Effects Of 5HT Research Articles

Intracranial-extracranial differences in the Ca2+ sensitivity of rabbit arteries.

We have previously demonstrated that the ratio of calcium uptake to force production varies widely with age, artery size, and method of contraction in cerebral arteries. The present experiments were conducted to examine the possibility that these differences involve corresponding variations in contractile force-calcium relations. Common carotid (COM), basilar (BAS), and middle cerebral (MCA) arteries from adult were denuded of endothelium and mounted in vitro for measurement of contractility. Following equilibration at optimum resting diameter, the arteries were permeabilized (beta-escin, 50 microg/ml) and depleted of intracellular Ca2+ by treatment with 1 microM A23187. Ca2+ depletion was verified by absence of any contracile response to either 25 mM caffeine or 1 microM inositol 1,4,5-trisphosphate. Then, in the continuous presence of 1 microM calmodulin, bath calcium concentration was raised from zero through 10 microM in half-log increments and the corresponding contractions were recorded. For all permeabilized arteries, the maximum force produced by 10 microM Ca was greater than or equal to that produced by 120 mM potassium-Krebs in the same segment before skinning. The pD2 (-log ED50) values for calcium averaged 6.39 +/- 0.03, 6.77 +/- 0.04, and 6.92 +/- 0.03 in COM, BA, and MCA segments, respectively. In arteries contracted by a constant submaximal concentration of calcium (0.1 microM for BAS and MCA, 0.3 microM for COM), the addition of 5HT produced a dose-dependent and GDPbetaS-sensitive increase in tension of up to 44% maximum. GTPgammaS mimicked the effects of 5HT and prevented further increases in Ca force induced by 5HT. Together, these data demonstrate that cerebrovascular calcium sensitivity is an anatomically heterogenous, physiologically regulated parameter responsive to agonist-induced perturbations.

Modulation of Antennal Scanning in the Honeybee by Sucrose Stimuli, Serotonin, and Octopamine: Behavior and Electrophysiology

Antennal motor activity of the honeybee was used to test the effects of sucrose stimuli and of serotonin and octopamine microinjections into the brain. The antennal scanning behavior was analyzed in behavioral experiments. Activity of an antennal muscle, the “fast pedicellus flexor muscle” which dominates scanning behavior, was used as a physiological measure of modulatory effects. A single sucrose stimulus applied to both the antenna and the proboscis leads to significant increases of the frequency of antennal scanning compared to those of untreated controls and animals stimulated with water. A single sucrose stimulus applied only to the antenna or the proboscis has no significant behavioral effects. Injection of small volumes (approximately 500 pl) of serotonin (5HT) or octopamine (OA) at concentrations of 10−5Minto the dorsal lobe, the sensory motor center of the antenna, leads to functionally antagonistic behavioral effects. While 5HT injection significantly reduces the antennal scanning frequency, OA significantly enhances it. The degree of behavioral modulation is significantly correlated with the activity of the animals. In animals which display low scanning activity, OA injection has an enhancing effect, while 5HT has no effect. In contrast, 5HT injection, but not OA injection, produces a behavioral effect in animals with high scanning activity. Behavioral changes and changes of activity of the fast pedicellus flexor muscle are closely correlated. Significant, functionally antagonistic effects of 5HT and OA on muscle activity were found after injections of the compounds into the dorsal lobe. 5HT leads to a reduction of the muscle potential frequency starting immediately after injection and lasting at least 15 min. OA injection results in an increase of frequency, which has its maximum 5 min after injection. The experiments demonstrate that sucrose, the reward stimulus during associative learning in the bee, also modulates motor activity under nonassociative conditions. The similar effects of sucrose stimulation and OA injection are consistent with the hypothesis that OA mediates the effects of sucrose stimuli.

Serotonergic effects on hypoglossal neural activity and reflex responses

We determined the effects of serotonin (5HT; 6 concentrations ranging from 0.005 to 500 μM) pressure microinjection into the hypoglossal (XII) motor nucleus (100–500 nl; pH = 7.2–7.4) on XII whole nerve activity and reflex response to upper airway negative pressure in 15 decerebrated, vagotomized, paralyzed and artificially ventilated cats. Increasing 5HT concentration resulted in a concentration dependent increase in ipsilateral tonic XII activity, with no change in phasic XII activity. Threshold concentrations ranged from 0.005 to 0.5 μM, with the maximal response reached at 5 μM. Increasing 5HT concentration also increased the duration of the XII response. This ranged from 50 s with 0.5 μM, to over 10 min with 500 μM 5HT. However, 5HT did not significantly change the XII whole nerve reflex response to upper airway negative pressure (−20 cm H 2O) at any 5HT concentration ( n = 5). All 5HT effects were reversed by microinjection of 1.0 mM methysergide. We conclude that XII responses to 5HT are elicited at low concentrations of 5HT, which have a relatively short duration of effect, but that 5HT at the XII motor nucleus has no effect on the XII reflex response to upper airway negative pressure.

Serotonergic effects on hypoglossal neural activity and reflex responses

We determined the effects of serotonin (5HT; 6 concentrations ranging from 0.005 to 500 μM) pressure microinjection into the hypoglossal (XII) motor nucleus (100–500 nl; pH = 7.2–7.4) on XII whole nerve activity and reflex response to upper airway negative pressure in 15 decerebrated, vagotomized, paralyzed and artificially ventilated cats. Increasing 5HT concentration resulted in a concentration dependent increase in ipsilateral tonic XII activity, with no change in phasic XII activity. Threshold concentrations ranged from 0.005 to 0.5 μM, with the maximal response reached at 5 μM. Increasing 5HT concentration also increased the duration of the XII response. This ranged from 50 s with 0.5 μM, to over 10 min with 500 μM 5HT. However, 5HT did not significantly change the XII whole nerve reflex response to upper airway negative pressure (−20 cm H 2 O) at any 5HT concentration ( n = 5 ). All 5HT effects were reversed by microinjection of 1.0 mM methysergide. We conclude that XII responses to 5HT are elicited at low concentrations of 5HT, which have a relatively short duration of effect, but that 5HT at the XII motor nucleus has no effect on the XII reflex response to upper airway negative pressure.

S-38-3 - Comorbidities in social phobia

Social phobia, particularly the generalized form, is strongly familial and frequently comorbid with major depression, panic disorder, and obsessive–compulsive disorder. It has also recently been shown to be responsive to selective serotonin reuptake inhibitors. We conducted a study to determine if generalized social phobia is genetically linked to either of two candidate genes: the serotonin transporter protein (5HTT) gene, or the 5HT2A receptor (5HT2AR) gene. Rates of social phobia (using several phenotype definitions) were ascertained and blood samples obtained from consenting first-degree family members of generalized social phobic probands. 5HT2AR and 5HTT genotyping was performed using the polymerase chain reaction (PCR). Linkage was tested using LINKAGE and GENEHUNTER software. No evidence of linkage was found; power analysis indicated that failure to find linkage was unlikely due to inadequate statistical power. These findings reasonably exclude linkage between generalized social phobia and the 5HTT or 5HT2AR genes in these samples, although modifier effects cannot be ruled out. Other 5HT receptor subtypes or indirect modulatory effects of 5HT on other neurotransmitter systems may be involved.

Serotonin modulates N- and P-type calcium currents in neocortical pyramidal neurons via a membrane-delimited pathway.

1. The effects of serotonin (5HT) on neocortical pyramidal neurons were studied using whole cell and ON-cell patch-clamp recordings from acutely dissociated neurons. 2. 5HT decreased high voltage-activated calcium channel currents in a dose-dependent and reversible manner in acutely dissociated neocortical pyramidal neurons. The maximum block was 30% of the peak whole cell current (at -10 mV). 3. The 5HT modulation was mimicked by 5HT1A agonists and was reduced by 5HT1A antagonists. 5HT2 antagonists had no effect on the modulation. These data suggest that the 5HT effects were mediated by 5HT1A receptors. 4. The 5HT1A modulation was reduced in the presence of the specific N-type blocker omega-conotoxin GVIA (CgTx) and by the P-type channel blocker omega-agatoxin IVA (AgTx), but not by the L-type blocker nifedipine. 5HT did not modulate the slowed tail currents in the presence of the dihydropyridine agonist Bay K 8644. These data suggest that N- and P-type channels (but not L-type channels) were targeted by 5HT. 5. The modulation involved G proteins and utilized a membrane-delimited pathway. The modulation was rapid in onset (tau approximately 600 ms) and offset. About 50% of the reduction in current by 5HT1A agonists was overcome by prepulses to 120 mV. 6. Slowing of current onset kinetics in response to 5HT1A agonists was seen rarely in neocortical pyramidal neurons (11% of cases). The presence of slowing depended on agonist concentration, being evident only with high micromolar doses.

The receptor binding profile of MDL 100,907

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

Pharmacological and kinetic characterization of two functional classes of serotonergic modulation in Aplysia sensory neurons.

1. Modulation of mechanoafferent sensory neurons (SNs) by the neutrotransmitter serotonin (5HT) plays a significant role in behavioral sensitization of several withdrawal reflexes in Aplysia. The modulatory effects of 5HT on these SNs include increased excitability, increased input resistance, action potential broadening, and increased synaptic transmission. Based on a previously described dissociation of some of these modulatory effects, revealed with the 5HT-receptor antagonist, cyproheptadine, we investigated whether a similar dissociation could be found by systematically varying the concentration of the endogenous agonist, 5HT. 2. We first applied a range of 5HT concentrations to isolated pleural/pedal ganglia (containing tail SNs and tail motor neurons, respectively), and measured the magnitude of 5HT-induced modulation of spike broadening and increased excitability. The resulting dose-response curve showed that both forms of modulation increase monotonically as a function of 5HT concentration, but that excitability has a lower threshold for modulation by 5HT than does spike duration. 3. We further characterized the modulatory effects of 5HT on Aplysia SNs by comparing the time course of onset of modulation by 5HT and the time course of recovery after washout. Independent of 5HT concentration, modulation of excitability increases rapidly in the presence of 5HT and recovers rapidly (< 3 min) after washout. Similarly, input resistance increases and recovers rapidly, mirroring the profile of increased excitability. However, modulation of spike duration exhibits two profiles, dependent on 5HT concentration. Low concentrations of 5HT (0.5 and 1 microM) induce a rapid-onset and transient-recovery form of spike broadening, which resembles the kinetics of increased excitability and increased input resistance. Higher concentrations of 5HT (2.5 and 5 microM) induce a more slowly developing and prolonged-recovery form of spike broadening (> 9 min). At these higher concentrations, the recovery profile for prolonged spike broadening is significantly different from those observed for both increased excitability and increased input resistance. 4. We next compared the relationship between spike broadening and short-term synaptic facilitation. We found that significant facilitation of synaptic transmission requires a high 5HT concentration, which is comparable with that required to induce prolonged spike broadening. Similarly, the recovery profiles for spike broadening and synaptic facilitation are strikingly similar, recovering in parallel. 5. Our experiments show that the modulatory effects of 5HT in the tail SNs can be dissociated both by their sensitivity to different concentrations of 5HT and by their kinetics of serotonergic modulation. Based on these results, together with extensive evidence from other laboratories, we propose that the short-term modulatory effects of 5HT fall into two distinct functional classes. The first class, which includes excitability, input resistance, and transient spike broadening, has a low threshold for 5HT modulation and recovers rapidly. The second class, which includes prolonged spike broadening and short-term synaptic facilitation, has a higher threshold for modulation and recovers more slowly. It now will be of interest to determine the functional contribution of each of these classes to different aspects of sensitization.

Reactions of the middle meningeal artery of the cat to neural and humoral stimulation.

The physiology and pharmacology of the middle meningeal artery was investigated in cats in order to determine whether this artery was subject to normal neural and humoral control mechanisms. Carotid and middle meningeal arterial blood flows and resistances were measured in 16 cats anaesthetized with chloralose. The cervical sympathetic nerves were stimulated electrically. Stimulation of the cervical sympathetic nerves pre-ganglionically reduced blood flow in the middle meningeal artery by producing vasoconstriction in its resistance bed. The vasoconstriction was mediated via catecholamine-containing nerves, as it was abolished by prior intravenous administration of bretylium. Intravenous injections of noradrenaline or adrenaline also produced vasoconstriction in the middle meningeal arterial bed. 5-Hydroxytryptamine (5HT), on the other hand, produced a dilatation in the middle meningeal artery. We conclude that neurally or humorally released catecholamines can provide a plausible mechanism for vasoconstriction in the middle meningeal artery. The dilator effect of 5HT contrasts with the constrictor effect of the 5HT1-like receptor agonist sumatriptan and suggests a complex 5HT receptor pharmacology for the artery.

Cognitive dysfunction in schizophrenia: A comparison of the impact of zotepine versus clozapine on the syndrome (a double blind trial)

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

Serotonin-induced changes in the excitability of cultured antennal-lobe neurons of the sphinx moth Manduca sexta

The modulatory actions of 5-hydroxy-tryptamine (5HT or serotonin) on a morphologically identifiable class of neurons dissociated from antennal lobes of Manduca sexta at stages 9-15 of the 18 stages of metamorphic adult development were examined in vitro with whole-cell patch-clamp recording techniques. Action potentials could be elicited from approximately 20% of the cells. These cells were used to examine effects of 5HT (5 x 10(-6) to 5 x 10(-4) M) on cell excitability and action-potential waveform. 5HT increased the number of spikes elicited by a constant depolarizing current pulse and reduced the latency of responses. 5HT also led to broadening of action potentials in these neurons and increased cell input resistance. Modulation of potassium channels by 5HT is likely to contribute to these responses. 5HT causes reversible reduction of at least 3 distinct potassium currents, one of which is described for the first time in this study. Because effects of 5HT on antennal-lobe neurons in culture mimic those observed in situ in the brain of the adult moth, in vitro analysis should contribute to elucidation of the cellular mechanisms that underlie the modulatory effects of 5HT on central olfactory neurons in the moth.

Quality of life in first episode schizophrenia

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

Symptomatology and level of functioning in first episode psychosis

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

Calcitonin gene-related peptide modulates neuronal activity in the mammalian cerebellar cortex

Calcitonin gene related peptide (CGRP) has been localized within specific populations of mossy fibers in the cat's cerebellar cortex. The intent of the present study was to determine the physiological role of this peptide in cerebellar circuitry. CGRP was iontophoretically applied and its effects on spontaneous, amino acid-induced, and synaptically-mediated activity were recorded. In addition, interactions between CGRP and serotonin (5HT), another neuromodulator in cerebellar circuitry, also were analyzed. The findings of this study reveal that the primary effect of CGRP is to suppress spontaneous and excitatory amino acid-induced activity. However, CGRP has a more potent effect in suppressing aspartate- and quisqualate-induced activity as compared to that elicited by glutamate. CGRP slowed or completely blocked synaptic activity mediated by stimulation of the inferior cerebellar peduncle. Finally, the individual suppressive effects of 5HT and CGRP were potentiated when both were applied simultaneously. However, the potentiation was greater when the neuron was exposed to 5HT before CGRP was applied. In summary, the presence of CGRP in selected populations of mossy fibers, together with serotoninergic afferents, decreases the responsiveness of Purkinje cells to excitatory amino acids as well as synaptically-driven activity. Thus, activation of an afferent system to the cerebellum can elicit distinct effects on different populations of neurons that are dependent on the microenvironment of the cell at a particular point in time.

Repetitive treatment with serotonin modifies protein synthesis and protein phosphorylation in the central nervous system of Hirudo medicinalis.

Serotonin (5HT) is the neurotransmitter involved in some forms of short-term memory in the leech. Behavioral experiments have demonstrated that long-term memory requires new protein synthesis. With the aim of studying the molecular mechanism underlying memory processes in the leech, we have analyzed the effect of 5HT on protein synthesis and protein phosphorylation. Segmental ganglia of the leech central nervous system have been labeled, proteins have been separated by two-dimensional-electrophoresis and labeled proteins detected by autoradiography. Our findings indicate that repetitive treatment with 5HT produces either the persistence of phosphorylation or changes in protein synthesis in several proteins.

Cardiovascular effects of 5HT 2 and 5HT 3 receptor stimulation in the nucleus tractus solitarius of spontaneously hypertensive rats

The effects of local application of 5-HT 2- and 5-HT 3-receptor agonists in the nucleus tractus solitarius (NTS) on the cardiovascular parameters were investigated in anaesthetized spontaneously hypertensive (SH) rats and their genetically normotensive precursors (WKY). Unilateral microinjection of picomolar doses of a 5HT 2 receptor agonist, 2,5-dimethoxy-3-bromo-amphetamine (DOB, 0.025 – 0.5 pmol), produced a dose-dependent hypotension and bradycardia in both SH and WKY rats. These effects could be prevented by prior local microinjection of a 5-HT 2 receptor antagonist, ketanserin (10 pmol). However, for both cardiovascular parameters, DOB was more potent in SH than in WKY rats. Thus, the dose-related responses to DOB were shifted to the left in SH as compared to WKY rats. Bilateral microinjection of the 5-HT 3 receptor agonist, phenylbiguanide (1.7 – 5 nmol), produced an increase in blood pressure and reduced the cardiovagal component of the baroreflex. These effects were not significantly different in SH and WKY rats. These data suggest that 5-HT 2 receptors, but not 5-HT 3 receptors, are supersensitive in the NTS of SH rats.

Stimulatory Effects of 5HT&lt;sub&gt;1A&lt;/sub&gt; Receptor Agonists on Luteinizing Hormone-Releasing Hormone Release from Cultured Fetal Rat Hypothalamic Cells: Interactions with Progesterone

Previous works have suggested an interactive stimulatory effect of progesterone (P) and serotonin (5-HT) on luteinizing hormone release. The purpose of the present study was to determine whether 5-HT via 5-HT1A receptors interacts with P in the process of luteinizing hormone-releasing hormone (LHRH) release. Using fetal hypothalamic neurons in primary cell cultures the first goal of this study was to determine the effects of 5-HT1A receptor agonists on LHRH secretion. 8-Hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) or ipsapirone (10(-5) M) significantly stimulated LHRH release. Pharmacological studies have allowed to rule out the possible involvement of alpha 2- or beta-adrenoreceptors, or 5-HT uptake sites, in the stimulatory effect of 8-OH-DPAT on LHRH release, thus demonstrating the specific involvement of 5-HT1A receptors in the stimulation of LHRH release. The second goal was to test the ability of P to stimulate LHRH release from fetal hypothalamic neurons. P (10(-6) M) applied for 30 or 120 min significantly stimulated LHRH secretion. The maintenance of the stimulation of LHRH release by P after a cycloheximide treatment or by an impermeable analog of P, P-3-BSA, has suggested a nongenomic effect of P on LHRH release. The effects of a pretreatment of cells by P on 8-OH-DPAT-induced LHRH release were tested. While 10(-7) M P alone did not stimulate LHRH release, this concentration of steroid potentiated the LHRH response to 10(-5) M 8-OH-DPAT. These findings led to the conclusion that P acting at the level of the plasma membrane potentiates the stimulatory effect of 5-HT1A receptor agonists on LHRH release.

Brainstem 5HT 3-receptor mechanisms in the central nervous system

5HT 3 receptor mechanisms have influences in pain, emesis and cardiovascular systems. Activation of the 5HT 3 receptors causes depolarisation/excitation of the sensory afferents of the vagus nerve [1] and depolarisation of the cell bodies situated in their dorsal root and nodose ganglia [2,3]. Within the termination zones of the afferents in the dorsal horn of the spinal cord and the nucleus tractus solitarius (NTS) of the brainstem much less information is available concerning the role of 5HT 3 receptors. Both the dorsal horn and the NTS have high densities of 5HT 3 binding sites and deafferentation markedly reduces this [4,5]. The peripheral effects of 5HT 3 receptor activation are excitatory, i.e. pain, wheal and flare [6] and mimicry of the effects of stimulating peripheral baroand chemoreceptors [7]. However, in the CNS the effects appear to be depressant on these systems, i.e. antinocioception [8,9], depression of the baroreflex and increased arterial blood pressure [10]. The anti-nocioception and cardiovascular effects are blocked by the administration of the GABA A receptor antagonist, bicuculline implying involvement of inhibitory systems in these actions. Application of the 5HT 3 receptor antagonists has demonstrated tonic control of nocioception but not cardiovascular systems [9,10]. We have been investigating the effects of 5HT 3 receptor activation in the rat NTS in vitro. The direct, postsynaptic effects of 2-methyl-5HT, a 5HT 3 agonist, obtained during complete synaptic block, was a small depolarisation and this could only be obtained at high, but still 5HT 3 specific, concentrations. However, the effects on synaptic transmission were more marked and could be obtained at much lower concentrations. Regarding synaptic transmission, there was a dramatic increase in the number and amplitude of spontaneous synaptic events. Excitatory transmission was mediated

Serotonin inhibits high-threshold Ca2+ channel currents in capsaicin-sensitive acutely isolated adult rat DRG neurons.

1. The effect of serotonin (5HT) was studied on high-threshold Ca2+ channel currents in a subpopulation of acutely isolated rat dorsal root ganglion cell bodies that had long-duration action potentials, lacked IH current, were capsaicin-sensitive, and thus resembled C-type nociceptors. 2. In these neurons, 10 microM 5HT inhibited peak high-threshold Ca2+ channel currents by 61.5 +/- 6.9% (mean +/- SE), (n = 7). The effects of 5HT were mimicked by 1 microM (+)8-hydroxy-2-(di-n-propylamino)-tetralin HBr [(+)8-OH-DPAT] in five neurons tested, and the effects of 1 microM (+)8-OH-DPAT were antagonized by 100 nM 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl]piperazine HBr (NAN-190) in six neurons tested. 3. The above data leads us to hypothesize that 5HT, released into the spinal cord by descending systems, may produce antinociception by inhibiting Ca2+ entry into afferent terminals of nociceptors via activation of 5HT1A receptors.

Modulation of rhythmic swimming activity in post-embryonic Xenopus laevis tadpoles by 5-hydroxytryptamine acting at 5HT1a receptors.

5HT modulates the rhythmic locomotor output of most vertebrates by enhancing the duration and intensity of motor bursts in each cycle, but there is little clear evidence on the pharmacological profile of the 5HT receptor subtype(s) involved. In this study we extend our previous work on the role of 5HT in the development and modulation of locomotor behaviour in newly hatched Xenopus tadpoles by examining the 5HT receptor type responsible for enhancing the swimming activity in immobilized preparations. By applying a range of agonists and antagonists against different 5HT receptor subtypes, we conclude that serotonergic modulation of swimming activity is accomplished via the activation of just one receptor type with a pharmacological profile similar to the mammalian 5HT1a receptor. The effects of 5HT on burst duration (an increase) and on episode length (a decrease) are mimicked by the 5HT1a receptor agonists, 5-carboxamidotryptamine (5CT) and R(+)-8-OH-DPAT, and reversed by the 5HT1a receptor antagonist NAN-190. Agents acting at other 5HT1, as well as 5HT2 and 5HT3, receptor subtypes were without noticeable effect on the 5HT-enhanced swimming rhythm.