our previous study showed that activation of classical dopamine receptor D(1) or D(2) elicits FGF-2 biosynthesis and secretion in astrocytes. Here, we report that astrocytic FGF-2 expression is also regulated by phosphatidylinositol (PI)-linked D(1)-like receptor. SKF83959, a selective PI-linked D(1)-like receptor agonist, upregulates the levels of FGF-2 protein in striatal astrocyte cultures in classical dopamine D(1) and D(2) receptor-independent manner. The conditional medium derived from SKF83959-activated astrocytes promoted the number of TH(+) neurons in vitro. Treatment of astrocytes with SKF83959 increased intracellular calcium in two phases. Inhibition of intracellular calcium oscillation by inositol 1,4,5-triphosphate (IP3) inhibitors blocked the SKF83959-induced increase in FGF-2 expression. Moreover, intraperitoneal administration of SKF83959 reversed l-methyl-4-phenyl-l,2,3,6-tetrahydropypridine (MPTP)-induced reduction in FGF-2 expression in both the striatum and ventral midbrain and resulted in marked protection of dopaminergic neurons from MPTP-induced neurotoxicity. These results indicate that IP3/Ca(2+)/calmodulin-dependent protein kinase is an uncharted intracellular signaling pathway that is crucial for the regulation of FGF-2 synthesis in astrocytes. PI-linked D(1)-like receptor plays an important role in the regulation of astrocytic FGF-2 expression and neuroprotection which may provide a potential target for the drug discovery in Parkinson's disease.

Dopamine receptor binding and quantitative autoradiographic study.

The central nervous system (CNS) dopamine system plays an important role in mediating the reinforcing effects of drugs of abuse (). In addition, dopamine receptors have been the principal target of drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. Until 1990, the dopamine receptor population in the brain and periphery was believed to consist of two subtypes, D1 and D2, which were distinguished by their pharmacology and coupling to signal transduction systems (for review see ref. ). D1 and D2 receptors exhibit similar distributions in brain with the highest densities in the striatum (for review see ref. ). A number of selective radioligands have been synthesized and extensively used to characterize the classical dopamine receptor subtypes. These radioligands include the D1-selective ligands [3H]SCH 23390 and [125I]SCH 23982. D2 receptor-selective ligands include the antagonists [3H]spiperone, [3H]YM 09151-2, and [125I]iodosulpiride and the agonists [3H]propylnorapomorphine and [3H]quinpirole.

Regulation of heme oxygenase-1 expression by dopamine in cultured C6 glioma and primary astrocytes

Heme oxygenase-1 (HO-1) is an inducible enzyme involved in heme catabolism, tissue iron homeostasis and the cellular response to oxidative stress. Elevated HO-1 expression in astrocytes has been observed in association with abnormal iron deposition and increased oxidative stress in Parkinson's disease (PD). Since HO-1 could contribute to these aspects of PD pathobiology we have investigated its regulation in cultured astrocytes and C6 glioma cells. Here we report that dopamine is a potent inducer of HO-1. This induction is not mediated by a classical dopamine receptor and is not mimicked by a range of catecholamines and dopamine metabolites. When the time-course of HO-1 expression was compared between dopamine and hemin, the latter induced the gene immediately while the former did so with a lag. This suggested two distinct signal transduction pathways. However, cycloheximide blocked both hemin- and dopamine-induced HO-1 expression, suggesting that both pathways may involve proteins with short half-lives. Ascorbic acid blocked dopamine induction of HO-1 but had no effect on hemin-induced expression. This suggested that dopamine may signal upstream of the unstable protein by producing pro-oxidant metabolites or byproducts. Inhibition of monoamine oxidases A or B or catechol- O-methyl transferase did not block HO-1 induction by dopamine, indicating that these enzymes were not converting dopamine to an active metabolite. These results suggest that dopamine, released or secreted from affected neurons, may trigger HO-1 expression in neighboring astrocytes. HO-1 and its metabolites could then contribute to the oxidative stress and iron deposition associated with PD.

Agonist and antagonist effects of apomorphine enantiomers on 5-HT 3 receptors

Direct effects of the enantiomers of the classical dopamine receptor ligand apomorphine on 5-HT 3 receptors were examined in N1E-115 neuroblastoma cells in whole-cell voltage clamp mode. R(−)-apomorphine (R(−)APO; 3–300 μM) evokes a small, transient inward ion current. At 30 μM, R(−)APO induces its maximum inward current, which is approximately 3% of the amplitude of the inward current induced by 10 μM 5-HT. The R(−)APO-induced current is completely and reversibly inhibited after superfusion of 50 nM of the selective 5-HT 3 receptor antagonist MDL 72222 and after desensitization of the 5-HT 3 receptors by 10 μM 5-HT. The results indicate that R(−)APO is a partial agonist at the 5-HT 3 receptor. R(−)APO (30 μM) evokes a depolarization of the membrane potential with an amplitude which is 26% of the 10 μM 5-HT-induced depolarization. In addition, the 5-HT-induced depolarization is reduced (from 29 to 15 mV) after prolonged exposure of the cell to R(−)APO. S(+)-apomorphine (S(+)APO; 3–300 μM) does not evoke an ion current. Instead, S(+)APO antagonizes the 5-HT 3 receptor with an IC 50 of 32 μM. The combined results indicate that enantiomers of apomorphine act directly on 5-HT 3 receptors, and suggest that the in vivo effects of apomorphine are partially attributable to a direct interaction with 5-HT 3 receptors.

The Role of Dopamine (D 2), α and β-adrenoceptor Receptors in the Decrease in Gastrointestinal Transit Induced by Dopamine and Dopamine-Related Drugs in the Rat

This study analyses the effects of dopamine receptor agonists and antagonists on rat gastrointestinal transit (GIT) in an attempt to identify the mechanisms involved. Dopamine (DA), apomorphine, quinpirole, bromocriptine and fenoldopam were given by subcutaneous (s.c.), intrathecal (i.t.), intracisternal (i.c.) and/or intraperitoneal (i.p.) routes. In general, DA (200 μg, i.t.), apomorphine (3, 5 and 10mg/kg, s.c.; or 10, 30 and 100 μg, i.t.), and bromocriptine (1, 5 and 10 mg/kg, s.c.) elicited decreases in gastrointestinal transit which were significantly antagonized by the D 2 receptor antagonists domperidone or alizapride (both 5 mg/kg, s.c.), but remained unaffected by the D 1 receptor antagonist SCH 23390 (5 mg/kg, s.c.). Similarly, DA (50, 100 and 200 μg, i.c.) and apomorphine (12 and 50 μg; i.c.) produced dose-dependent decreases in gastrointestinal transit amenable to blockade by the classical DA receptor antagonist haloperidol (10 μg, i.c.). The responses to apomorphine (3, 5 and 10 mg/kg, s.c.) were unaltered by 6-hydroxydopamine (100 mg/kg, i.p.)-induced sympathectomy but were antagonized by both propranolol (1 mg/kg, s.c.) and phentolamine (5 mg/kg, s.c.). Significantly, after bilateral (cervical) vagotomy, gastrointestinal transit was markedly reduced, but apomorphine (5 mg/kg, s.c.) apparently further reduced gastrointestinal transit. The D 1 agonists fenoldopam (5, 10 and 20 mg/kg, s.c.) significantly reduced GIT. Fenoldopam-induced antitransit effects were markedly modified by the D 1 receptor antagonist, SCH 23390 (5 mg/kg, s.c.); only the response induced by 5 mg/kg of fenoldopam was apparently antagonized by SCH 23390. The mixed D 2 and D 3 receptor agonist quinpirole (4 and 8 mg/kg, s.c.; or 8 mg/kg, i.p.; 200 μg, i.t.) did mimic DA eliciting significant reductions in gastrointestinal transit which, however, were not antagonized by domperidone (5 mg/kg, s.c.). Taken together, the present results support the contention that the decrease in rat gastrointestinal transit induced by DA and apomorphine may be mediated by an interaction with central and/or peripheral D 2 receptors. The presence of dopamine receptors (D 2) in the alimentary canal are strengthened by antitransit effect of fenoldopam and bromocriptine in the gastrointestinal tract.

NSD 1034: an amino acid decarboxylase inhibitor with a stimulatory action on dopamine synthesis not mediated by classical dopamine receptors.

The accumulation rates of 3,4'-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(DL-seryl)-2- (2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis.

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors.

N-alkylated and N,N-dialkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins were tested for central dopamine receptor antagonism using in vivo biochemical and behavioral models in rats. The di-methyl analogue showed a profile similar to classical dopamine receptor antagonists. It produced a marked hypomotility including catalepsy and a pronounced increase in dopamine synthesis rate. This compound also displaced DiPr-5, 6-ADTN from striatal binding sites and antagonized the hyperactivity induced by the ligand. In contrast, the mono-propyl analogue increased locomotor activity and dopamine synthesis rate over a wide dose range. This compound failed to antagonize the hyperactivity induced by DiPr-5, 6-ADTN and to displace this in-vivo binding ligand. Thus, the mono-propyl analogue appears to lack postsynaptic dopamine receptor antagonistic properties; it seems to produce its effects via a selective dopamine autoreceptor antagonism. The di-ethyl and di-propyl, but not the dibutyl, analogues were also active in the models used. Whereas the di-ethyl compound shows a profile similar to classical dopamine receptor blockers, the di-propyl compound appears to act preferentially on autoreceptors.

Possible dissociation of central dopamine receptor antagonism and cataleptic behavior

A new chemical, 2-[4-[4-(7,9-dioxo-6-thia-8-azaspiro[4.4] nonan-8-yl)-butyl]-1-piperazinyl]pyridine-3-carbonitrile hydrochloride (MJ-13980-1), referred to in this report as MJ-13980, displaced in vitro [ 3H]spiperone binding, elevated serum prolactin concentrations, and decreased apomorphine-induced stereotyped behavior in male rats. These actions indicated that MJ-13980 acts as a dopamine (DA) receptor antagonist. However, MJ-13980 (10 mg/kg) elicited only a very small amount of cataleptic behavior and antagonized that produced by haloperidol (HAL), a classical DA receptor blocker and potent inducer of cataleptic behavior. At a lower dose, MJ-13980 (1.0 mg/kg) produced no cataleptic behavior but again decreased that produced by HAL. These results suggest that the antagonistic interaction of MJ-13980 at central DA receptors is not associated with the production of cataleptic behavior.

Resolved 3-(3-hydroxyphenyl)-N-n-propylpiperidine and its analogues: central dopamine receptor activity.

Seven enantiomeric pairs of N-alkyl analogues of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) have been synthesized and evaluated pharmacologically (biochemistry and behavior) in order to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulkier than n-propyl. Likewise, the S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors. In the total series, (S)-(-)-3-PPP [(S)-12] seems to be the most interesting compound both from the theoretical and the therapeutical point of view, possibly attenuating DA function in two different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.

The pharmacology of sulpiride—A dopamine receptor antagonist

1. 1. The clinical and experimental pharmacology of sulpiride, its effects on the CNS, gastrointestinal tract and cardiovascular system have been reviewed. 2. 2. The majority of its actions are attributable to blockade of dopamine receptors. 3. 3. Although sulpiride has a high affinity for dopamine receptors involved in emesis and prolactin secretion, it lacks part of the behavioural and biochemical profiles of the classical dopamine receptor antagonist neuroleptics. 4. 4. In the cardiovascular system, sulpiride is a potent prejunctional dopamine receptor antagonist but has variable effectiveness in postjunctional dopamine receptor models. 5. 5. These properties are discussed with reference to the mechanisms of action of sulpiride and the classification of dopamine receptors.

Effect of 3-PPP, a putative dopamine autoreceptor agonist, on rat serum prolactin levels

3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) has been reported to be a relatively selective agonist for dopamine (DA) auto-receptors in the striatal and limbic region. We have examined the effect of 3-PPP on rat plasma or serum prolactin levels. 3-PPP produced a non-significant decrease in baseline plasma prolactin levels. It produced a dose-dependent inhibition of the increase in serum prolactin levels produced by gamma-butyrolactone. Both doses of 3-PPP tested completely reversed the increase in serum prolactin levels.produced by reserpine and alpha-methylparatyrosine. These results strongly indicate that 3-PPP directly stimulated DA receptors on pituitary lactotrophes. 3-PPP only weakly inhibited the ability of 3H-spiroperidol to bind to pituitary or striatal membranes, suggesting that it may act at a different DA receptor than classical DA receptor blocking drugs. This DA receptor could have properties in common with the autoreceptors of the mesolimbic and nigrostriatal DA neurons.