Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The administration of the 5-HT1A agonist 8-OH-DPAT (0.8 mumols kg-1 s.c.-40 min) produced an increase in dopamine (DA) turnover, estimated by the quotient (DOPAC + HVA) DA-1, in the ventral striatum of the rat. No statistically significant effects were obtained in the dorsal striatum. The accumulation of 3-MT in pargyline-treated animals (375 mumols kg-1 s.c.-60 min) was not affected by 8-OH-DPAT treatment (0.15-2.4 mumols kg-1 s.c.-30 min). These findings indicate that 8-OH-DPAT has weak antagonist properties at striatal DA receptors in normal rats. Both the 5-HT1A agonist flesinoxan (0.06-17.8 mumos kg-1 s.c. -50 min) and the mixed 5-HT1 and 5-HT2 agonist 5-MeODMT (1.6-26.0 mumols kg-1 s.c.-50 min) produced a decrease in forebrain 5-HTP accumulation (striatum and neocortex), following decarboxylase inhibition by means of NSD-1015 in reserpine treated rats, indicating stimulation of central 5-HT receptors by these two compounds. At the same time, the DOPA accumulation by the ventral striatum was decreased by flesinoxan and increased by 5-MeODMT treatment. These observations show that, under these conditions, the decrease in DA synthesis is not directly coupled to the decreased 5-HT synthesis produced by flesinoxan, as previously demonstrated for 8-OH-DPAT. Taken together with previous observations, the present results suggest that 8-OH-DPAT, depending on the experimental conditions, is an agonist or antagonist at striatal DA receptors, in all probability due to partial DA receptor agonist properties of the compound.
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PMID:Increased dopamine turnover in the ventral striatum by 8-OH-DPAT administration in the rat. 197

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock ("conflict" procedure). Under the multiple schedule, spiroxatrine (0.3-1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01-1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.
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PMID:Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine. 252 83

The interaction of SCH 23390 with dopamine (DA) and serotonin (5-HT) systems has been examined in vivo and in vitro. Like selective 5-HT2 blockers, SCH 23390 inhibited in vivo [3H]spiperone binding in the rat frontal cortex (ID50: 1.5 mg/kg) without interacting at D2 sites. SCH 23390 was equipotent to cinanserin and methysergide. In vitro, SCH 23390 inhibited [3H]ketanserin binding to 5-HT2 sites (IC50 = 30 nM). Biochemical parameters linked to DA and 5-HT were not changed excepted in striatum where SCH 23390 increased HVA and DOPAC. In the L-5-HTP syndrome model, SCH 23390 clearly showed antagonism of 5-HT2 receptors. SCH 23390 had weak affinity for 5-HT1B (IC50 = 0.5 microM), 5-HT1A (IC50 = 2.6 microM) and alpha 1-adrenergic receptors (IC50 = 4.4 microM).
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PMID:Interaction of the D1 receptor antagonist SCH 23390 with the central 5-HT system: radioligand binding studies, measurements of biochemical parameters and effects on L-5-HTP syndrome. 329 Apr 70

Intrastriatal administration of ipsapirone (IPSA, 0.5 and 1 mM), an agonist of 5-HT1A serotonergic receptors, enhanced in a dose-dependent manner DA release in the rat striatum, without affecting levels of the DA metabolites DOPAC and HVA. The IPSA evoked-enhancement of DA release was followed by a decrease in 5-HIAA concentration. The effects of intrastriatal administration of IPSA were mimicked by 8-OH-DPAT (0.5 mM), another agonist of 5-HT1A receptors, and were antagonized by the peripheral administration of metergoline (5 mg/kg ip) and intrastriatal administration of NAN-190 (0.5 mM). IPSA given peripherally (10 mg/kg ip) also enhanced DA release; that effect was accompanied by an increase in DOPAC and HVA levels. It is postulated that IPSA increases the release of DA from nigrostriatal terminals via activation of striatal 5-HT1A receptors in a manner independent of the activation of 5-HT1A receptors in the dorsal raphe nuclei.
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PMID:Enhancement by ipsapirone of dopamine release in the rat striatum. 769 36

SR 57746A (1-[2-(naphth-2-yl) ethyl]-4-(3-trifluoromethylphenyl)-1, 2, 5, 6 tetra-hydropyridine hydrochloride) binds competitively, and with high affinity (Ki = 2.0 +/- 0.7 nM) to 5-HT1A receptors from rat hippocampus in vitro, but has much less affinity for other 5-HT receptor subtypes (IC50 > 650 nM). SR 57746A produces a concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates, with a maximal effect identical to that of 8-OH-DPAT, suggesting that SR 57746A behaves as a full agonist in this experimental model. SR 57746A potently displaces [3H]8-OH-DPAT binding to rat hippocampal membranes ex vivo, with an ID50 of 11.1 mg/kg po, 30 min after administration, and 2.8 mg/kg po, 2 h after administration. This effect of SR 57746A is long-lasting (at least 24 hours at 10 mg/kg po). SR 57746A does not modify the levels of 5-HT or DA in various brain areas, but decreases the concentrations of 5-HIAA, and increases those of DOPAC, HVA and 3-MT. Following i.v. administration, SR 57746A (0.095 to 0.25 mg/kg) inhibits the spontaneous firing of dorsal raphe neurones, but does not modify the activity of DA neurones in the substantia nigra or ventral tegmental area. Thus, SR 57746A is a potent, selective and full agonist at 5-HT1A receptors in vitro and vivo.
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PMID:Biochemical and electrophysiological properties of SR 57746A, a new, potent 5-HT1A receptor agonist. 831 96

The effect 5-HT1A receptor activation on the temperature dependence of HVA calcium channel currents has been studied in acutely isolated DR neurones, using barium as the charge carrier. 8-OH-DPAT caused a reduction in the temperature dependence of the peak current amplitude. However the most dramatic effect of 8-OH-DPAT was a large reduction in Q10 for the current activation rate. This also occurred with direct G-protein activation using GTP gamma S. In the presence of GTP gamma S, current activation became bi-exponential, rather than mono-exponential as in the control situation. The time constants of both components were significantly slower than the controls, and the Q10 for both components was significantly lower. GDP beta S had no effect on the temperature dependence or kinetics of activation of HVA current. Depolarizing prepulses applied prior to test pulses were able to reverse the action of 8-OH-DPAT on the Q10 of the activation rate. When prepulses were applied to cells containing GTP gamma S, the activation rate Q10 was similar to control values. We postulate that the highly significant reduction in activation rate Q10, seen with both 8-OH-DPAT and GTP gamma S, is as a result of a change in the mechanism underlying activation of HVA channels on depolarization. Contrary to previous models of calcium current modulation our results show that the mechanisms responsible for slowed activation by transmitters and facilitation of the residual current by depolarizing prepulses have little in common. We present a new model of transmitter modulation of HVA current, consistent with a mechanistic approach to channel subunit structure.
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PMID:The modulation of calcium channel currents recorded from adult rat dorsal raphe neurones by 5-HT1A receptor or direct G-protein activation. 860 96

1. Whole-cell Ca2+ currents (ICa) from cultured rat melanotrophs were identified by their sensitivity to Ca2+ channel blockers, and their modulation by serotonin (5-HT) was studied. All cells displayed high voltage-activated (HVA; > -30 mV) Ca2+ currents. A low voltage-activated (LVA; > -60 mV) Ca2+ current was detected in 92% of the cells. 2. The whole-cell ICa was insensitive to omega-conotoxin GVIA (0.5-1 microM) indicating the absence of N-type Ca2+ channels. 3. At a holding potential (Vh) of -70 mV, the L-type channel blocker nifedipine reduced ICa in a dose-dependent manner with a half-maximal effective concentration (IC50) of 28 nM. The L-type current represented 39% of the total ICa. 4. omega-Agatoxin IVA (omega-Aga IVA) produced a biphasic dose-dependent inhibition of ICa, with IC50 values of 0.4 and 91 nM, indicating the presence of P-type and Q-type Ca2+ channels, which accounted respectively for 16 and 45% of the total ICa. The P-type current was also blocked by synthetic funnel-web spider toxin (sFTX 3.3; 1-10 microM) and was present only in a subpopulation (60-70%) of cells. 5. All cells possessed a Ca2+ current which was resistant to nifedipine (10 microM) and omega-Aga IVA (50 nM). This current was not affected by Ni2+ (40 microM) but was abolished by a low concentration of Cd2+ (10 microM) and by omega-conotoxin MVIIC (1 microM) indicating that it was a Q-type Ca2+ current. 6. 5-HT (10 microM) inhibited the whole-cell ICa in 70% of the cells tested (n = 120) by activating 5-HT1A and 5-HT2C receptors. 5-HT produced either a kinetic slowing of the activation phase (37% of the cells) or a scaling down (14% of the cells) of ICa. In the majority of cells (49%) both types of inhibition were found to coexist. 7. The effects of 5-HT were voltage dependent, rendered irreversible when GTP-gamma-S (30 microM) was present in the pipette solution and abolished by pretreatment of the cells with pertussis toxin (PTX; 150 ng ml-1, 18 h). 8. Low concentrations of omega-Aga IVA (20 nM), which blocked mainly P-type channels, did not reduce the effect of 5-HT on ICa. The scaling down effect of 5-HT on ICa was eliminated in the presence of nifedipine (10 microM) and the kinetic slowing effect of 5-HT persisted after blockade of L- and P-type channels but was abolished by omega-conotoxin MVIIC (1 microM). 9. We conclude that rat melanotrophs possess functional L-, P- and Q-type Ca2+ channels and that 5-HT inhibits selectively L-type and Q-type Ca2+ currents with different modalities. These effects are voltage dependent and mediated by a PTX-sensitive G-protein.
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PMID:Selective inhibition of high voltage-activated L-type and Q-type Ca2+ currents by serotonin in rat melanotrophs. 868 60

1. The present study has examined the effect of (+)-WAY 100135, a selective antagonist of 5-HT1A receptors, and ketanserin, an antagonist of 5-HT2 receptors, on the urinary excretion of Na+, K+, dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in rats treated with the selective type A monoamine oxidase (MAO-A) inhibitor, Ro 41-1049 (15 mg kg-1 day-1) in conditions of normal sodium (NS) and high sodium (HS; 1.0% NaCl in drinking water) intake. 2. Male Wistar rats were placed in metabolic cages and were given tap water (NS diet) in the first 4 days of the study and then challenged to a HS diet for another 7 days. Ro 41-1049 was given in drinking water only in the last 3 days of the HS diet, whereas (+)-WAY 100135 (5 and 10 mg kg-1 day-1, s.c.) or ketanserin (2 mg kg-1 day-1, s.c.) were administered in the last 4 days of the HS intake period. 3. Daily urinary excretion (in nmol kg-1 day-1) of dopamine (82 +/- 2), 3,4-dihydroxyphenylacetic acid (DOPAC; 198 +/- 9), homovanillic acid (HVA; 915 +/- 47), 5-HT (586 +/- 37) and 5-hydroxyindoleacetic acid (5-HIAA; 1035 +/- 64) in the HS intake period was similar or higher than that in NS diet (dopamine = 68 +/- 2, DOPAC = 197 +/- 4, HVA = 923 +/- 42, 5-HT = 539 +/- 132, 5-HIAA = 1286 +/- 95). The administration of Ro 41-1049 on 3 consecutive days reduced the urinary excretion of dopamine, DOPAC and HVA, respectively, by 35-51% (P < 0.05), 73-85% (P < 0.05) and 59-66% (P < 0.05); the urinary excretion of 5-HT increased 2 fold (P < 0.01) and the levels of 5-HIAA were reduced by 39-77% (P < 0.05). 4. During HS intake (7 days), daily urinary excretion of Na+ increased 5.5 fold (from 6.7 +/- 0.2 to 36.5 +/- 0.9 mmol kg-1 day-1), without changes in the urinary excretion of K+ (from 11.2 +/- 0.2 to 11.9 +/- 0.5 mmol kg-1 day-1) and urinary osmolality (from 1083.8 +/- 26.7 to 1117.7 +/- 24.1 mOsm kg-1 H2O). MAO-A inhibition during HS intake was found to produce a 47-68% decrease in Na+ excretion (from 39.1 +/- 0.7 to 15.1 +/- 2.5 mmol kg-1 day-1, n = 4; P < 0.02) and urine volume (from 160.4 +/- 3.3 to 43.8 +/- 9.0 ml kg-1 day-1, n = 4; P < 0.02) without changes in K+ (from 11.1 +/- 0.5 to 9.2 +/- 0.6 mmol kg-1 day-1, n = 4) and creatinine (from 29.1 +/- 2.3 to 28.4 +/- 2.1 mg kg-1 day-1) excretion; urine osmolality increased 2 fold (from 936.3 +/- 40.3 to 2210.7 +/- 157.4 mOsm kg-1 H2O, n = 4; P < 0.02). Administration of (+)-WAY 100135 (5 and 10 mg kg-1 day-1), but not of ketanserin (2 mg kg-1 day-1), was found to inhibit the antinatriuretic effect induced by Ro 41-1049 during HS intake. 5. It is suggested that MAO-A inhibition during HS intake leads to an increased availability of 5-HT in renal tissues, the effect of which is a decrease in the urinary excretion of Na+, involving the activation of tubular 5-HT1A receptors.
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PMID:Antagonistic actions of renal dopamine and 5-hydroxytryptamine: endogenous 5-hydroxytryptamine, 5-HT1A receptors and antinatriuresis during high sodium intake. 888 15

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.
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PMID:Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway. 902 99

The aim of the present study was to investigate whether the voltage-dependent inhibition of calcium currents by serotonin 5-HT1A agonists can be alleviated (facilitated) by action potential-like depolarizations. In dissociated cholinergic basal forebrain neurons using whole-cell recordings, it is shown that a selective serotonin 5-HT1A agonist (8-OH-DPAT) predominantly blocks N-type HVA calcium current, although a minor reduction of P-type current was also observed. The inhibition may principally occur through Gi-Go subtypes of G-proteins because it was prevented by N-ethylmaleimide, a substance known to block specifically pertussis-sensitive G-proteins. The inhibitory effect of 8-OH-DPAT on calcium currents is voltage-dependent because it was alleviated by long-lasting depolarizing prepulses. Interestingly, the inhibition could also be reversed by prepulses made-up of action potential-like depolarizations that were given at a frequency of 200 Hz. This observation may have important implications during periods of high-frequency rhythmic bursts, a firing pattern that is prevalent in cholinergic basal forebrain neurons.
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PMID:The serotonin inhibition of high-voltage-activated calcium currents is relieved by action potential-like depolarizations in dissociated cholinergic nucleus basalis neurons of the guinea-pig. 978 23


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