RESUMEN
Levodopa-induced dyskinesia (LID) is experienced by most patients of Parkinson's disease (PD) upon the long-term use of the dopamine precursor levodopa. Striatal dopaminergic signaling plays a critical role in the pathogenesis of LID through its interactions with dopamine receptors. The specific roles of striatal dopaminergic D5 receptors in the pathophysiological process of LID are still poorly established. In the study, we investigated the role of striatal dopamine D5 receptor in LID by using PD rats with or without dyskinetic symptoms after chronic levodopa administration. The experimental results showed that the expression level of D5 receptors in the sensorimotor striatum of dyskinetic rats is significantly higher than that of the non-dyskinetic controls. The administration of levodopa increased c-Fos expression in a subpopulation of sensorimotor striatum neurons of dyskinetic rats, but not in non-dyskinetic rats. The majority of the c-Fos+ neurons activated by levodopa in the striatum are positive for D5 receptor staining. Intrastriatal injection of D1-like (D1 and D5) dopamine receptor antagonist, SCH-23390, significantly inhibited dyskinetic behavior in dyskinetic rats after the injection of levodopa, meanwhile, intrastriatal administration of SKF-83959, a partial D5 receptor agonist, yielded significant dyskinetic movements in dyskinetic rats without levodopa. In contrast, intrastriatal perfusion of small interfering RNA directed against DRD5 downregulated D5 receptors expression and moderately inhibited dyskinetic behavior of dyskinetic animals. Our data suggested that the striatal dopamine D5 receptor might play a novel role in the pathophysiology of LID.
Asunto(s)
Benzazepinas/farmacología , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Dopamina D5/efectos de los fármacos , Animales , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Masculino , Oxidopamina/farmacología , Enfermedad de Parkinson/metabolismo , Ratas Sprague-DawleyRESUMEN
Dopamine-mediated regulation of Na(+)-K(+)-ATPase activity in the posterior gills of some crustaceans has been reported to be involved in osmoregulation. The dopamine receptors of invertebrates are classified into three groups based on their structure and pharmacology: D1- and D2-like receptors and a distinct invertebrate receptor subtype (INDR). We tested the hypothesis that a D1-like receptor is expressed in the blue crab Callinectes sapidus and regulates Na(+)-K(+)-ATPase activity. RT-PCR, using degenerate primers, showed the presence of D1ßR mRNA in the posterior gill. The blue crab posterior gills showed positive immunostaining for a dopamine D5 receptor (D5R or D1ßR) antibody in the basolateral membrane and cytoplasm. Confocal microscopy showed colocalization of Na(+)-K(+)-ATPase and D1ßR in the basolateral membrane. To determine the effect of D1-like receptor stimulation on Na(+)-K(+)-ATPase activity, intact crabs acclimated to low salinity for 6 days were given an intracardiac infusion of the D1-like receptor agonist fenoldopam, with or without the D1-like receptor antagonist SCH23390. Fenoldopam increased cAMP production twofold and decreased Na(+)-K(+)-ATPase activity by 50% in the posterior gills. This effect was blocked by coinfusion with SCH23390, which had no effect on Na(+)-K(+)-ATPase activity by itself. Fenoldopam minimally decreased D1ßR protein expression (10%) but did not affect Na(+)-K(+)-ATPase α-subunit protein expression. This study shows the presence of functional D1ßR in the posterior gills of euryhaline crabs chronically exposed to low salinity and highlights the evolutionarily conserved function of the dopamine receptors on sodium homeostasis.
Asunto(s)
Braquiuros/enzimología , AMP Cíclico/metabolismo , Branquias/enzimología , Receptores de Dopamina D5/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Adaptación Fisiológica , Animales , Braquiuros/efectos de los fármacos , Braquiuros/genética , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Regulación hacia Abajo , Branquias/efectos de los fármacos , Masculino , Osmorregulación , ARN Mensajero/metabolismo , Receptores de Dopamina D5/efectos de los fármacos , Receptores de Dopamina D5/genética , Salinidad , Regulación hacia ArribaRESUMEN
Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D1/5 receptors.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Morfolinas/farmacología , Nootrópicos/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D5/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Animales , Cognición/efectos de los fármacos , Depresión/metabolismo , Depresión/fisiopatología , Depresión/psicología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Hipocampo/metabolismo , Hipocampo/fisiopatología , Masculino , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-Dawley , Reboxetina , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Natación , Factores de TiempoRESUMEN
Dopamine D1-like receptors play important roles in many brain activities such as cognition and emotion. We have generated human hD5 and mutant human hD5 (hD(5m)) transgenic rats. The C-terminal juxtamembrane domain of mutant hD5 was identical to that of hD5 pseudogenes. The transgenes were driven by the CAMKII promoter that led the expression mainly in the cerebral cortex and hippocampus. We have used different dopamine receptor agonists to compare the pharmacological profiles of the human hD5 and hD(5m) receptors. The results showed that they exhibited distinct pharmacological properties. Our results of pharmacological studies indicated that the C-terminal of D5 receptor could play important roles in agonist binding affinity. Hippocampal long-term potentiation (LTP) evoked by tetanic stimulation was significantly reduced in both transgenic rats. In addition, we found that the overexpression of dopamine hD5 and hD(5m) receptors in the rat brain resulted in memory impairments. Interestingly, an atypical D1-like receptor agonist, SKF83959, could induce anxiety in hD(5m) receptor transgenic rats but had no effect on the anxiety-like behavior in D5 receptor transgenic and wild-type rats.
Asunto(s)
Receptores de Dopamina D5/genética , Secuencia de Aminoácidos , Animales , Ansiedad/genética , Ansiedad/psicología , Clonación Molecular , AMP Cíclico/metabolismo , Proteínas del Citoesqueleto/metabolismo , Estimulación Eléctrica , Fenómenos Electrofisiológicos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HEK293 , Hipocampo/fisiología , Humanos , Potenciación a Largo Plazo/fisiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/psicología , Datos de Secuencia Molecular , Mutación/genética , Mutación/fisiología , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Prosencéfalo/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores de Dopamina D5/efectos de los fármacos , Receptores de Dopamina D5/fisiologíaRESUMEN
Large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channels hyperpolarize coronary artery smooth muscle cells, causing vasorelaxation. Dopamine activates BK(Ca) channels by stimulating D(1)-like receptor-mediated increases in cAMP in porcine coronary artery myocytes. There are two D(1)-like receptors (R), D(1)R and D(5)R. We hypothesize that the specific D(1)-like receptor involved in BK(Ca) channel activation in human coronary artery smooth muscle cells (HCASMCs) is the D(5)R and that activation occurs via cAMP cross-activation of cGMP-dependent protein kinase (PKG), rather than cAMP-dependent protein kinase (PKA). The effects of D(1)-like receptor agonists and antagonists on BK(Ca) channel opening in HCASMCs were examined in the presence and absence of PKG/PKA inhibition by cell-attached patch clamp. In the absence of commercially available ligands specific for D(1)R or D(5)R, D(1)R or D(5)R protein was down-regulated by transfecting HCASMCs with human D(1)R or D(5)R antisense oligonucleotides, respectively: cells transfected with scrambled oligonucleotides and nontransfected HCASMCs served as controls. The predominant ion channel conducting outward currents in nontransfected HCASMCs was identified as the large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel, which was activated by D(1)-like receptor agonists despite PKA inhibition with (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid (KT 5720) (300 nM), but was abolished by inhibiting PKG with 9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b-11a-triazadibenzo(a,g) cycloocta(cde)-trinden-1-one (KT 5823) (300 nM). D(1)-like receptor agonists activated BK(Ca) channels in all transfected cells except those transfected with D(5)R antisense oligonucleotides. Thus, the dopamine (D(1)-like) receptor mediates activation of BK(Ca) channels in HCASMCs by D(5)R, not D(1)R, and via PKG, not PKA. This is the first report of differential D(1)-like receptor regulation of vascular smooth muscle function in human cells.
Asunto(s)
Vasos Coronarios/fisiología , Canales de Potasio de Gran Conductancia Activados por el Calcio/fisiología , Miocitos del Músculo Liso/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D5/fisiología , Carbazoles/farmacología , Células Cultivadas , Vasos Coronarios/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Humanos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Miocitos del Músculo Liso/efectos de los fármacos , Oligonucleótidos Antisentido/farmacología , Pirroles/farmacología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D5/efectos de los fármacos , Receptores de Dopamina D5/genéticaRESUMEN
BACKGROUND: Ion transport in the renal proximal tubule (RPT) is regulated by numerous hormones and humoral factors, including insulin and dopamine. Previous studies show an interaction between insulin and the D(1) receptor. Because both D(1) and D(5) receptors belong to the D(1)-like receptor subfamily, it is possible that an interaction between insulin and the D(5) dopamine receptor exists in RPT cells from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). METHODS: D(5) receptor expression in immortalized RPT cells from WKY and SHRs was quantified by immunoblotting and D(5) receptor function by measuring Na(+)-K(+) ATPase activity. RESULTS: Insulin increased the expression of the D(5) receptor. Stimulation with insulin (10(-7) mol/l) for 24 h increased D(5) receptor expression in RPT cells from WKY rats. This effect of insulin on D(5) receptor expression was aberrant in RPT cells from SHRs. The stimulatory effect of insulin on D(5) receptor expression in RPT cells from WKY rats was inhibited by a protein kinase C (PKC) inhibitor (PKC inhibitor peptide 19-31, 10(-6) mol/l) or a phosphatidylinositol 3 (PI3) kinase inhibitor (wortmannin, 10(-6) mol/l), indicating that both PKC and PI3 kinase were involved in the signaling pathway. Stimulation of the D(5) receptor heterologously expressed in HEK293 cells with fenoldopam (10(-7) mol/l/15 min) inhibited Na(+)-K(+) ATPase activity, whereas pretreatment with insulin (10(-7) mol/l/24 h) increased the D(5) receptor-mediated inhibition. CONCLUSIONS: Insulin and D(5) receptors interact to regulate renal sodium transport; an aberrant interaction between insulin and D(5) receptor may participate in the pathogenesis of hypertension.
Asunto(s)
Insulina/farmacología , Túbulos Renales Proximales/metabolismo , Receptores de Dopamina D5/fisiología , Animales , Células Cultivadas , Expresión Génica/efectos de los fármacos , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Insulina/metabolismo , Receptores de Dopamina D5/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Estimulación QuímicaAsunto(s)
Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/toxicidad , Espinas Dendríticas/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Encéfalo/fisiopatología , Trastornos Relacionados con Cocaína/rehabilitación , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Espinas Dendríticas/fisiología , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Humanos , Factores de Transcripción MEF2 , Factores Reguladores Miogénicos/genética , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiopatología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D5/efectos de los fármacos , Receptores de Dopamina D5/fisiología , Recompensa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by 2,5-dimethoxy-4-iodoamphetamine (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT(2A/2C) receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABA(A) antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia.
Asunto(s)
Alucinógenos/farmacología , Corteza Prefrontal/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D5/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Técnicas In Vitro , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Técnicas de Placa-Clamp , Racloprida/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D5/efectos de los fármacosRESUMEN
The persistence of new memory traces in the hippocampus, encoded following appropriate activation of glutamatergic receptors and the induction of synaptic plasticity, can be influenced by heterosynaptic activation of neuromodulatory brain systems. We therefore investigated the effects of a hippocampus-specific blockade of dopamine D1/D5 receptors on the persistence of spatial memory encoded in one trial using a delayed matching-to-place (DMP) task in a watermaze in which rats learn a new escape location each day. A within-subjects design was used such that both short (20 min) and long (6 h) retention intervals, and both drug (SCH23390, a D1/D5 receptor antagonist) and vehicle (aCSF) infusions were tested on different days in the same animals. Bilateral intrahippocampal infusion of SCH23390 (5 microg in 1 microL per side) prior to trial 1 (encoding) caused a differential impairment as a function of memory delay-with no effect during trial 2 (memory retrieval) after a 20-min interval, but a block of memory at 6 h. Further experiments revealed that infusion of SCH23390 immediately after trial 1 had no effect on retention 6 h later, and the poor memory seen at long retention intervals when the drug was present at encoding was not due to a state-dependent failure of retrieval. These results suggest that activation of D1/D5 receptors during memory encoding is necessary for the formation of a persistent memory trace in the hippocampus. The complementary effects of D1/D5 receptor blockade on the persistence of LTP and the duration of memory are consistent with the idea that changes in synaptic strength underlie memory.