Dopamine Receptor Subfamily Research Articles

Comparative Evaluation of A Partial Dopamine Agonist with A Preferential D2 and D3 Receptor Antagonist on Ethanol Induced Conditioned Place Preference in Mice

Background:The role of dopamine receptor sub-families in the rewarding and reinforcing effects of drugs of abuse has been established in numerous studies. </P><P> Objectives: In view of the extensive role of mesolimbic dopaminergic transmission in rewarding and reinforcing effect of abused drugs including ethanol, the present study evaluated three mechanistically different drugs viz a partial dopaminergic agonist (PDA, aripiprazole), preferential D3 (mixed D2/D3) receptor antagonist (nafadotride), and a preferential D2 antagonist (haloperidol), on ethanol-induced conditioned place preference (CPP) in mice. </P><P> Method: The study was carried out in Swiss strain albino mice. Ethanol (20%, 2g/kg) was used to induce CPP in mice. After the acquisition of CPP, behavioral tests (elevated plus maze and locomotor activity) were conducted and effect of drugs on expression and on reinstatement (after extinction) was studied.Results:We found that aripiprazole (1 and 2 mg/kg but not 0.5mg/kg), haloperidol (0.2 mg/kg), and nafadotride (4.5 mg/kg) administered for 1 week during the conditioning phase prevented acquisition, expression and reinstatement of ethanol-induced CPP. All the three drugs reduced the ethanol-induced locomotor stimulation and produced antianxiety effects in elevated plus maze following the acquisition of ethanol CPP.Conclusion:Partial dopaminergic agonism by aripiprazole was found to be a better strategy for normalizing dopaminergic neurotransmission in alcoholics as seen in rodents.

Trace amine-associated receptor 1 agonists RO5263397 and RO5166017 attenuate quinpirole-induced yawning but not hypothermia in rats.

Increasing evidence suggests that trace amine-associated receptor 1 (TAAR1) is an important modulator of the dopaminergic system. Existing molecular evidence indicates that TAAR1 regulates dopamine levels through interactions with dopamine transporters and D2 receptors. However, investigations to date have not been exhaustive and other pathways may be involved. In this study, we used a well-described set of behaviors, quinpirole-induced yawning and hypothermia, to explore the potential interaction of TAAR1 and D3 receptors, which are members of the 'D2-like' dopamine receptor subfamily. Previous studies have shown that for D2/D3 receptor agonists, the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of yawning and induction of hypothermia are D2 receptor-mediated effects. Quinpirole produced an inverted U-shaped dose-effect curve for yawning, which was shifted downward dose-dependently by each of the TAAR1 agonists RO5263397 and RO5166017. Quinpirole also produced dose-dependent hypothermia, which was not affected by either TAAR1 agonist. These results suggest that TAAR1 agonists may interact with D3 receptors and/or its downstream pathways, as opposed to D2 receptors. These findings may shed light on a previously unexplored possibility for the mechanism of TAAR1-mediated effects.

GPCR Handshake in the Spotlight: Exploring the Dimerization Interface of Dopamine D2 Receptors by Simulations at Multiple Resolutions

Dopamine is an important central nervous system neurotransmitter, involved in the reward-response mechanism of the brain. Dopamine receptors belong to Class-A family of G Protein-Coupled Receptor (GPCR) superfamily and share the characteristic fold of seven transmembrane helices with the rest of the GPCR superfamily. It is known that a member of the dopamine receptor subfamily, Dopamine D2 receptor (D2R), forms dimers via transmembrane helix 4 (TM4). These TM4 dimers have been implicated in diverse pharmacological responses.The key to understanding the behavior of these dimers is the molecular basis of their dimerization. Although previous computational studies have investigated GPCR dimerization, a systematic sampling of conformational space has not been explored to find out the dimer interface in D2R. Our work focuses on this dimerization interface, involving TM4 helices of D2R. To begin with, a homology model derived from D3R crystallographic structure was used to develop a coarse-grained membrane model of TM4 dimers. A systematic biased Molecular Dynamics (MD) study was performed on this system to obtain the free-energy surface of dimerization. Our initial results suggest that D2R forms a TM4-TM4 dimer, with a free-energy profile characteristic of weak GPCR dimers. We are further analyzing the behavior of the D2R dimer, with TM4 interface, using all-atom MD simulations.To verify the possibility of other interfaces, we are investigating different dimer configurations by systematically varying the monomer orientation within them. These interfaces, such as the TM1/H8 interface, have been reported in dimers and higher-order oligomers of other GPCRs. A comparison between them and the TM4 interface will provide useful insights into D2R dimerization.

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated. To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials. Effects of raclopride (0-1.2mg/kg) and SCH-23390 (0-0.3mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0-0.3mg/kg) before conditioning sessions with LiCl (experiment 4). Whereas raclopride (0-1.2mg/kg) did not affect acquisition, SCH-23390 (0.1-0.3mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1-0.3mg/kg) did not perturb the acquisition of LiCl-induced CPA. Our results support a role for dopamine D1-like but not D2-like receptors in ethanol's unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.

Dopamine D1 receptor, but not dopamine D2 receptor, is a critical regulator for acute cocaine-enhanced gene expression

Objective: The aim of present study is to investigate the roles of dopamine receptor subfamilies and their subsequent molecular events in cocaine-enhanced gene expression in striatum.Methods: Acute cocaine-treated mice models were build to address this issue. Specific antagonists for dopamine D1 and D2 receptors (SCH 23390 and raclopride, respectively) and specific inhibitor for extracellular signal-regulated protein kinase 1/2 (ERK1/2) kinase were pretreated. Immunofluorescence was used to detect the expressions of c-Fos, phosphorylated cAMP response element binding (p-CREB) and phosphorylated Elk-1 (p-Elk-1) in striatum.Results: Acute cocaine injection significantly enhanced expressions of c-Fos, p-CREB and p-Elk-1 in the striatum. Notably, these enhancements were totally blocked to normal level by SCH 23390 pre-treatment, while no changes occurred in the presence of raclopride. Moreover, we found that dopamine D1 receptor was involved in acute cocaine-induced activation of ERK1/2 in the striatum. Blockade of this dopamine D1 receptor-dependent ERK1/2 activation by SL 327 could reduce cocaine-enhanced expressions of c-Fos, p-CREB and p-Elk-1 in the striatum.Discussion: These results suggest that dopamine D1 receptor, but not dopamine D2 receptor, plays a critical role in regulating acute cocaine-enhanced gene expression in the striatum, and ERK1/2 pathway may contribute to this regulation.

Dopamine D(3) receptors in the rat kidney: role in physiology and pathophysiology.

It is well accepted that dopamine receptors play an important role in the regulation of cardiovascular and kidney function. Most of the knowledge on the renal actions of dopamine has been accumulated focussing on the prototypes of the two known dopamine receptor subfamilies, i.e. D1 and D2. The dopamine D3 receptor is a member of the D2-like subfamily and has been intensively studied in the neurosciences. Recently, the peripheral actions of this receptor subtype have also raised considerable interest as well because its effects on kidney function appear to be different from that of the other dopamine receptors. This short overview will summarize the data reported and add new results on the role of D3 receptors in the regulation of renal function as well as their potential pathophysiological implications.

Reduced eticlopride-induced fos expression in caudate–putamen and globus pallidus after unilateral frontal cortex injury: relation to neglect

Unilateral ablation of medial agranular cortex in rats results in neglect of contralateral stimuli and reductions in amphetamine-induced expression of the immediate early gene, c-fos, in both caudate–putamen and globus pallidus. Both unilateral neglect and the reductions in dopamine agonist induction of subcortical Fos immunoreactivity dissipate over a matter of weeks. Dopamine agonism induces Fos predominantly in striatonigral cells and in globus pallidus via striatopallidal disinhibition, whereas Fos is induced in striatopallidal cells by administration of antagonists of the D2 dopamine receptor subfamily. To examine more directly effects of cortical injury on striatopallidal function, induction of striatal Fos by the D2 antagonist eticlopride (0.1mg/kg, s.c.) was examined in rats with medial agranular cortex ablation. In the same animals, eticlopride-induced Fos in globus pallidus was also examined. Five days after unilateral cortex injury, in rats showing neglect, the numbers of Fos immunoreactive nuclei induced by eticlopride were reduced by 50% in caudate–putamen and 25% in globus pallidus of the ipsilateral hemisphere. These lesion effects were restricted to dorsolateral caudate–putamen and dorsal pallidum. Three or more weeks after cortical injury, in rats recovered from neglect, eticlopride-induced Fos was normalized in caudate–putamen, but still decreased by 20% in globus pallidus.Along with previous findings, these results suggest that behavioral recovery from neglect produced by cortical injury may be at least partially mediated by normalizations of function of both striatopallidal and striatonigral neurons. In addition, the present findings suggest that normalization of function of pallidal cells activated by eticlopride is not necessary for behavioral recovery from frontal cortex ablation. Lingering reductions in excitatory cortico-subthalamo-pallidal input may be responsible for the longer-lasting dysfunctions of these pallidal cells.

Differential inhibition of secretagogue-stimulated sodium uptake in adrenal chromaffin cells by activation of D4 and D5 dopamine receptors.

Recent studies have demonstrated that D1-selective and D2-selective dopamine receptor agonists inhibit catecholamine secretion and Ca2+ uptake into bovine adrenal chromaffin cells by receptor subtypes that we have identified by PCR as D5, a member of the D1-like dopamine receptor subfamily, and D4, a member of the D2-like dopamine receptor subfamily. The purpose of this study was to determine whether activation of D5 or D4 receptors inhibits influx of Na+, which could explain inhibition of secretion and Ca2+ uptake by dopamine agonists. D1-selective agonists preferentially inhibited both dimethylphenylpiperazinium- (DMPP) and veratridine-stimulated 22Na+ influx into chromaffin cells. The D1-selective agonists chloro-APB hydrobromide (CI-APB; 100 microM) and SKF-38393 (< 00 microM) inhibited DMPP-stimulated Na+ uptake by 87.5 +/- 2.3 and 59.7 +/- 4.5%, respectively, whereas the D2-selective agonist bromocriptine (100 microM) inhibited Na+ uptake by only 22.9 +/- 5.0%. Veratridine-stimulated Na+ uptake was inhibited 95.1 +/- 3.2 and 25.7 +/- 4.7% by 100 microM CI-APB or bromocriptine, respectively. The effect of CI-APB was concentration dependent. A similar IC50 (approximately 18 microM) for inhibition of both DMPP- and veratridine-stimulated Na+ uptake was obtained. The addition of 8-bromo-cyclic AMP (1 mM) had no effect on either DMPP- or veratridine-stimulated Na+ uptake. These observations suggest that D1-selective agonists are inhibiting secretagogue-stimulated Na+ uptake in a cyclic AMP-independent manner.

Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors

This study's goal is to identify adaptations involving striatal glutamate (GLU) or dopamine (DA) receptors that may contribute to recovery of function following cortical injury. Unilateral aspiration of the medial agranular region of frontal cortex (AGm) in rats produces neglect of contralateral stimuli. Pharmacological and immunocytochemical studies suggest that glutamatergic and dopaminergic processes within striatum may contribute to spontaneous recovery from this neglect. This study examined by autoradiography radioligand binding to striatal GLU and DA receptor subfamilies in AGm-ablated rats surviving 5 days (unrecovered) or 3 or more weeks (recovered) postsurgery. Density of radioligand binding was quantified in striatal subregions by computerized image analysis. Compared to striatal binding densities in the intact hemisphere, [3H]kainate binding and [3H]GLU binding to NMDA receptors were decreased in the lesioned hemisphere of unrecovered AGm-ablated rats, but normalized (for kainate) or increased (for NMDA) in the lesioned hemisphere of recovered rats. Ablation of AGm did not affect [3H]AMPA binding or the binding of [3H]SCH23390, [3H]spiperone, or [3H]mazindol to dopaminergic D1 or D2 receptor subfamilies, or to DA uptake sites, respectively. The results suggest that a small percentage of NMDA and kainate receptors are located on corticostriatal axon terminals, and that over time an upregulation of striatal NMDA and/or kainate receptors may offset the loss of cortical glutamatergic input caused by cortical injury. These time-dependent alterations in GLU receptors may contribute to the recovery of function and normalizations of immediate early gene expression seen weeks after AGm ablation. Upregulation of striatal dopamine receptors was not evident, and thus is unlikely to mediate recovery from neglect produced by cortical injury.

Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.