Functional significance of the serotoninergic influence on neuronal activity of the somatosensory cortex in 12-day-old kittens

Monoamines, which participate in synaptic transmission as transmitters, also accomplish the modulation of neuronal activity. The role of serotonin (5-hydroxytryptamine--5-HT) was investigated in 8 to 14-day-old kittens by means of iontophoretic application onto neurones of the somatosensory cerebral cortex. The most typical response was the inhibition of neuronal activity. Another type of reaction was generated by inhibitory interneurones. After the microiontophoretic application of 5-HT, the tonic response of cortical neurones to the stimulation of the sciatic nerve changed into a phasic response. It is being suggested that the application of 5-HT to cortical neurones increases the excitability of inhibitory neurones. Hence, the serotoninergic regulation of neuronal activity in the somatosensory cortex may be operational from the 11th to the 12th day of postnatal life in cats.     

Role of the serotoninergic system in inhibition of jaw-opening reflex induced by stimulating the midbrain central gray matter

The effects were studied in waking cats of brief stimulation (20 stimuli at a rate of 400 Hz) of the central gray matter (CGM) and dorsal raphe nucleus (DRN) on high-threshold jaw-opening reflex (HJOR) evoked by tooth pulp stimulation during blockade of serotonin synthesis produced by application of 300 mg/kg parachlorophenylalanine (PCPA) i.p. Inhibitory effects of CGM and DRN stimulation had already declined in comparison with post-stimulation (but pre-PCPA) level within 24 h after PCPA application; 96 h afterwards, inhibition of HJOR induced by CGM and DRN stimulation had become only minimal: amplitude of the reflex had declined to 30–35% and duration of inhibitory effects ws 200–250 msec. It is therefore deduced that serotonin contributes to the HJOR depression induced by CGM and DRN stimulation and the possible involvement of other neuromodulators in this effect is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 1, pp. 45–52, January–February, 1989.     

Interaction of serotonin and nitric oxide (NO) in activation of the serotoninergic system in Helix

Serotonin and the NO donors were shown to induce excitation in all serotoninergic neurones under study and to activate synchronous synaptic input in the Helix brain. The serotonin effects may be blocked by 5,7-DOT and N-monomethyl-L-arginine. The 5,7-DOT blocked activation of the NO-induced synchronous bursts but did not affect their activating effect. The data obtained suggest that serotonin and NO equally regulate the serotoninergic system's function in the snail brain. The effects of serotonin and NO are interconnected and interdependent. A possible role of the NO as a second messenger during serotonin activation and as a serotonin co-transmitter in presynaptic neurones, is discussed.     

Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms

The effects of brain-derived neurotrophic factor (BDNF) and cAMP on the neuronal serotoninergic phenotype were studied in primary cultures of E14 rat embryonic rostral raphe. Short treatments (for 18 h) with BDNF or dibutyryl-cAMP induced an almost two-fold increase in the number of serotoninergic neurones and a dramatic extension and ramification of their neurites. These changes were associated with marked increases in the levels of mRNAs encoding the serotonin transporter, the 5-HT1A and 5-HT1B receptors and the BDNF receptor tyrosine kinase B (TrkB). Concomitant blockade of tyrosine kinases by genistein suppressed all the up-regulating effects of BDNF and cAMP on 5-hydroxytryptamine (5-HT) neurones. These findings suggest that an auto-amplifying mechanism underlies the promoting effect of BDNF on the differentiation of serotoninergic neurones through TrkB activation, which is also triggered by cAMP.     

Effect of acute administration of L-tryptophan on the release of 5-HT in rat hippocampus in relation to serotoninergic neuronal activity: an in vivo microdialysis study.

Here we have used the brain microdialysis method to test the effect of the 5-HT precursor L-tryptophan on 5-HT release. The release of endogenous 5-HT was measured in ventral hippocampus of the anesthetized rat both under basal conditions and when serotoninergic neuronal activity was raised by electrical stimulation of the dorsal raphe nucleus (DRN). Low frequency electrical stimulation of the DRN evoked a frequency-dependent (2-10 Hz) release of hippocampal 5-HT. The electrically evoked release of 5-HT was markedly enhanced by pretreatment with L-tryptophan (50 and 100 mg/kg i.p.). The effect of L-tryptophan on evoked release of 5-HT was dose-related, detectable at low (2 Hz) stimulation frequencies, and became stronger as the stimulation frequency increased. L-Tryptophan (10, 50 and 100 mg/kg i.p.) had no effect on basal output of 5-HT. We conclude from these findings that elevation of 5-HT precursor availability increases 5-HT release in hippocampus in vivo under conditions of increased serotoninergic neuronal activity.     

Significance of serotonin in the activity of the taste receptor apparatus of the frog Rana temporaria

Studies have been made of the effect of exogeneous serotonin on responses of taste receptors recorded from the hypoglossal nerve during adequate stimulation. It was shown that serotonin evokes afferent discharge in this nerve and significantly increases responses of taste receptors. Stimulating effect of serotonin appears 15-20 min after its application and gradually develops reaching maximum within 60 min after injection. Competitive antagonist of serotonin, 7-methyltryptamine, inhibits taste afferent responses and blocks stimulating effect of serotonin. Possible role of serotoninergic mechanism in afferent impulse activity of the taste receptive apparatus is discussed.     

GABA(B) receptors in 5-HT transporter- and 5-HT1A receptor-knock-out mice: further evidence of a transduction pathway shared with 5-HT1A receptors

The functional properties of GABA(B) receptors were examined in the dorsal raphe nucleus (DRN) and the hippocampus of knock-out mice devoid of the 5-HT transporter (5-HTT-/-) or the 5-HT(1A) receptor (5-HT(1A)-/-). Electrophysiological recordings in brain slices showed that the GABA(B) receptor agonist baclofen caused a lower hyperpolarization and neuronal firing inhibition of DRN 5-HT cells in 5-HTT-/- versus 5-HTT+/+ mice. In addition, [(35)S]GTP-gamma-S binding induced by GABA(B) receptor stimulation in the DRN was approximately 40% less in these mutants compared with wild-type mice. In contrast, GABA(B) receptors appeared functionally intact in the hippocampus of 5-HTT-/-, and in both this area and the DRN of 5-HT(1A)-knock-out mice. The unique functional changes of DRN GABA(B) receptors closely resembled those of 5-HT(1A) autoreceptors in 5-HTT-/- mice, further supporting the idea that both receptor types are coupled to a common pool of G-proteins in serotoninergic neurons.     

The cholinergic system of the forebrain modulates the activity of the GABA-ergic interneurons which realize presynaptic regulation in the neocortex of kittens

It has been found that at the end of the second week of postnatal life, stimulation of cholinergic ascending paths causes a selective inhibition of cortical neurones reaction to sensory stimulation, without influencing the background activity. The observed inhibition is blocked both by atropine and picrotoxin, but not by bicuculline. It is suggested that the observed phenomenon characterizes, presynaptic control of cortical neurones activity in the early ontogenesis. This inhibition is formed on the basis of cooperative choline- and GABA-ergic brain systems participation and is performed not through GABA-receptors.     

Possible Participation of Serotonin in the Peripheral Link of the Defensive Reflex in the Mollusc Lymnaea stagnalis

The contractions of the dorsal longitudinal muscle of the mollusc Lymnaea stagnalis L., which are evoked by electric stimulation of n. cervicalis inferior were studied. It has been shown that an increase of magnesium ion concentration in saline to 10–15 mM decreases reversibly amplitude of the evoked contractions. Application of serotonin produced a dual effect: at concentrations of 2 × 10^–5–10^–6 M, it enhanced muscle contractions, whereas at concentrations above 10-5 M, on the contrary, decreased them. The inhibitory effect of the serotonin antagonist mianserin on the evoked contraction amplitude increased with elevation of its concentrations in the studied range (from 10^–5 to 10^–3 M). The enhancing effect of serotonin on muscle contractions was blocked either by previous mianserin application or its application on the background of the already acting serotonin. A participation of serotoninergic mechanisms in the control of the contractile function of the studied muscle is suggested.     

Effect of serotonin and noradrenaline on the magnitude of the response of the command neurons for defensive behavior in Helix lucorum L

Changes in synaptic responses of identified command neurones of avoidance behaviour to the electric nerve stimulation were investigated in the isolated nervous system of the snail during bath application of serotonin or noradrenaline. Serotonin (10(-5) M) elicited an increase of summary EPSP amplitude in the cells without changes of input resistance and resting potential. Noradrenaline (10(-5) M) application evoked an increase of EPSP amplitude, accompanied by an increase of the input resistance. Mechanisms of serotonin and noradrenaline influence on synaptic responses are discussed.     

Is it possible to modify serotonin receptor sensitivity?

It is possible to induce sub- and super-sensitivity of β-adrenergic receptors by long-term treatment with drugs acting on catecholamine systems. In contrast, analogous treatment with drugs acting on serotoninergic systems does not modify serotonin receptor sensitivity as measured by serotonin binding. Firstly, chronic 1-5HTP, the precursor amino acid, increases serotonin turnover but does not decrease serotonin binding. Secondly, chronic clomipramine, a predominantly serotonin uptake inhibitor also has no effect on serotonin binding. Thirdly, chronic metergoline, a selective serotonin antagonist in the cortex, does not induce supersensitivity.This apparent intractability of the serotonin receptor to changes after long-term treatment indicates a different post-synaptic regulatory mechanism than that found in catecholaminergic neurones. Furthermore, modification of serotonin receptor sensitivity is probably not relevant to the mode of action of antidepressant drugs. Rather, the response of pineal melatonin stimulation found after chronic clomipramine in these experiments implicates induction of β-receptor subsensitivity.     

β-CARBOLINES: A TOOL FOR INVESTIGATING STRUCTURE-ACTIVITY RELATIONSHIPS OF THE HIGH-AFFINITY UPTAKE OF SEROTONIN,NORADRENALINE, DOPAMINE,GABA AND CHOLINE INTO A SYNAPTOSOME-RICH FRACTION OF VARIOUS REGIONS FROM RAT BRAIN1

Abstract— Tetrahydronorharmane (tryptoline), the condensation product of tryptamine and formaldehyde, inhibits the high-affinity uptake of serotonin and to a smaller extent that of noradrenaline into a synaptosome-rich fraction from the hippocampus and hypothalamus respectively of rats. The uptake mechanisms of dopaminergic neurones of the hypothalamus, cholinergic neurones of the hippocampus, and GABA-ergic neurones of the cerebral cortex are affected to a much lesser degree. Substitution of tetrahydronorharmane by fluor-, chlor-, methyl-, hydroxy-, methoxy-, and catechol-groups alters the inhibition. Drugs with substituents which attract electrons are relatively good inhibitors of the uptake of serotonin. The indole-ring contributes to the binding of the molecule probably by forming a charge transfer complex with the uptake molecule. Pyrido (3,4-b)-indoles (harmala alkaloids) are weak inhibitors of the serotonin-uptake compared with respective piperidoindoles (tetrahydro-β-carbolines). The potency of the drugs to inhibit uptake is different for each uptake system. The order among the drugs with respect to their affinity for the uptake site varies, too.     

Regulation of the plastic properties of an electro-excitable neuronal membrane by serotonin

The action of serotonin on plastic properties of electroexcitable membrane was studied in Helix lucorum parietal ganglia on neurones of two types: habituating (HC) and nonhabituating (NHC) to rhythmic intracellular stimulation by impulses of depolarizing current. Serotonin produced an effect of facilitation on HC (increase of responses to stimulation against the background of depolarization and rise of input resistance of the cell). Besides, serotonin completely blocked the ability of these cells to habituate to rhythmic stimulation. The obtained data testify that such action of serotonin may be based on suppression by it of C-dependent K-conductivity. Serotonin suppresses responses of NHC to stimulation and contributes to their habituation to rhythmic stimulation. Such action is due to serotonin suppression of Ca-conductivity, and, consequently, to elimination of the mechanism of action potential generation.     

Effect of serotonin on the activity of the neurons involved in the realization of the avoidance reflex of the snail

Bath application of 10(-5) mol/l of serotonin (5-HT) elicited a 50% increase of summary EPSPs recorded in command neurones for avoidance behaviour. No significant changes of rest potential and input resistance were seen in these cells. 5-HT evoked an increase of spontaneous level of firing in motoneurones involved in the same reflex, as well as an increase in the number of spikes which paralleled increase of EPSPs to the same stimulus in command neurones. In sensory cells, presynaptic to the command neurones, application of 5-HT evoked a significant increase of excitability and of input resistance. Monosynaptic EPSPs recorded in the command neurones showed a 40% increase after serotonin application. It is concluded that the major locus of plastic changes evoked by 5-HT application in the neuronal chain underlying avoidance reflex is the synaptic contact between sensory and command neurones.     

Effect of microelectrophoretically applied acetylcholine, noradrenaline, dopamine and serotonin on the discharge of paraventricular oxytocinergic neurones in the rat

The effects of microelectrophoretic applications of neurotransmitter substances and their antagonists on the activity of paraventricular oxytocinergic neurones were studied in urethane anesthetized lactating rats. Oxytocinergic neurones were identified by their antidromic response to the stimulation of the neurohypophysis and by their characteristic high frequency discharge of action potentials approximately 15-20s before reflex milk ejection. Acetylcholine (ACh) excited the majority (75%) of paraventricular oxytocinergic neurones, and none of the cells was inhibited in its activity by ACh. In about half of the oxytocinergic cells, atropine and hexamethonium reduced the number of action potentials during the burst discharge preceding reflex milk ejection. Noradrenaline (NE), dopamine (DA) and serotonin (5-HT) reduced the activity of most (75-100%) of oxytocinergic neurones, and none of the cells was excited by these catecholamines. These results suggest that paraventricular oxytocinergic neurones receive excitatory cholinergic inputs and inhibitory noradrenergic, dopaminergic and serotonergic inputs.     

Contribution of serotonin to establishing a conditioned food aversion reflex in the snail

Combined presentation of food and noxious electrical stimulation produced no response in snails injected 6–16 days previously with 5,7-dihydrooxytryptamine, which produces degeneration of serotoninergic nerve terminals and reduced serotonin synthesis, although a defense (aversive) response was observed in the control group. Application of serotonin to a preparation of the snail central nervous system (contained in a bath) was used as reinforcement during neurophysiological experiments. The amplitude of synaptic response to nerve stimulation increased significantly in preparations in which stimulation was paired with serotonin application. After 3–7 sets of twin stimuli consisting of serotonin application and applying a drop of juice to the chemoreceptive surface area of the skin, a spike response to the latter stimulus was produced. No such effects were seen in response to unpaired stimuli. It was deduced that serotonin makes a major contribution to establishing conditioned aversive reactions in the snail.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 18, No. 3, pp. 291–298, May–June, 1986.     

The role of dopamine and serotonin in modulating the defensive behavior of the edible snail

Dopamine application in concentration of 10(-5)-10(-6) M into saline around the snail CNS leads to decrease of excitability of LPa7 neurone which is presynaptic in relation to defensive behaviour command neurones, and to decrease of amplitude of monosynaptic excitatory postsynaptic potential (EPSP) in the command neurones elicited by intracellular stimulation of LPa7 neurone. Besides, the dopamine causes a decrease of summated EPSP amplitude in the studied neurones in response to intestinal nerve stimulation (70% in average), a change of rest potential towards hyperpolarization for 6-8 mV, a reduction of the command neurones input resistance (20% in average). The described influences can lead to a general increase of the threshold of defensive system reaction to stimulation. Dopamine action on the defensive behaviour command neurones is significantly weakened in serotonine presence. Against the dopamine background, the efficiency of serotonine influence on the value of EPSP in command neurones in response to testing stimulus is reduced. According to the obtained data, a conclusion is made that interrelation of dopamine and serotonine concentrations can be a base for formation of behaviour choice in snail.     

Role of the serotoninergic raphe-hippocampus system for the antinocifensive effect of morphine

As revealed in earlier studies, the antinocifensive effect of morphine is brought about, among other things, with involvement of serotoninergic transmission mechanisms. In this context the role of the serotoninergic raphe-hippocampus system has been studied in this paper. Topical microinjections of serotonin into the dorsal hippocampus increased morphine analgesia in a dose-dependent fashion, while application into the striatum had no effect. Morphine injections into the median raphe nucleus in relatively low doses exert an antinocifensive effect which is inhibitable by methysergide. Lysergic acid diethylamide administered into the median raphe nucleus also abolished the effect of morphine in a dose-dependent manner. The results in connection with literature data lend support to the presumed integrative function of the serotoninergic raphe-hippocampus system in the mechanism of antinocifensive action of morphine.     

Role of Serotonin2A and Serotonin2B/2C Receptor Subtypes in the Control of Accumbal and Striatal Dopamine Release Elicited In Vivo by Dorsal Raphe Nucleus Electrical Stimulation

This study investigates, using in vivo microdialysis, the role of serotonin2A (5-HT2A) and 5-HT(2B/2C) receptors in the effect of dorsal raphe nucleus (DRN) electrical stimulation on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) extracellular levels monitored in the nucleus accumbens (NAC) and the striatum of halothane-anesthetized rats. Following DRN stimulation (300 microA, 1 ms, 20 Hz, 15 min) DA release was enhanced in the NAC and reduced in the striatum. The 5-HT2A antagonist SR 46349B (0.5 mg/kg) and the mixed 5-HT(2A/2B/2C) antagonist ritanserin (0.63 mg/kg) significantly reduced the effect of DRN stimulation on DA release in the NAC but not in the striatum. DA responses to DRN stimulation were not affected by the 5-HT(2B/2C) antagonist SB 206553 (5 mg/kg) in either region. None of these compounds was able to modify the enhancement of DOPAC and 5-HIAA outflow induced by DRN stimulation in either the NAC or the striatum. Finally, in both brain regions basal DA release was significantly increased only by SB 206553. These results indicate that 5-HT2A but not 5-HT(2B/2C) receptors participate in the facilitatory control exerted by endogenous 5-HT on accumbal DA release. Conversely, 5-HT(2B/2C) receptors tonically inhibit basal DA release in both brain regions.