(1/66) Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment.
1. Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine (5-HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light-dark cycle. 2. Infusion of the 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) 0.1, 1.0 and 10 microM through the microdialysis probe led to a concentration-dependent decrease (49, 56 and 65% respectively) in 5-HT output. The effect of RU24969 (1 and 5 microM) was prevented by concurrent infusion of methiothepin (1 and 10 microM) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10 microM) increased (15 and 142% respectively) 5-HT output. 3. Infusion of RU24969 (5 microM) through the probe at mid-light and end-light resulted in a quantitatively greater decrease in 5-HT output at end-light compared with mid-light. 4. Following treatment with either paroxetine hydrochloride (10 mg kg(-1) i.p.) or desipramine hydrochloride (10 mg kg)(-1) i.p.) for 21 days the function of the terminal 5-HT1B autoreceptor was more markedly attenuated at end-light. 5. The data show that, as defined by the response to RU24969, the function of the 5-HT1B receptors that control 5-HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time-of-day-dependent manner. (+info)
(2/66) Influence of the endothelium, nitric oxide and serotonergic receptors on coronary vasomotor responses evoked by ergonovine in conscious dogs.
1. The respective contributions of coronary vascular endothelium, nitric oxide (NO) and serotonergic receptors to the effects of ergonovine on large and small coronary arteries were investigated in conscious dogs. 2. In seven dogs with an endothelium intact, ergonovine (30 - 1000 microg, i.v.) induced a biphasic response on large coronary artery with an early and transient vasodilatation (up to +2.9+/-0.5% from 3310+/-160 microm, P<0.01) followed by a sustained vasoconstriction (down to -4.9+/-0.5%, P<0.001) which occurred simultaneously with a sustained increase in coronary blood flow (CBF) (up to +100+/-26% from 28+/-4 ml min(-1), P<0.001). After endothelium removal (balloon angioplasty), the ergonovine-induced vasodilatation was abolished and vasoconstriction potentiated (-6.4+/-0.9% after vs -4.9+/-0.5% before endothelium removal, P<0.01). 3. After blockade of NO synthesis by Nomega-nitro-L-arginine (30 mg kg(-1)) in four other dogs, the early vasodilatation induced by ergonovine was abolished but the delayed vasoconstriction as well as the increase in CBF remained unchanged. 4. Both ketanserin and methiothepin (0.3 mg kg(-1)) abolished the early vasodilatation and reduced the delayed vasoconstriction induced by ergonovine. Ketanserin decreased and methiothepin abolished the reduction in coronary resistance induced by ergonovine. 5. Thus, the complex interactions between vascular endothelium and serotonergic receptors to ergonovine-induced constriction of large coronary arteries might explain the induction of coronary spasms in patients with endothelial dysfunction. (+info)
(3/66) Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area.
The ventral tegmental area (VTA) is the origination zone for dopaminergic neurons involved in reward and addictive properties of a variety of abused substances. A major excitatory projection to VTA neurons originates in the medial prefrontal cortex, and several lines of evidence suggest that glutamatergic synapses on VTA neurons are activated and modified during exposure to psychostimulant drugs. Here, we report for the first time that amphetamine depresses excitatory glutamatergic synaptic transmission onto VTA neurons in the midbrain slice preparation. Unexpectedly, this depression is mediated not by activation of dopamine receptors, but instead by activation of serotonin receptors. Our findings suggest that an acute effect of amphetamine exposure is the release of serotonin in the VTA, which in turn modulates excitation of VTA neurons. This process may be an important early component of permanent changes occurring in the reward pathway that contribute to drug addiction. (+info)
(4/66) Limited contributions of serotonin to long-term hyperexcitability of Aplysia sensory neurons.
Serotonin (5-HT) has provided a useful tool to study plasticity of nociceptive sensory neurons in Aplysia. Because noxious stimulation causes release of 5-HT and long-term hyperexcitability (LTH) of sensory neuron somata and because 5-HT treatment can induce long-term synaptic facilitation of sensory neuron synapses, a plausible hypothesis is that 5-HT also induces LTH of the sensory neuron soma. Prolonged or repeated exposure of excised ganglia to 5-HT produced immediate hyperexcitability of sensory neurons that showed little desensitization, but the hyperexcitability decayed within minutes of washing out the 5-HT. Prolonged or repeated treatment of either excised ganglia or dissociated sensory neurons with various concentrations of 5-HT failed to induce significant LTH even when long-term synaptic facilitation was induced in the same preparations. Use of a high-divalent cation solution to reduce interneuron activity during 5-HT treatment failed to enable the induction of LTH in excised ganglia. Pairing 5-HT application with nerve shock failed to enhance LTH produced by nerve shock or to reveal covert LTH produced by 5-HT. The induction of LTH by nerve stimulation was enhanced rather than inhibited by treatment with methiothepin, a 5-HT antagonist reported to block various 5-HT receptors and 5-HT-induced adenylyl cyclase activation. This suggests that endogenous 5-HT may have inhibitory effects on the induction of LTH by noxious stimulation. Methiothepin blocked immediate hyperexcitability produced by exogenous 5-HT and also inhibited the expression of LTH induced by nerve stimulation when applied during testing 1 day afterward. At higher concentrations, methiothepin reduced basal excitability of sensory neurons by mechanisms that may be independent of its antagonism of 5-HT receptors. Several observations suggest that early release of 5-HT and consequent cAMP synthesis in sensory neurons is not important for the induction of LTH by noxious stimulation, whereas later release of 5-HT from persistently activated modulatory neurons, with consequent elevation of cAMP synthesis, may contribute to the maintenance of LTH. (+info)
(5/66) Effect of serotonin receptor antagonist on phosphate excretion.
To determine whether endogenous intrarenal 5-hydroxytryptamine affects phosphate excretion, the serotonin receptor antagonist methiothepin (20 microgram/kg, +6 microgram/kg per h) was infused into the renal interstitium of rats fed a normal phosphate diet (0.7% phosphate [Pi]) in the presence of endogenous parathyroid hormone (PTH). Renal interstitial infusion of methiothepin significantly increased fractional phosphate excretion (FE(Pi)) from 23 +/- 4 to 30 +/- 4% (n = 8, P < 0.05). To determine whether serotonin modulates the phosphaturic response to PTH during conditions of dietary phosphate excess or deprivation, rats were fed either a high (1.8% Pi, HPD) or low (0.07% Pi, LPD) phosphate diet, and methiothepin (100 microgram/kg, +30 microgram/kg per h) or saline vehicle was infused intravenously before and during PTH infusion (33 U/kg, +1 U/kg per min). Methiothepin infusion significantly increased FE(Pi) in thyroparathyroidectomized rats fed a HPD from 25 +/- 4 to 32 +/- 4% (n = 9, P < 0.05), and the subsequent administration of PTH further increased the FE(Pi) to 64 +/- 3% (P < 0.05). The increase in FE(Pi) during PTH infusion was similar in the absence (Delta27 +/- 5%, n = 7) and presence (Delta33 +/- 6%) of methiothepin, P > 0.05. In thyroparathyroidectomized rats fed a LPD, methiothepin infusion did not increase phosphate excretion (0.8 +/- 0.4 to 1.3 +/- 0.9%, n = 7, P > 0.05). However, the increase in FE(Pi) during PTH infusion was significantly greater in the presence of methiothepin (1.3 +/- 0.9 to 20.0 +/- 4.0%, Delta18.7 +/- 3.5%) than in the vehicle-infused rats (0.5 +/- 0.2 to 8.8 +/- 1.1%, Delta8.3 +/- 1.2%; n = 8, P < 0.05). In conclusion, these observations suggest that endogenous intrarenal serotonin enhances phosphate reabsorption in phosphate-replete rats, and attenuates the phosphaturic response to PTH in phosphate-deprived rats. (+info)
(6/66) Intrarenal serotonin, dopamine, and phosphate handling in remnant kidneys.
BACKGROUND: Serotonin (5-HT) and dopamine (DA) are intrarenal autocrine/paracrine substances that regulate phosphate reabsorption. The present studies explored intrarenal serotonin and DA metabolism and the implications for phosphate homeostasis in rats with remnant kidneys, a model for renal failure. METHODS: The intrarenal productions of serotonin and DA were determined from measurements of renal interstitial fluid (microdialysate) and urine in rats with remnant or intact kidneys. In clearance studies, the effects of infusion of methiothepin, a serotonin receptor antagonist, or gludopa, a renal selective DA precursor, on phosphate and sodium excretion were determined in rats with a remnant or intact kidneys. RESULTS: Renal interstitial serotonin (5-HT, 3.4 +/- 0.9 pg/min) was fourfold higher than DA (0.6 +/- 0.1 pg/min) in remnant kidneys. Conversely, urinary excretion of serotonin was fourfold less than DA in rats with a remnant kidney (5-HT 0.4 +/- 0.02 vs. DA 1.5 +/- 0.1 ng/min). Infusion of methiothepin or gludopa significantly increased the fractional excretion of phosphate (FE(Pi)) in rats with a remnant kidney from 54 +/- 3 to 67 +/- 7% (P < 0.05) and from 36 +/- 10% to 51 +/- 13% (P < 0.05), respectively. CONCLUSION: We conclude that serotonin preferentially accumulates in the renal interstitium, whereas DA exits primarily via the tubular lumen. Phosphate excretion is increased by both the acute infusion of the serotonin receptor antagonist and the infusion of gludopa, suggesting that both serotonin and DA modulate phosphate excretion in rats with remnant kidneys. (+info)
(7/66) Hyperpolarization caused by serotonin contributes to endothelium-dependent relaxations in the porcine coronary artery.
AIM: The present study was designed to investigate the contribution of membrane hyperpolarization to endothelium-dependent relaxations induced by serotonin in the porcine coronary artery. METHODS: Rings with and without endothelium of porcine coronary arteries were suspended in conventional organ chambers for the measurement of isometric force. The cell membrane potential of the vascular smooth muscle cells was measured using glass microelectrodes, in the presence of indometacin, ketanserin, and/or N omega-nitro-L-arginine. RESULTS: Serotonin induced a transient endothelium-, and concentration-dependent relaxation in rings contracted with prostaglandin F2 alpha in the presence of N omega-nitro-L-arginine (maximal relaxation: 19%). The N omega-nitro-L-arginine resistant relaxation was abolished by high K+ and tetrabutylammonium chloride. Serotonin also caused an endothelium-, concentration-dependent membrane hyperpolarizations with a maximal amplitude of -8.8 mV. The nitro-L-arginine resistant relaxations and hyperpolarizations were abolished by methiothepin, but not by glibenclamide. The time course of the endothelium-dependent relaxations and hyperpolarizations was similar. CONCLUSION: These results suggest a contribution of cell membrane hyperpolarization to the endothelium-dependent relaxations induced by serotonin in the porcine coronary artery. (+info)
(8/66) Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat.
We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors. (+info)