Serotonin upregulates the activity of phagocytosis through 5-HT1A receptors.
(1/126)
1 In this study, we investigated whether serotonin could regulate the in vitro activity of phagocytosis through 5-hydroxytryptamine or serotonin (5-HT(1A)) receptors. 2 Mouse peritoneal macrophages were cultured with serotonin and the activity of phagocytosis was assessed by the uptake of zymosan and latex particles added to the culture media. Specific binding of [(3)H]8-OH-DPAT and immunohistochemistry using an affinity-purified anti-5-HT(1A)-receptor antibody were assayed in the macrophages. In addition, we took advantage of the availability of pharmacological inhibitors of nuclear factor-kappaB (NF-kappaB) to explore its role in the regulation of the 5-HT(1A) receptor. 3 Serotonin increased the in vitro activity of phagocytosis in a dose-dependent manner. The 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propyl-amino)-tetralin (R(+)-8-OH-DPAT) reproduced these effects. Serotonin- or R(+)-8-OH-DPAT-induced increases in phagocytosis were blocked by the 5-HT(1A) receptor antagonist WAY100635 and the NF-kappaB inhibitor pyrrolidinedithiocarbamate. Moreover, mouse peritoneal macrophages expressed specific binding sites for [(3)H]8-OH-DPAT when cultivated in the presence of zymosan or latex beads. Immunohistochemistry confirmed the expression of the 5-HT(1A) receptor protein in the macrophages. 4 These results show that serotonin can upregulate the activity of peritoneal macrophages through 5-HT(1A) receptors. (+info)
SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.
(2/126)
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-az abicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia. (+info)
Stress sensitization of ethanol withdrawal-induced reduction in social interaction: inhibition by CRF-1 and benzodiazepine receptor antagonists and a 5-HT1A-receptor agonist.
(3/126)
Repeated withdrawals from chronic ethanol sensitize the withdrawal-induced reduction in social interaction behaviors. This study determined whether stress might substitute for repeated withdrawals to facilitate withdrawal-induced anxiety-like behavior. When two 1-h periods of restraint stress were applied at 1-week intervals to rats fed control diet, social interaction was reduced upon withdrawal from a subsequent 5-day exposure to ethanol diet. Neither this ethanol exposure alone nor exposure to three restraint stresses alone altered this measure of anxiety. Further, the repeatedly stressed singly withdrawn rats continued to exhibit a reduction in social interaction 16 days later, upon withdrawal from re-exposure to 5 days of chronic ethanol, consistent with a persistent adaptation by the multiple-stress/withdrawal protocol. Weekly administration of corticosterone in place of stress induced no significant change in social interaction upon withdrawal from the single chronic ethanol exposure, indicative that corticoid release is not responsible for the stress-induced reduction in anxiety-like behavior during withdrawal. In the multiple-withdrawal protocol, stress applied during withdrawal from voluntary ethanol drinking by P-rats facilitated ethanol drinking sufficiently, to induce a withdrawal-induced reduction in social interaction. Administration of a CRF-1 receptor antagonist, a benzodiazepine receptor antagonist, or a 5-HT(1A) receptor agonist prior to each stress minimized sensitization of the withdrawal-induced reduction in anxiety-like behavior. Since these pharmacological consequences on the induction of anxiety-like behavior following the stress/withdrawal protocol are like those previously seen when these drug treatments were given prior to multiple withdrawals, evidence is provided that repeated stresses and multiple withdrawals sensitize the withdrawal reduction in social interaction by similar central adaptive mechanisms. (+info)
In vivo characterization of 5-HT1A receptor-mediated gastric relaxation in conscious dogs.
(4/126)
Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT1A receptors mediating relaxation of the proximal stomach in conscious dogs. Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean+/-s.e.m.). All drugs were injected intravenously. The 5-HT1A receptor agonist flesinoxan (10, 50, 100 and 150 microg kg-1) induced a dose-dependent relaxation of the canine proximal stomach (50+/-10, 230+/-51, 290+/-38 and 275+/-33 ml, respectively; n=9-11). The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. NG-nitro-l-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317+/-50 vs 142+/-28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves. (+info)
Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala.
(5/126)
The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA. (+info)
5-Hydroxytryptamine1B receptor-mediated contraction of rabbit saphenous vein and basilar artery: role of vascular endothelium.
(6/126)
This study characterizes the sumatriptan-sensitive [5-hydroxytryptamine (5-HT)(1B/1D)] receptor in rabbit saphenous vein and basilar artery. (S)-(-)-1-[2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl]isochroman-6-carboxylic acid methylamide (PNU-109291), a 5-HT(1D) subtype-selective agonist (human K(i) = 2.5 +/- 0.07 nM), did not contract either tissue, whereas o-methoxyphenylpiperazide derivative 4F (MPPA-4F), a 5-HT(1B) subtype-selective antagonist (human K(i) = 4.6 +/- 0.6 nM) potently inhibited sumatriptan-induced contraction in the saphenous vein and basilar artery. These results suggested that sumatriptan-induced contraction was mediated via the 5-HT(1B) receptor in these blood vessels. 5-HT(1B) receptor-mediated contraction was then compared in endothelium-intact and denuded vessels to evaluate the role of the endothelium in regulating sumatriptan-induced contractility in these tissues. The presence of an intact endothelium inhibited 5-HT(1B)-induced contraction in both tissues. Endothelial denudation or nitric-oxide synthase inhibition with N(omega) nitro-L-arginine methyl ester (L-NAME) (100 microM) increased the efficacy and potency of sumatriptan in the saphenous vein and basilar artery. Surprisingly, in endothelial-denuded vascular tissues, L-NAME (100 microM) also significantly increased the maximal 5-HT(1B) receptor-induced contraction in both tissues, with no effect on potency of sumatriptan. The effect of L-NAME after endothelial denudation may reflect the presence of a low density of residual endothelial cells as estimated by CD31 antibody staining combined with the modulating effect of nitric oxide released from nonendothelial cells in vascular tissue. Endothelial modulation was specific to 5-HT(1B) receptors because removal of the endothelium did not significantly alter contraction to norepinephrine, histamine, prostaglandin, or potassium chloride in the saphenous vein or basilar artery. (+info)
Serotonergic facilitation of synaptic activity in the developing rat prefrontal cortex.
(7/126)
Previous studies have outlined an important role for serotonin (5-HT) in the development of synaptic connectivity and function in the cerebral cortex. In this study, we have examined the effects of 5-HT on synaptic function in prefrontal cortex at a time of intense synapse formation and remodelling. Whole-cell recordings in slices derived from animals aged postnatal (P) days 16-20 showed that administration of 5-HT induced a robust increase in synaptic activity that was blocked by CNQX but not by bicuculline. This 5-HT-induced increase in glutamate-mediated synaptic activity was pharmacologically heterogeneous as it was differentially inhibited by the receptor subtype-selective antagonists SB-269970, MDL 100907 and GR 113808 and thus involved 5-HT(7), 5-HT(2A) and 5-HT(4) receptors. These results, obtained in juvenile cortex, contrast with those seen in adults where the increase in spontaneous excitatory postsynaptic currents (sEPSCs) was mediated solely by 5-HT(2A) receptors. In developing cortex, activation of 5-HT(7), but not 5-HT(2A) or 5-HT(4) receptors, elicited a robust inward current. However, the facilitation of synaptic activity mediated by all three of these receptors involved increases in both the amplitude and frequency of sEPSCs and was blocked by TTX. These results are best interpreted as indicating that all three receptor subtypes increase synaptic activity by exciting neuronal elements within the slice. No evidence was found for a postsynaptic facilitation of synaptic currents by 5-HT. Together, these results show that the repertoire of electrophysiologically active 5-HT receptors in prefrontal cortex is developmentally regulated, and that 5-HT(7) and 5-HT(4) receptors play a previously unsuspected role in regulating synaptic activity in this region. (+info)
Effects of the potential antidepressant OPC-14523 [1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolino ne monomethanesulfonate] a combined sigma and 5-HT1A ligand: modulation of neuronal activity in the dorsal raphe nucleus.
(8/126)
OPC-14523 (OPC; [1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolino ne monomethanesulfonate)] is a novel compound with high affinity for sigma and 5-HT(1A) receptors as well as for the 5-HT transporter. OPC has previously been shown to produce antidepressant-like effects in animal models of depression. This project set out to determine the effect of OPC on serotonergic neurotransmission and to shed light on its mechanism(s) of action. In an electrophysiological model of in vivo extracellular recordings in anesthetized rats, a 2-day treatment (1 mg/kg/day) with OPC induced a significant increase in dorsal raphe nucleus (DRN) putative 5-HT neurons' firing activity. This increase was blocked by the coadministration of NE-100 [N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine], a selective sigma(1) antagonist (10 mg/kg/day). Furthermore, after 2-day treatments with OPC, the 5-HT(1A) autoreceptor response was altered, as demonstrated by the dramatically reduced response to an increase of endogenous 5-HT induced by the acute administration of paroxetine (500 microg/kg, i.v.). However, the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (4 microg/kg, i.v.) maintained its ability to decrease 5-HT firing activity, an effect that was reversible by the subsequent administration of the 5-HT(1A) antagonist WAY 100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexanecarboxami de] (100 microg/kg, i.v.). As 8-OH-DPAT has been shown to act preferentially through postsynaptic 5-HT(1A) receptors, our data suggests that this effect of OPC is mediated primarily by the 5-HT(1A) autoreceptor. The decreased response of the 5-HT(1A) autoreceptor to paroxetine was not blocked by the coadministration of NE-100 indicating that sigma(1) receptors are not involved in this effect. Thus, both sigma and 5-HT(1A) receptors play a role in the "antidepressant-like" effects produced by OPC, which is in keeping with previously published behavioral data. In addition, the current series of experiments suggest that OPC might have potential as an antidepressant with a rapid onset of action compared with selective serotonin reuptake inhibitor treatments, which initially suppress the firing activity of putative 5-HT neurons and require at least 2 to 3 weeks to restore the firing activity to baseline neuronal firing activity through a desensitization of the 5-HT(1A) autoreceptor. (+info)