Dopamine Receptor Interactions Research Articles

Partial agonists of dopamine receptors: clinical effects and dopamine receptor interactions in combining aripiprazole with a full antagonist in treating psychosis

SUMMARYPartial agonists of dopamine receptors are used in combination with full antagonists in treating psychosis, either to mitigate side-effects or in the hope of increasing effectiveness. We examine how combinations may affect the occupancy of D2/D3dopamine receptors and explore how these can explain the outcomes in the light of the dopamine hypothesis of psychosis. The combinations considered here are from published studies combining aripiprazole with amisulpride, with risperidone in people with hyperprolactinaemia and with olanzapine to mitigate weight gain. We discuss possible worsening of symptoms by the addition of a partial agonist or switching. We also examine the potentially adverse interaction with a full antagonist such as haloperidol given during a subsequent relapse to control severe agitation.

Potential mechanisms underlying the therapeutic roles of sinisan formula in depression: Based on network pharmacology and molecular docking study.

The incidence of depression has been increasing globally, which has brought a serious burden to society. Sinisan Formula (SNSF), a well-known formula of traditional Chinese medicine (TCM), has been found to demonstrate an antidepressant effect. However, the therapeutic mechanism of this formula remains unclear. Thus, the present study aimed to explore the mechanism of SNSF in depression through network pharmacology combined with molecular docking methods. Bioactive compounds, potential targets of SNSF, and related genes of depression were obtained from public databases. Essential ingredients, potential targets, and signaling pathways were identified using bioinformatics analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, Autodock software was further performed for conducting molecular docking to verify the binding ability of active ingredients to targets. A total of 91 active compounds were successfully identified in SNSF with the use of the comprehensive network pharmacology approach, and they were found to be closely connected to 112 depression-related targets, among which CREB1, NOS3, CASP3, TP53, ESR1, and SLC6A4 might be the main potential targets for the treatment of depression. GO analysis revealed 801 biological processes, 123 molecular functions, and 67 cellular components. KEGG pathway enrichment analysis indicated that neuroactive ligand-receptor interaction, serotonergic synapse pathways, dopaminergic synapse pathways, and GABAergic synapse pathways might have played a role in treating depression. Molecular docking suggested that beta-sitosterol, nobiletin, and 7-methoxy-2-methyl isoflavone bound well to the main potential targets. This study comprehensively illuminated the active ingredients, potential targets, primary pharmacological effects, and relevant mechanism of the SNSF in the treatment of depression. SNSF might exert its antidepressant effects by regulating the signaling pathway of 5-hydroxytryptamine, dopamine, GABA, and neuroactive ligand receptor interactions. Still, more pharmacological experiments are needed for verification.

Dopamine regulates adult neurogenesis in the ventricular-subventricular zone via dopamine D3 angiotensin type 2 receptor interactions.

Adult neurogenesis is a dynamic and highly regulated process, and different studies suggest that dopamine modulates ventricular-subventricular zone (V-SVZ) neurogenesis. However, the specific role of dopamine and the mechanisms/factors underlying its effects on physiological and pathological conditions such as Parkinson's disease (PD) are not fully understood. Recent studies have described counter-regulatory interactions between renin-angiotensin system (RAS) and dopamine in peripheral tissues and in the nigrostriatal system. We have previously demonstrated that angiotensin receptors regulate proliferation and generation of neuroblasts in the rodent V-SVZ. However, possible interactions between dopamine receptors and RAS in the V-SVZ and their role in alterations of neurogenesis in animal models of PD have not been investigated. In V-SVZ cultures, activation of dopamine receptors induced changes in the expression of angiotensin receptors. Moreover, dopamine, via D2-like receptors and particularly D3 receptors, increased generation of neurospheres derived from the V-SVZ and this effect was mediated by angiotensin type-2 (AT2) receptors. In rats, we observed a marked reduction in proliferation and generation of neuroblasts in the V-SVZ of dopamine-depleted animals, and inhibition of AT1 receptors or activation of AT2 receptors restored proliferation and generation of neuroblasts to control levels. Moreover, intrastriatal mesencephalic grafts partially restored proliferation and generation of neuroblasts observed in the V-SVZ of dopamine-depleted rats. Our data revealed that dopamine and angiotensin receptor interactions play a major role in the regulation of V-SVZ and suggest potential beneficial effects of RAS modulators on the regulation of adult V-SVZ neurogenesis.

Estrogen Deficiency and Colonic Function: Surgical Menopause and Sex Differences in Angiotensin and Dopamine Receptor Interaction.

The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin-angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin-angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.

Issue Cover (August 2018)

Journal of NeurochemistryVolume 146, Issue 3 Issue CoverFree Access Issue Cover (August 2018) First published: 30 July 2018 https://doi.org/10.1111/jnc.14187 Read the full article: ‘Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+/calmodulin-dependent protein kinase II’ by L. Xiong, Q. Meng, X. Sun, X. Lu, Q. Fu, Q. Peng, J. Yang, K.-W. Oh, Z. Hu (J. Neurochem. 2018, vol. 146 (3), pp. 289–303) on doi: 10.1111/jnc.14289 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Front cover: Background: Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Main findings: Here we show that cocaine administration enhances the phosphorylated Ca2+/calmodulin-dependent protein kinaseIIα (pCaMKIIα)- D3 dopamine receptor (D3R) interaction in the NAc shell, while intra-accumbal injection of CART peptide decreases cocaine-induced locomotor sensitization. Implication: Therefore, we propose that CART peptide exerts its inhibitory effect on cocaine-induced locomotor sensitization via inhibition of the pCaMKIIα-D3R interaction, calcium influx and D3R signaling in the NAc shell, which could provide new evidence for the application of CART peptide to treat cocaine-induced behavioral sensitivity. Image content: The image shows a immunofluorescence image of CaMKIIα-GFP-overexpressing NAc neurons (green) stained with pCaMKIIα antibodies (red), nuclei (DAPI, blue). Read the full article ‘Cocaine- and amphetamine-regulated transcript peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient over-expression of α-Ca2+/calmodulin-dependent protein kinase II’ by L. Xiong, Q. Meng, X. Sun, X. Lu, Q. Fu, Q. Peng, J. Yang, K.-W. Oh, Z. Hu (J. Neurochem. 2018, vol. 146 (3), pp. 289–303) on doi: 10.1111/jnc.14289 Volume146, Issue3August 2018 RelatedInformation

Dopamine receptor D2 gene polymorphism and interaction with the body mass index: A study among two tribal populations of Central India

One of the neurotransmitters i.e. dopamine receptor D2 (DRD2) is reported to regulate food by modulating food reward through meso-limbic circuitry. This neurotransmitter is controlled by gene on chromosome 11q23 which exhibits a polymorphism at Taq1A site (rs1800497). A1 allele of this gene is found to be associated with obesity as it is reported to decrease the activity of the DRD2 receptor. Thus, in the present study an attempt has been made to explore and understand the regulatory role of dopamine 2 receptor gene (TaqIA1 allele) in body mass index (BMI) among two tribal populations of Madhya Pradesh, India. DNA samples from Gonds (n=126) and Panikas (n=112) of Madhya Pradesh, unrelated up to 1st cousins, have been analysed for the DRD2 TaqIA1 polymorphism and correlated with their BMI. Homozygous TaqIA1 allele was found to be more among obese and underweights as compared to normal individuals in both Gonds and Panikas. However, the presence of same was more among Panikas in obese category (35.7%) as compared to Gonds (28.6%), but strikingly, the trend reversed in the underweight and the normal BMI categories. Dopamine, a neurotransmitter that modulates rewarding properties of food is found to interact with BMI through TaqIA1 allele among the studied populations.

Aging-related dysregulation of dopamine and angiotensin receptor interaction

It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.

A synergistic approach towards understanding the functional significance of dopamine receptor interactions

The importance of the neurotransmitter dopamine (DA) in the nervous system is underscored by its role in a wide variety of physiological and neural functions in both vertebrates and invertebrates. Binding of dopamine to its membrane receptors initiates precise signaling cascades that result in specific cellular responses. Dopamine receptors belong to a super-family of G-protein coupled receptors (GPCRs) that are characterized by seven trans-membrane domains. In mammals, five dopamine receptors have been identified which are grouped into two different categories D1- and D2-like receptors. The interactions of DA receptors with other proteins including specific Gα subunits are critical in deciding the fate of downstream molecular events carried out by effector proteins. In this mini-review we provide a synopsis of known protein-protein interactions of DA receptors and a perspective on the potential synergistic utility of Caenorhabditis elegans as a model eukaryote with a comparatively simpler nervous system to gain insight on the neuronal and behavioral consequences of the receptor interactions.

Infusions of ascorbic acid into the medial preoptic area facilitate appetitive sexual behavior in the female rat

Ascorbic acid (AA), also known as Vitamin C, enhances dopamine (DA) transmission in mesolimbic and nigrostriatal terminals and augments DA-mediated behaviors. It is not yet known whether AA has a similar influence in other DA terminals, in particular terminals of the incertohypothalamic system that modulate the function of the medial preoptic area (mPOA). In female rats, DA in the mPOA plays a critical role in the generation of appetitive sexual responses, notably solicitations, hops, and darts, and we have shown previously that the role of DA in this region on female sexual behavior changes depending on the hormonal profile of the female. Since AA has often been used as a vehicle control in the examination of rat sexual behavior, the present study examined the effect of infusions of AA to the mPOA of sexual experienced ovariectomized rats under two hormonal conditions: partially-primed with estradiol benzoate (EB) alone or fully-primed with EB and progesterone. Relative to saline baselines, females under both hormonal conditions displayed a significant increase in appetitive sexual behaviors following infusions of AA. No difference in lordosis behavior was observed following AA infusions relative to saline baselines. We suggest that the mechanism by which AA infusions to the mPOA increase appetitive sexual behaviors in female rats may be through dose-dependent DA receptor interactions, possibly through both presynaptic release mechanisms and postsynaptic DA D1-related messenger systems.

Parkinson disease drug screening based on the interaction between D2 dopamine receptor and beta-arrestin 2 detected by capillary zone electrophoresis

Parkinson’s disease is the second most common neurodegenerative disease in the world. Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization, which is essential to Parkinson’s disease. Moreover, the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson’s disease has recently been shown. We studied the interaction between D2 dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis. The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D2 dopamine receptor interaction among them. These compounds are promising therapies for Parkinson’s disease, and the method used in this study has great potential for application in large-scale drug screening and evaluation.

The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing

Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors.

Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

A(2A) adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A(2A) adenosine receptors are regulated by D(2) dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A(2A) adenosine receptor functional responses caused by the chronic blockade/activation of D(2) dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A(2A) adenosine receptors induced by antipsychotic drugs, commonly acting as D(2) dopamine receptor antagonists, in a cellular model co-expressing both A(2A) and D(2) receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A(2A) receptor and also affected the degree of A(2A)-D(2) receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A(2A) adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine-dopamine receptor interaction. Modifications to A(2A) adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A(2A) adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction. The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users.

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr₁/sstr₂, sstr₂/sstr₅, sstr₅/dopamine (DA) type 2 receptor (D₂R), and sstr₂/D₂R dimers. BIM-23704 (sstr₁- and sstr₂-preferential compound) increased the co-immunoprecipitation of sstr₁/sstr₂ and significantly inhibited proliferation (-30.98%). BIM-23244 (sstr₂-sstr₅ selective agonist) significantly increased the co-immunoprecipitation of sstr₂/sstr₅, and induced a -41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr₂ and D₂R and a moderate affinity for sstr₅, significantly increased the sstr₅/D₂R and sstr₂/D₂R complexes and was the most powerful in inhibiting proliferation (-42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D₂R/sstr₅ and inhibiting cell proliferation (-30.54%). However, behind BIM-23A760, BIM-53097 (D₂R-preferential compound) also significantly inhibited Calu-6 proliferation (-17.71%), suggesting a key role for D₂R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

D2 dopamine receptor expression and trafficking is regulated through direct interactions with ZIP

We have used the yeast two-hybrid system to identify protein kinase C-zeta interacting protein (ZIP) as a novel interacting protein for the D(2) dopamine receptor (DAR). This interaction was identified by screening a rat brain cDNA library using the third intracellular loop of the D(2) DAR as bait. A partial-length cDNA encoding ZIP was isolated and characterized as specifically interacting with the third intracellular loop of the D(2) DAR, but not with the third intracellular loops of other DAR subtypes. Biochemical confirmation of the ZIP-D(2) DAR interaction was obtained by expressing the full-length ZIP and D(2) DAR proteins in mammalian cells and demonstrating that they could be co-immunoprecipitated. We further showed that ZIP and the D(2) DAR could be co-immunoprecipitated from endogenous brain tissues. Immunohistochemical analyses further revealed that ZIP and the D(2) DAR were extensively co-localized within numerous neurons in various brain regions. ZIP exists as three protein isoforms of varying length, which are derived from alternative RNA splicing. All three isoforms were found to interact with the D(2) DAR, which allowed for the delineation of the receptor interacting domain to within 38 residues of ZIP. Functionally, over-expression of ZIP was found to result in decreased expression of the D(2) DAR with a corresponding decrease in receptor modulation of cAMP accumulation. Confocal microscopy revealed that ZIP over-expression also lead to an intracellular accumulation of D(2) DAR protein in lysosome compartments. These results suggest that ZIP can physically interact with the D(2) DAR leading to increased intracellular trafficking to lysosomes with subsequent down-regulation of receptor expression and function.

Adenosine receptor–dopamine receptor interactions in the basal ganglia and their relevance for brain function

The dopamine D 1 and D 2 receptors are major receptors in the regulation of striatal function and striatal adenosine A 1 and A 2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A 1–D 1 heteromeric receptor complexes in the basal ganglia and prefrontal cortex and especially in the direct striatonigral–striatoentopeduncular GABA pathways. The neurochemical and behavioral findings showing antagonistic A 1–D 1 receptor interactions can be explained by the existence of such A 1–D 1 heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A 2A–D 2 receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A 2A receptors reduces D 2 receptor recognition, coupling and signaling. As a result of the A 2A receptor-induced reduction of D 2 receptor signaling, the activity of these GABA neurons is increased resulting in reduced motor and reward functions mediated via the indirect pathway, causing a reduced glutamate drive to the prefrontal and motor areas of the cerebral cortex. Thus, A 2A receptor antagonists and A 2A receptor agonists, respectively, may offer novel treatments of Parkinson's disease (reduced D 2 receptor signaling) and of schizophrenia and drug addiction (increased D 2 receptor signaling).

The differential effects of 5-HT 1A receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat

Serotonin 1A receptor (5-HT 1AR) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson’s disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT 1AR stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT 1AR stimulation on DA receptor-mediated behaviors. Male Sprague–Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH 2O) or the 5-HT 1AR agonist ± 8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg + benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT 1AR stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT 1AR and DA receptor interactions may contribute to the unique profile of 5-HT 1AR agonists for the improvement of PD treatment.

Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease

Preclinical evidence strongly indicate that adenosine A 2A receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A 2A receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A 2A antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 μg/μl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A 2A antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A 2A antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A 2A antagonists.

Characterization of D 1 and D 2 dopamine receptor interactions with the Na + /K + ‐ATPase

It is evident that dopamine receptors (DARs) do not exist as singular independent units within the synaptic membrane, but rather are part of a large macromolecular complex of interacting proteins. These interacting proteins may be transmembrane or cytosolic, and can play a variety of roles in receptor function. We have employed a co-immunoprecipitation assay for DARs (from mouse brain and transfected cell lines), coupled with mass spectrometry (MS) sequencing to identify these interacting partners. Interacting proteins identified through these experiments include the α1 subunit of sodium-potassium ATPase (NKA α1). The NKA is a transmembrane protein consisting of both an α and β subunit, with α1 being the predominant α isoform. Studies indicate that the α subunit is primarily responsible for the transport of Na+ and K+ ions across the plasma membrane. Co-immunoprecipitation of DARs followed by Western analysis has confirmed specific D1 and D2 DAR interactions with NKA α1. To determine the impact of NKA on the DARs, biological assays were conducted in the presence of enhanced levels of NKA. Over-expression of NKA DNA yields a dramatic decrease in total D2 DAR expression, but has little impact on the expression of D1 DAR; a functional consequence of this diminished receptor level is also evident. These preliminary data indicate that NKA interactions are distinct across DAR isoforms. Experiments are underway to determine the impact of DAR expression on NKA function and activity, and to ascertain whether the observed effects are mediated by direct or indirect interactions. Support Contributed By: NIH and NIGMS PRAT Program

Topographical effects of D1-like dopamine receptor agonists on orofacial movements in mice and their differential regulation via oppositional versus synergistic D1-like: D2-like interactions: cautionary observations on SK&F 82958 as an anomalous agent

Using a novel procedure, the regulation of individual topographies of orofacial movement in the mouse by oppositional versus cooperative/synergistic D1-like: D2-like dopamine receptor interactions was studied. The D1-like agonists SK&F 38393 and SK&F 83959 each induced vertical, but not horizontal, jaw movements, together with tongue protrusions and incisor chattering; however, SK&F 82958 induced a different profile which, consistent with other neurochemical and neurophysiological studies, suggests that this agent shows anomalous properties relative to other D1-like agonists. When given alone, the D2-like agonist quinpirole reduced horizontal jaw movements and incisor chattering. On coadministration, both SK&F 38393- and SK&F 83959-induced vertical jaw movements and tongue protrusions were inhibited by quinpirole, while SK&F 82958 again showed an anomalous profile. These findings indicate that, in the mouse, vertical jaw movements and tongue protrusions are regulated by oppositional D1-like: D2-like interactions, and appear to involve a D1-like receptor that is not coupled to adenylyl cyclase, whereas horizontal jaw movements are inhibited by D2-like receptors. Additionally, results obtained using SK&F 82958 as a probe for D1-like mechanisms should be treated with considerable caution until they are confirmed using other D1-like agonists.

Topographical effects of D1-like dopamine receptor agonists on orofacial movements in mice and their differential regulation via oppositional versus synergistic D1-like: D2-like interactions: cautionary observations on SK&F 82958 as an anomalous agent

Using a novel procedure, the regulation of individual topographies of orofacial movement in the mouse by oppositional versus cooperative/synergistic D1-like: D2-like dopamine receptor interactions was studied. The D1-like agonists SK&F 38393 and SK&F 83959 each induced vertical, but not horizontal, jaw movements, together with tongue protrusions and incisor chattering; however, SK&F 82958 induced a different profile which, consistent with other neurochemical and neurophysiological studies, suggests that this agent shows anomalous properties relative to other D1-like agonists. When given alone, the D2-like agonist quinpirole reduced horizontal jaw movements and incisor chattering. On coadministration, both SK&F 38393- and SK&F 83959-induced vertical jaw movements and tongue protrusions were inhibited by quinpirole, while SK&F 82958 again showed an anomalous profile. These findings indicate that, in the mouse, vertical jaw movements and tongue protrusions are regulated by oppositional D1-like: D2-like interactions, and appear to involve a D1-like receptor that is not coupled to adenylyl cyclase, whereas horizontal jaw movements are inhibited by D2-like receptors. Additionally, results obtained using SK&F 82958 as a probe for D1-like mechanisms should be treated with considerable caution until they are confirmed using other D1-like agonists.