Sodium-dependent interaction of benzamides with dopamine receptors

Sulpiride and other benzamide (BM)-displacing activity on [³H]-spiroperidol ([³H]SPIR) binding by rat striatal dopaminergic receptors was found to be uniquely sodium-dependent, while classical neuroleptic (NL) activity was not influenced by NaCl.These results suggest the existence of at least two populations of striatal dopaminergic receptors, sodium-dependent and sodium-independent, through which BM and NL respectively interact.     

多巴胺受体的结构和功能

多巴胺是大脑中含量最丰富的儿茶酚胺类神经递质。多巴胺作为神经递质调控中枢神经系统的多种生理功能。多巴胺系统调节障碍涉及帕金森病，精神分裂症，Tourette综合征，注意力缺陷多动综合征和垂体肿瘤的发生等。本文综述了多巴胺受体的共同特征和各个受体的独特特征，以及它们在中枢神经系统的分布和功能，重点强调了多巴胺受体与学习记忆的关系。     

Glutamate-induced cell death and formation of radicals can be reduced by lisuride in mesencephalic primary cell culture

Summary. Oxidative stress evoked by excitotoxicity is considered an important factor for the loss of dopaminergic neurons in Parkinson’s disease. In vitro, protective effects of the dopamine agonist lisuride on complex I inhibition in primary dopaminergic cell culture have been reported. However, little is known about the effects of lisuride on glutamate-induced radical formation. Here, effects of lisuride on the formation of nitric oxide (NO) and superoxide radicals following glutamate exposure were studied on primary cell cultures prepared from mouse mesencephala. Glutamate treatment resulted in doubling of NO and superoxide radical formation, increased dopaminergic cell degeneration and extensively altered neuronal appearance. Pretreatment with lisuride significantly lowered the levels of either reactive species and increased the survival of dopaminergic neurons compared to glutamate-treated cultures. Moreover, the beneficial effect of lisuride could be completely inhibited by the D2/D3 receptor antagonist sulpiride when co-treated in cultures.     

Regulation of dopamine release and metabolism in rat striatum in vivo: Effects of dopamine receptor antagonists

1. 1. The acute effects of some of typical and atypical antipsychotic drugs on the dopamine release and metabolism in the dorsal striatum of freely moving rats were studied using transcerebral microdialysis technique.

2. 2. Classical neuroleptic drugs haloperidol (0.05, 0.1 and 0.2 mg/kg), thioproperazine (0.1, 0.2 and 0.4 mg/kg) and spiperone (0.02, 0.04 and 0.07 mg/kg) administered i.p. induced pronounced elevation of extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) up to 250–300 % to basal level while producing less increase in that of dopamine (DA) (up to 150–170 %).

3. 3. Atypical neuroleptics clozapine and thioridazine (both 2, 5 and 20 mg/kg) increased striatal DA release and DOPAC level approximately at the same degree (maximally up to 200% and 160%, respectively).

4. 4. Dopamine D3 receptor and autoreceptor preferring antagonists (+)-UH232 and (+)-AJ76 (both 4, 7 and 14 mg/kg) more potently increased DA release in comparison with DOPAC dialysate level ( (+)-AJ76 elevated DA level maximally up to 330 %, DOPAC - up to 250 %).

5. 5. The features of typical and atypical neuroleptics in preferential action on DA release or DOPAC output were observed in all doses of the drugs studied .

6. 6. The ability of the drugs to affect preferentially DA release or DOPAC extracellular level in rat striatum correlates to their relative affinities at D3 and D2 DA receptors.

7. 7. It is concluded that typical and atypical antipsychotic drugs might be clearly distinguished on the basis of their ability to affect preferentially DA synthesis/metabolism or release in rat dorsal striatum in vivo.

     

Cerebellar and striatal dopamine receptors: Effects of reeler and weaver murine mutations

The presence and the binding characteristics of D₁ and D₂ receptors were investigated in normal-reeler and normal-weaver mutant mice utilizing [³H]spiperone (D₂ antagonist), [³H]SKF 38393 (D₁ agonist), and [³H]DA as ligands. Analysis of the binding data showed that in the cerebellum there are two binding components for all [³H]ligands. Comparison of the binding constants from cerebellum and striatum showed that in cerebellum the high affinity-low capacity component has similar affinity with that of striatum. The reeler and weaver mutations affected the binding of all ligands: In reeler, total cerebellar specific binding sites for [³H]spiperone and [³H]SKF 38393 decrease significantly (≈50% and ≈70%, respectively), while those for [³H]DA show a small (≈10–15%) but not significant decrease. In weaver, total cerebellar specific binding sites for [³H]spiperone, [³H]SKF 38393, and [³H]DA also decrease significantly (≈60%, ≈70%, and ≈50%, respectively). In reeler striatum [³H]SKF 38393 binding (B_max) is significantly decreased (≈24%), while [³H]spiperone and [³H]DA binding (B_max) is not affected. In weaver striatum, [³H]SKF 38393 binding is significantly increases significantly (≈40%), while [³H]DA binding (B_max) decreases significantly (≈70%). On the basis of the cytoarchitectural aberrations that characterize the cerebellum of these mutants and some well-established information regarding the dopaminergic system of the cerebellum, the above results indicate that in this region (a) D₁ receptors are mainly localized on granule cells and (b) D₂ receptors are localized postsynaptically on granule cells and presynaptically on the DA fibers innervating the cerebellum. © 1993 Wiley-Liss, Inc.     

Prenatal haloperidol alters striatal dopamine and opiate receptors

Adult male rats were given a single i.p. injection of 2-deoxyglucose (2-DG, 100-400 mg/kg b. wt). The animals were decapitated 1-4 h later and trunk blood was collected for ACTH, corticosterone (CS) and glucose determinations. Serum ACTH and CS were markedly elevated when compared with saline-treated animals; these elevations were correlated with given doses of 2-DG so that with the higher dose, an approximately 6-fold increase in serum levels of both hormones was observed. Injection of 2-DG up to 200 mg/kg did not change serum glucose levels; injection of 400 mg/kg of 2-DG increased serum glucose by approximately 2-fold. A time course study showed that levels of serum ACTH, CS and glucose were maximal 1 h after 2-DG administration and returned to basal values 3 h later. Injection of 2-DG to animals with complete hypothalamic deafferentation failed to induce any change in serum ACTH, CS or glucose. This study demonstrates that: (1) 2-DG can stimulate the hypothalamo-hypophyseal-adrenal (HHA) axis as measured by ACTH and CS; this effect is not related to blood glucose levels; (2) the HHA response to 2-DG is mediated by sites outside the mediobasal hypothalamus.     

Comparison of the effects of dopamine D 1 and D 2 receptor antagonists on rat striatal,limbic and nigral dopamine synthesis and utilisation

Summary The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA afterin vivo inhibition of tyrosine hydroxylase by H 44/68, and the accumulation of L-DOPA afterin vivo inhibition of 1-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23mol/kg i. p.), sulpiride (293mol/kg i. p.) and remoxipride (5.6mol/kg i. p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45mol/kg i. p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293mol/kg i. p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36mol/kg i. p.).     

Inhibition by lithium of dopamine receptors in rat prolactin release

We investigated the effect of lithium on prolactin (PRL) secretion in both urethane-anesthetized rats and right atrial catheter-bearing conscious rats. Basal plasma PRL levels were not significantly altered for 4 h after lithium administration. However, lithium treatment apparently potentiated PRL release by haloperidol in both conscious and urethane-anesthetized rats. In addition, the inhibition by apomorphine of PRL secretion was significantly antagonized by lithium in conscious rats. Lithium had no effect on the enhancement of PRL secretion by either 5-hydroxytryptophan or β-endorphin in conscious rats.These observations indicate that lithium affects PRL secretion when dopaminergic neural activity is altered. Therefore, it is possible to postulate that the decrease of dopamine receptor sensitivity by lithium may be related to the therapeutic action of the drug on affective disorders.     

Influence of anaesthetics on rat striatal dopamine metabolism in vivo

The effects of 4 anaesthetics, halothane, α-chloralose, chloral hydrate and pentobarbitone, on rat striatal extracellular dihydroxyphenylacetic acid (DOPAC) levels were determined using in vivo voltammetry. Stable baseline levels of DOPAC were maintained under halothane/N ₂O and α-chloralose while the extracellular levels of DOPAC gradually declined under chloral hydrate or pentobarbitone anaesthesia. Administration of haloperidol (0.3 mg/kg i.p.) significantly increased DOPAC using halothane/N ₂O, α-chloralose or chloral hydrate but not under pentobarbitone anaesthesia. The greatest increase in DOPAC was seen in rats anaesthetized with α-chloralose>halothane/N₂O>chloral hydrate > pentobarbitone. Apomorphine (0.5 mg/kg s.c.) given 2 h after haloperidol partially reversed the increase in DOPAC produced by haloperidol. The results suggest care needs to be exercised in the choice of anaesthetic used for voltammetric studies with pentobarbitone being the least recommended.     

Effects of estrogen agonists on amphetamine-stimulated striatal dopamine release

Based upon the observation that estrogen acts in the striatum to rapidly modulate dopamine (DA) neural transmission and DA-mediated behaviors, it has been postulated that these effects of estrogen are mediated by a specific, membrane-bound receptor mechanism. To further characterize the pharmacological specificity of the estrogen binding site, the present experiments examine effects of various estrogen agonists on amphetamine (AMPH)-induced DA release from striatal tissue of ovariectomized female rats, using a superfusion method. Catechol estrogens 4-, and 2-hydroxyestradiol, but not 2-methoxyestradiol, significantly enhance AMPH-induced striatal DA release. Estrogen metabolites, estrone and estriol, and the non-steroidal estrogen analog, diethylstilbestrol, are without effects. Estradiol conjugated to bovine serum albumin (BSA) mimics the effect of estradiol to enhance stimulated striatal DA release. These results indicate that the steroidal configuration and hydroxylation on the A-ring of estrogenic compounds may be important determinants of ligand binding to the putative estrogen binding site in the striatum. Furthermore, the effectiveness of the estradiol conjugated to BSA reinforces the idea of an external membrane-bound receptor binding site in the striatum. Synapse 29:379–391, 1998. © 1998 Wiley-Liss, Inc.     

Modulation of the voltage-gated sodium current in rat striatal neurons by DARPP-32, an inhibitor of protein phosphatase

DARPP-32 is a cyclic adenosine monophosphate-regulated inhibitor of protein phosphatase 1, highly enriched in striatonigral neurons. Stimulation of dopamine D₁ receptors increases phosphorylation of DARPP-32, whereas glutamate acting on N-methyl-d -aspartate receptors induces its dephosphorylation. Yet, to date, there is little direct evidence for the function of DARPP-32 in striatal neurons. Using a whole cell patch-clamp technique, we have studied the role of DARPP-32 in the regulation of voltage-gated sodium channels in rat striatal neurons maintained in primary culture. Injection of phospho-DARPP-32, but not of the unphosphorylated form, reduced the sodium current amplitude. This effect was similar to those induced by okadaic acid, with which there was no additivity and by tautomycin. Our results indicate that, in striatal neurons, sodium channels are under dynamic control by phosphorylation/dephosphorylation, and that phospho-DARPP-32 reduces sodium current by stabilizing a phosphorylated state of the channel or an associated regulatory protein. We propose that the DARPP-32-mediated modulation of sodium channels, via inhibition of phosphatase 1, contributes to the regulation of these channels by D₁ receptors and other neurotransmitters which influence the state of phosphorylation of DARPP-32.     

Adenosine A1 receptor-mediated inhibition of dopamine release from rat striatal slices is modulated by D1 dopamine receptors

Dopamine release is regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented. In the present study, dopamine release from isolated striatal slices from Wistar rats was measured using fast cyclic voltammetry. Single-pulse stimulation (0.1 ms, 10 V) was applied every 5 min over a 2-h period. Superfusion with the adenosine (A)(1) receptor agonist N(6)-cyclopentyladenosine (CPA), but not the A(2) receptor agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl] phenyl]propanoic acid (CGS 21680), inhibited dopamine release in a concentration-dependent manner (IC(50) 3.80 x 10(-7) m; n = 10). The dose-response curve to CPA was shifted to the right (IC(50) 6.57 x 10(-6) m; n = 6, P < 0.05 vs. control) by the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Neither the D(1) agonist 6-chloro-APB nor the D(1) antagonist R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol (SCH 23390) altered dopamine release on their own. However, SCH 23390 (3 microm) significantly attenuated the response to CPA (IC(50) 1.44 x 10(-5) m; n = 6, P < 0.01 vs. control). Furthermore, the inhibitory effect of CPA was significantly increased in the presence of 6-chloro-APB (1 microm). In radioligand binding experiments, CPA interacted with high- and low-affinity states of [(3)H]DPCPX-lableled A(1) receptors. The high-affinity agonist binding to A(1) receptors was inhibited by the stable guanosine triphosphate analogue Gpp(NH)p. In contrast, neither the proportion nor the affinity of high-affinity A(1) receptors was altered by dopamine or SCH 23390. These results provide evidence that the inhibition of dopamine release by adenosine A(1) receptors is dependent, at least in part, on the simultaneous activation of D(1) dopamine receptors. While the mechanism underlying this interaction remains to be determined, it does not appear to involve an intramembrane interaction between A(1) and D(1) receptors.     

Release of endogenous dopamine and cholecystokinin from rat striatal slices: effects of amphetamine and dopamine antagonists

The release of immunoreactive cholecystokinin (CCK) and dopamine was monitored simultaneously from superfused rat striatal slices. Exposure of the tissue to medium containing elevated of dopamine (10⁻⁷ and 10⁻⁶)M), the dopamine agonist pergolide (10⁻⁷, M), the D₂-antagonist sulpride (1 μM) or the D₁-antagonist (SCH 23390) had no significant effect on basal overflow or on evoked release of CCK. On the other hand, preincubation of striatal slices withd-amphetamine (10⁻⁵ M) enhanced basal and veratrine-stimulated dopamine release but markedly suppressed evoked CCK release. Sulpiride blocked this action of amphetamine whereas SCH 23390 was ineffective. The data suggests that whereas it is difficult to observe any effects of exogenous dopamine agonists or antagonists on evoked CCK release, endogenously released dopamine appears to interact with D₂-receptors to suppress evoked CCK release from rat striatal slices.     

Involvement of corticostriatal glutamatergic terminals in striatal dopamine release elicited by stimulation of delta-opioid receptors

We have previously shown that striatal dopamine release induced locally by a delta-opioid receptor agonist was totally inhibited by a glutamate N-methyl-D-aspartate receptor antagonist, indicating the involvement of glutamatergic receptors in this effect. The aim of the present study was to specify this mechanism. Firstly, we investigated the effect of [D-Pen2,D-Pen5]-enkephalin (DPDPE) on glutamate release in rats by intrastriatal microdialysis. The infusion of DPDPE (10 microm) enhanced the glutamate content in dialysate by approximately 34%, an effect which did not appear to result from inhibition of glutamate uptake. We then considered the consequences of a unilateral thermocoagulation of the frontal cortex on either glutamate or dopamine release induced by stimulation of delta-opioid receptors 2 days later. This lesion, which decreased the glutamate content in ipsilateral striatum by approximately 30%, totally prevented the increase in dialysate levels of glutamate induced by DPDPE. Moreover, whereas DPDPE (10 microm) was found to increase the striatal dopamine release in intact animals by approximately 59%, this effect was also completely suppressed by the cortical lesion. Finally, we studied the effect of the lesion on the [3H]-DPDPE binding to striatal membranes prepared from the whole striatum. In the ipsilateral striatum a significant decrease in this [3H]-DPDPE binding (by approximately 18%) was found 2 days after the lesion. Our results indicate that the increase in striatal dopamine release induced by DPDPE probably depends on glutamate release from corticostriatal glutamatergic afferents in response to the stimulation of delta-opioid receptors located on terminals of these neurons.     

Chronic lithium administration has no effect on haloperidol-induced supersensitivity of pre- and postsynaptic dopamine receptors in rat brain

We have studied the effect of chronic lithium administration on haloperidol-induced dopaminergic supersensitivity in rat brain. Lithium had no effect on haloperidol-induced increases in apomorphine inhibition of dopamine synthesis in the striatum and mesolimbic regions. Similarly, lithium was without effect on haloperidol-induced increases in density of [³H]spiperone binding sites in the striatum. These results indicate that lithium has no effect on haloperidol-induced supersensitivity of presynaptic dopamine receptors in the striatum and mesolimbic regions and on postsynaptic dopamine receptors in the striatum.     

The dopamine D2 receptor agonist alpha-dihydroergocryptine modulates voltage-gated sodium channels in the rat caudate-putamen

Summary. Alpha-Dihydroergocryptine (α-DHEC), a Dopamine (DA) D2 receptor agonist, is widely used as dopaminergic drug in the treatment of Parkinson's disease. To study the mechanisms involved in the signal transduction process induced by α-DHEC on the presynaptic site of the dopaminergic neuron, we incubated slices of the rat caudate-putamen with α-DHEC and the indicated substances in static chambers. Following incubation the resulting DA outflow was measured by high-performance-liquid chromatography with electrochemical detection. The addition of α-DHEC (10 μM–0.1 mM) did not modulate basal DA outflow. Activation of voltage-gated sodium channels by veratridine (VER) from low to relatively high concentrations (1–10 μM) led to a concentration-dependent increase of DA outflow. Using concentrations as high as 10 μM a dramatic increase of DA levels (600% of baseline levels) was observed. The ability of VER to provoke DA release was sensitive to the addition of tetrodotoxin (TTX) and was completely blocked by 1 mM TTX. Coincubation of α-DHEC (10 μM–0.1 mM) and VER (10 μM) reduced VER-stimulated DA outflow in a concentration-dependent manner. The time-concentration course of VER-induced DA outflow was not modulated by α-DHEC. As described in our earlier studies, the specific D2 receptor antagonist (−)sulpiride (SLP) concentration-dependently enhances extracellular DA levels. Addition of α-DHEC almost completely blocked SLP-induced DA-outflow. When slices were incubated with the non-selective DA receptor agonist haloperidol (HLP, 0.1 mM) the effect of α-DHEC on VER-induced DA outflow was partially but not completely abolished. These data strongly suggest that the effect of α-DHEC on the presynaptic site implies an activation of D2 receptors as well as an inhibitory action on voltage-gated sodium channels. α-DHEC seems to modulate voltage-gated sodium channels in part independently from DA receptors since blockade of D2 receptors with saturating concentrations of haloperidol did not completely abolish its effect. Based on our data we have no evidence that voltage-gated potassium channels, N-type calcium channels or D1, D3-receptors are involved in the action of α-DHEC at the presynaptic site of the dopaminergic neuron. The results give one rationale for the proposed neuroprotective effect of α-DHEC Received August 23, 1999; accepted October 20, 1999