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Progress in Neuro-psychopharmacology &... Aug 2009The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce... (Comparative Study)
Comparative Study
The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D(1) receptor selective antagonist, 0.5 mg/kg; L-741,626, D(2) receptor selective antagonist, 2 mg/kg; U-99194, D(3) receptor selective antagonist, 5 mg/kg; L-745,870, D(4) receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D(2) receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D(2) receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D(1), D(2), and D(3) receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate-putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.
Topics: Animals; Antipsychotic Agents; Brain; Carrier Proteins; Dopamine Antagonists; Gene Expression Regulation; Homer Scaffolding Proteins; Male; Protein Subunits; Rats; Rats, Sprague-Dawley; Receptors, Dopamine
PubMed: 19243698
DOI: 10.1016/j.pnpbp.2009.02.009 -
The Journal of Neuroscience : the... Mar 2008Single action potentials (APs) backpropagate into the higher-order dendrites of striatal spiny projection neurons during cortically driven "up" states. The timing of... (Comparative Study)
Comparative Study
Single action potentials (APs) backpropagate into the higher-order dendrites of striatal spiny projection neurons during cortically driven "up" states. The timing of these backpropagating APs relative to the arriving corticostriatal excitatory inputs determines changes in dendritic calcium concentration. The question arises to whether this spike-timing relative to cortical excitatory inputs can also induce synaptic plasticity at corticostriatal synapses. Here we show that timing of single postsynaptic APs relative to the cortically evoked EPSP determines both the direction and the strength of synaptic plasticity in spiny projection neurons. Single APs occurring 30 ms before the cortically evoked EPSP induced long-term depression (LTD), whereas APs occurring 10 ms after the EPSP induced long-term potentiation (LTP). The amount of plasticity decreased as the time between the APs and EPSPs was increased, with the resulting spike-timing window being broader for LTD than for LTP. In addition, we show that dopamine receptor activation is required for this spike-timing-dependent plasticity (STDP). Blocking dopamine D(1)/D(5) receptors prevented both LTD and LTP induction. In contrast, blocking dopamine D(2) receptors delayed, but did not prevent, LTD and sped induction of LTP. We conclude (1) that, in combination with cortical inputs, single APs evoked in spiny projection neurons can induce both LTP and LTD of the corticostriatal pathway; (2) that the strength and direction of these synaptic changes depend deterministically on the AP timing relative to the arriving cortical inputs; (3) that, whereas dopamine D(2) receptor activation modulates the initial phase of striatal STDP, dopamine D(1)/D(5) receptor activation is critically required for striatal STDP. Thus, the timing of APs relative to cortical inputs alone is not enough to induce corticostriatal plasticity, implying that ongoing activity does not affect synaptic strength unless dopamine receptors are activated.
Topics: Action Potentials; Animals; Cerebral Cortex; Corpus Striatum; Excitatory Postsynaptic Potentials; Neuronal Plasticity; Rats; Rats, Wistar; Receptors, Dopamine
PubMed: 18322089
DOI: 10.1523/JNEUROSCI.4402-07.2008 -
Gerontology 1982Parkinson's disease ranks among the most prevalent neurological diseases in the elderly. The disease usually begins after the age of 50 years, and the risk of the... (Review)
Review
Parkinson's disease ranks among the most prevalent neurological diseases in the elderly. The disease usually begins after the age of 50 years, and the risk of the disease rises steeply with advancing age. The primary etiology of Parkinson's disease is still unknown, although the aging process may be an important predisposing factor. There is some overlapping between Parkinson's disease and senile dementia of Alzheimer's type, although both seem to be disease entities. In Parkinson's disease, the most prominent and significant neuropathological change is the progressive loss of substantia nigra dopamine neurons. Studied of striatal dopamine receptors showed that the specific binding of 3H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the number of receptors, but no significant changes in the mean dissociation constant. Increased binding of 3H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3H-spiroperidol was found in patients treated with levodopa. The behavior of dopamine receptors in the nucleus accumbens was similar to that of dopamine receptors in the striatum. Clinically, the patients with low binding of 3H-spiroperidol in the striatum were more disabled and had lost the beneficial response to levodopa. Thus in some patients with Parkinson's disease a denervation supersensitivity seemed to develop and in others a loss of postsynaptic dopamine receptor sites in the neostriatum. The latter alteration may contribute to the decreased response of parkinsonian patients to long-term levodopa therapy. However, in patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors to alleviate directly the parkinsonian disability. Indeed, dopaminergic agonists seem to be a significant and valuable adjuvant therapy to levodopa for parkinsonian patients with a deteriorating response and/or on-off phenomena.
Topics: Aged; Aging; Brain; Corpus Striatum; Humans; Models, Biological; Parkinson Disease; Receptors, Dopamine; Spiperone
PubMed: 7044903
DOI: 10.1159/000212572 -
Autonomic & Autacoid Pharmacology Oct 2006Dopamine induces vasorelaxation of pulmonary artery primarily through an endothelium-dependent mechanism, but dopamine receptor subtypes involved in these mechanisms...
Dopamine induces vasorelaxation of pulmonary artery primarily through an endothelium-dependent mechanism, but dopamine receptor subtypes involved in these mechanisms have not been identified yet. The expression and localization of dopamine D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptors were investigated in hilar, lobar and intrapulmonary branches of human pulmonary artery by immunoblotting and immunohistochemistry. Pulmonary artery expresses dopamine D1, D2, D4 and D5 receptor subtypes, but not the D3 receptor subtype. Dopamine D1 and to a lesser extent D5 receptors were accumulated primarily in the endothelium of extrapulmonary branches of pulmonary artery. A faint dopamine D1 and D5 receptor immunoreactivity was found in the inner media of extrapulmonary and of large sized intrapulmonary branches of pulmonary artery, but not in medium- or small-sized intrapulmonary artery branches. Dopamine D2 and to a lesser extent D4 receptor immunoreactivity co-localized with the tyrosine hydroxylase-immunoreactive sympathetic plexus supplying pulmonary artery was found in the adventitia and in the adventitia-media of both extra- and different-sized intrapulmonary branches of pulmonary artery. These findings suggest the possible role of dopamine receptors in the pulmonary endothelium-dependent vasorelaxing activity. The D1 receptor subtype seems to be the most involved in this mechanism. Dopamine D2-like receptors are prejunctional and are located at the level of sympathetic neuroeffector plexus. The heterogeneous distribution and density of dopamine receptor subtypes along the human pulmonary arterial tree may be related to the different functional roles of dopamine at various levels of the pulmonary circulation.
Topics: Adolescent; Adult; Dopamine; Female; Humans; Immunoblotting; Immunohistochemistry; Male; Middle Aged; Pulmonary Artery; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4; Receptors, Dopamine D5; Tyrosine 3-Monooxygenase
PubMed: 16968475
DOI: 10.1111/j.1474-8673.2006.00376.x -
Proceedings of the Western Pharmacology... 1990
Review
Topics: Animals; Dopamine Agents; Dopamine Antagonists; Humans; Receptors, Dopamine
PubMed: 1980362
DOI: No ID Found -
International Review of Neurobiology 1989
Review
Topics: Animals; Arousal; Brain; Receptors, Dopamine
PubMed: 2689381
DOI: 10.1016/s0074-7742(08)60280-9 -
Brain Research Jun 1994Anti-peptide antibodies were generated against amino acid sequences of intracellular and extracellular portions of the native proteins for the cloned rat D1A and D3...
Anti-peptide antibodies were generated against amino acid sequences of intracellular and extracellular portions of the native proteins for the cloned rat D1A and D3 dopamine receptor subtypes in order to determine the cellular distribution of these specific forms in the brain. These polyclonal antisera exhibited high specific titers, assessed by ELISA and immunofluorescent detection of functional recombinant receptor proteins expressed in stably transfected Chinese hamster ovary (CHO) cells. Central nervous system (CNS) areas of the male rat were examined using standard immunofluorescent methods in fresh frozen tissues. This paradigm detected D1A-like and D3-like dopamine receptor staining primarily in larger-sized neurons throughout layers 3 and 5 of the cortex, in medium-diameter somata of the striatum, and in the densely packed cells of the olfactory tubercle and hippocampal formation. More attenuated immunoreactivity for both dopamine receptor subtypes was noted in the substantia nigra, not associated with perikarya. Differences in cellular staining patterns and intensity were evident between the D1A-like and D3-like dopamine receptor subtypes. Equivalent morphological elements exhibited dopamine receptor expression following incubation using antisera generated against either extracellular or intracellular epitopes of either the D1A or D3 native proteins. Dopamine receptor immunoreactivity could not be detected in the cerebellum at equivalent antisera dilutions used to discriminate cellular staining patterns within the forebrain. Fluorescent-labeled latex microspheres were infused into the substantia nigra terminal fields to retrogradely identify the cell bodies of the striatonigral projection system. This paradigm showed that 80% of striatonigral neurons expressed D1A-like receptors, while 65% demonstrated D3-like dopamine receptor staining. This distribution for the D1A-like and D3-like receptor subtypes suggests that overlap may occur in the expression of the receptors in the striatonigral neuron population. Our previous results localizing cellular D2-like receptor expression patterns in this projection system of the rat neostriatum implies that all three of these dopamine receptor subtypes may be co-expressed in this efferent system.
Topics: Amino Acid Sequence; Animals; Antibody Specificity; Brain; CHO Cells; Cricetinae; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Immunohistochemistry; Male; Microscopy, Fluorescence; Molecular Sequence Data; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 7953659
DOI: 10.1016/0006-8993(94)91052-9 -
Proceedings of the National Academy of... Nov 1992Dopaminergic neurons of the substantia nigra provide one of the major neuromodulatory inputs to the neostriatum. Recent in situ hybridization experiments have suggested...
Dopaminergic neurons of the substantia nigra provide one of the major neuromodulatory inputs to the neostriatum. Recent in situ hybridization experiments have suggested that postsynaptic dopamine receptors are segregated in striatonigral and striatopallidal neurons. We have tested this hypothesis in acutely isolated, retrogradely labeled striatonigral neurons by examining the neuromodulatory effects of selective dopaminergic agonists on Na currents and by probing single-cell antisense RNA populations with dopamine receptor cDNAs. In most of the neurons examined (20/31), the application of the D1 dopamine receptor agonist SKF 38393 reduced evoked whole-cell Na+ current. The D2 agonists quinpirole and bromocriptine had mixed effects; in most neurons (23/42), whole-cell Na+ currents were reduced, but in others (8/42), currents were increased. In cell-attached patch recordings, bath application of SKF 38393 decreased currents as in whole-cell recordings, whereas quinpirole consistently (6/10) enhanced currents--suggesting that D2-like receptors could act through membrane delimited and non-delimited pathways. Changes in evoked current were produced by modulation of peak conductance and modest shifts in the voltage dependence of steady-state inactivation. Antisense RNA probes of dopamine receptor cDNA Southern blots consistently (5/5) revealed the presence of D1, D2, and D3 receptor mRNA in single striatonigral neurons. These findings argue that, contrary to a strict receptor segregation hypothesis, many striatonigral neurons colocalize functional D1, D2, and D3 receptors.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antisense Elements (Genetics); Base Sequence; Blotting, Southern; Bromocriptine; DNA; Ergolines; Evoked Potentials; Microscopy, Fluorescence; Molecular Sequence Data; Neostriatum; Neurons; Oligodeoxyribonucleotides; Quinpirole; RNA Probes; RNA, Messenger; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Sodium Channels; Substantia Nigra
PubMed: 1332033
DOI: 10.1073/pnas.89.21.10178 -
Annals of the New York Academy of... Nov 1993
Review
Topics: Animals; Behavior, Animal; Corpus Striatum; Dopamine Agents; Receptors, Dopamine
PubMed: 7906498
DOI: 10.1111/j.1749-6632.1993.tb17248.x -
Neurochemistry International Mar 1992
Review
Topics: Amino Acid Sequence; Animals; Humans; Molecular Biology; Molecular Sequence Data; Nervous System; Neurobiology; Receptors, Dopamine
PubMed: 1365419
DOI: 10.1016/0197-0186(92)90205-6