Effects of peripheral electric stimulation on the central 5-hydroxytryptamine turnover and drug-induced head-twitches in mice.
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Animals↗
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Spinal modulation of the acoustic startle response: the role of norepinephrine, serotonin and dopamine.
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Acoustic Stimulation↗
Activity of serotonin-containing neurons in the nucleus raphe pallidus of freely moving cats.
Serotonergic neurons within nucleus raphe pallidus (NRP) of freely moving cats initially were distinguished by their slow (less than 8 Hz), regular discharge and long duration (mean = 2.3 ms) action potentials. The activity of serotonergic NRP neurons was highest during active waking (mean = 4.85 +/- 0.37 spikes/s) and gradually slowed, with little change in firing pattern, during the transition from waking through slow wave sleep (middle of SWS: mean = 3.76 +/- 0.36 spikes/s). In REM sleep there was a precipitous decrease in firing rate (mean = 0.92 +/- 0.23 spikes/s) and loss of discharge regularity. Although there was no significant difference in firing rate between active and quiet waking, discharge rates were significantly increased during transient elevations of the EMG, but these rate increases usually were associated with specific motor behaviors only. The activity of serotonergic NRP neurons during SWS was not related to the occurrence of either sleep spindles in the cortical EEG or PGO waves recorded from the lateral geniculate nucleus. These neurons also were relatively unresponsive to phasic auditory or visual stimuli, with most of the neurons examined showing weak excitatory responses. Activity of all serotonergic NRP neurons tested was suppressed (mean = -81.3 +/- 4.3%) by the serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (250 micrograms/kg, i.m.). The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus of freely moving cats and the issue of homogeneity in central serotonergic systems is discussed.
Acoustic Stimulation↗
Analgesia induced by brief footshock: blockade by fenfluramine and 5-methoxy-N,N-dimethyltryptamine and prevention of blockade by 5-HT antagonists.
Analgesia induced by footshock (2 mA, 30 s) is decreased by the 5-HT releaser, fenfluramine, and the rapidly acting 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). These decreases are blocked by the 5-HT antagonists, cyproheptadine and methiothepin. However, the antagonists when given alone do not influence shock-induced analgesia. Therefore, analgesia induced by brief footshock in the absence of drugs may not involve 5-HT-dependent mechanisms even though it may be influenced by pharmacologically provoked changes of 5-HT release or by 5-MeODMT. This drug was also able to attenuate the analgesia after its induction, possibly reflecting a disruption of memory processes rather than of nociceptive mechanisms per se.
Animals↗
Behavior and binding: desensitization to alpha 1-adrenergic stimulation of acoustic startle is associated with a decrease in alpha 1-adrenoceptor binding sites.
Desensitization of the excitatory effects of alpha 1-adrenergic agonists on acoustic startle occurred 6 h after intrathecal administration of the alpha 1-adrenergic agonist, phenylephrine. This desensitization was associated with a decrease in alpha 1-adrenoceptor sites in the lumbar spinal cord.
Acoustic Stimulation↗
Biphasic effect of 5-methoxy-N,N-dimethyltryptamine on rat prolactin secretion.
5-Methoxy-N,N-dimethyltryptamine (5-MeODMT), a potent serotonin (5-HT) receptor agonist, exerts a biphasic effect on rat prolactin (PRL) secretion. 5-MeODMT (2.5-10 mg/kg) produces a marked, dose-related but short-lasting (less than 30 min) rise in serum PRL levels. At intervals longer than 30 min, 5-MeODMT (1-15 mg/kg) inhibits the stimulation of PRL secretion by another 5-HT agonist, 5-methoxytryptamine (5-MeOT, 10 mg/kg), by alpha-methylparatyrosine (50 mg/kg) or by haloperidol (0.15 mg/kg). 5-MeODMT did not significantly alter the PRL-releasing effect of gamma-butyrolactone (500 mg/kg) or a higher dose of haloperidol (1 mg/kg). The biphasic effect of 5-MeODMT on rat PRL secretion is shared by the centrally-acting 5-HT agonist quipazine, but not by 5-MeOT, an indole derivative excluded by the blood-brain barrier. The initial stimulation of PRL secretion by 5-MeODMT is probably due to its ability to activate postsynaptic 5-HT receptors. The subsequent inhibitory effect of 5-MeODMT appears to be due to increased functional activity of tuberoinfundibular dopamine neurons. The possible mechanisms underlying the inhibitory effect of 5-MeODMT on PRL release are discussed.
Animals↗
Denervation supersensitivity to 5-hydroxytryptamine in the rat spinal cord is not due to the absence of 5-hydroxytryptamine.
D,L-5-Hydroxytryptophan and 5-HT agonists administered systemically, stimulate motoneuronal discharges as measured by the spontaneous EMG activity of the hindlimbs in paraplegic rats. Denervation supersensitivity is observed after surgical section of the spinal cord or after treatment with 5,7-dihydroxytryptamine (5,7-DHT). Such denervation supersensitivity, however, cannot be reproduced by equivalent depletion of 5-HT by synthesis inhibition or reversed by chronic intrathecal administration of 5-HT agonists. These results suggest that in the anterior horn of the spinal cord, the trigger of denervation supersensitivity to serotonin is not the absence of the neurotransmitter itself but the absence of the terminals or some other compound contained therein.
5,7-Dihydroxytryptamine↗
Chronic phenytoin and the stereotyped motor response induced by 5-methoxy-N,N-dimethyltryptamine in rats.
Male Sprague-Dawley rats were injected with phenytoin (PHT) once a day for 20 consecutive days and then tested as to their response to 5-methoxy-N,N-dimethyltryptamine (5-MDMT), a 5-hydroxytryptamine (5-HT) agonist, at 1 and 3 mg/kg on days 21 and 28. It was found that long-term PHT administration decreased the intensity of a stereotyped motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (1.7, 3.2 mg/kg). It is suggested that PHT increases the functional availability of 5-HT before its receptors, and thereby causes 5-HT receptor subsensitivity.
Animals↗
Blockade and reversal of 5-methoxy-N,N-dimethyltryptamine-induced analgesia following noradrenaline depletion.
The acute effects of the 5-hydroxytryptamine agonist, 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), upon pain sensitivity, using shock titration, tail-flick and hot-plate methods, in noradrenaline- and 5-hydroxytryptamine-depleted rats were examined. Noradrenaline depletion, following the systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 2 X 50 mg/kg, i.p.), caused a reversal of the analgesic effect of 5-MeO-DMT on shock-titration from hypo- to hypersensitivity, and a total blockade of the antinociceptive effect of 5-MeO-DMT upon pain responses in the hot-plate and tail-flick tests. Pretreatment with either p-chloroamphetamine (2 X 10 mg/kg) or p-chlorophenylalanine (200, 100, 100 mg/kg), that depletes central 5-hydroxytryptamine stores, failed to alter the analgesia caused by acute 5-MeO-DMT. Strong evidence is provided for the effect of central noradrenaline depletion upon the analgesic effect of the 5-HT agonist. These findings suggest an important tonic influence of the noradrenaline system upon the descending spinal 5-HT pathway in rats.
Analgesics↗
Antidromic activation of dorsal raphe neurons from neostriatum: physiological characterization and effects of terminal autoreceptor activation.
Three types of neurons, distinguished on the basis of their spontaneous firing rates and patterns, extracellularly recorded waveforms and responses to neostriatal stimulation, were observed in the dorsal raphe nucleus in urethane-anesthetized rats. Type 1 neurons (presumed to be serotonergic) fired spontaneously from 0.1 to 3 spikes/s in a regular pattern, with initial positive-going bi- or triphasic action potentials. Type 1 cells exhibited long-latency antidromic responses to neostriatal stimulation (mean +/- S.E.M. 24.9 +/- 0.3 ms) that sometimes occurred at discrete multiple latencies, and supernormal periods persisting up to 100 ms following spontaneous spikes. Type 2 cells fired spontaneously in an irregular, somewhat bursty pattern from 0 to 2 spikes/s with initial negative-going biphasic spikes, and were antidromically activated from neostriatal stimulation at shorter latencies than Type 1 cells (21.8 +/- 0.9 ms). Type 3 cells were characterized by initial positive-going biphasic waveforms and displayed a higher discharge rate (5-30 spikes/s) than Type 1 or Type 2 cells. Type 3 cells could not be antidromically activated from neostriatal stimulation. The relatively long conduction time to neostriatum of the Type 1 presumed serotonergic neuron is discussed with respect to previous interpretations of the synaptic action of serotonin in the neostriatum. In conjunction with these antidromic activation studies, the neurophysiological consequences of serotonergic terminal autoreceptor activation were examined by measuring changes in the excitability of serotonergic terminal fields in the neostriatum following administration of the serotonin autoreceptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The excitability of serotonergic terminal fields was decreased by intravenous injection of 40 micrograms/kg 5-MeODMT, and by infusion of 10-50 microM 5-MeODMT directly into the neostriatum. These results are interpreted from the perspective of mechanisms underlying autoreceptor-mediated regulation of serotonin release.
Animals↗
Reduced-5-hydroxytryptamine-dependent behavior in rats following chronic corticosterone treatment.
The effect of chronic corticosterone treatment (50 mg/kg s.c. 2 x daily) for up to 4 days on behavioural responses to drugs affecting 5-hydroxytryptamine (5-HT) and dopamine (DA) systems was examined in rats 20 h after the last treatment, when placed in experimental cages, to which they had become habituated. Corticosterone- and vehicle-treated rats exhibited both comparable spontaneous behavior when given 0.9% NaCl i.p. and showed similar behavioural responses following amphetamine (3 mg/kg i.p.). However, responses to the 5-HT-releasing drug p-chloroamphetamine (PCA, 4 mg/kg i.p.) were altered with decreased head-weaving hind-limb abduction and forepaw treading. Postsynaptic changes appear to be involved as responses to the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg/kg i.p.) (tremor, hind-limb abduction and forepaw treading) were also decreased. Hind brain and striatal concentration of 5-HT, DA and their metabolites were comparable in corticosterone and vehicle treated rats killed 20 h after the last treatment. Brain PCA levels determined 30 min after injection were also comparable in both groups. PCA induced behaviour was not altered 20 h after 1 day corticosterone treatment or 4 day after 1 day treatment and 5-MeODMT-induced behaviour was not altered 20 h after 14 days treatment with a lower dose of corticosterone (10 mg/kg s.c. x 2). Twenty h after 1 day corticosterone treatment (50 mg/kg s.c. x 2), rats placed in an open field for the first time showed significantly more activity and dropped fewer faecal pellets than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Stimulation of spinal serotonergic receptors facilitates seminal emission and suppresses penile erectile reflexes.
Penile erection and ejaculation are produced by spinal reflexes subject to tonic control from the brain. This study examines the possible involvement of serotonergic transmission in the supraspinal modulation of such reflexes. The effects of two drugs which facilitate serotonergic transmission by different mechanisms, namely the direct receptor agonist, 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), and the reuptake inhibitor, zimelidine, were compared in intact and spinal rats. Results show that serotonergic stimulation in intact rats by either drug produces a dose-related increase in the incidence of seminal emission as well as a definite decrease of the display of erectile responses. In the spinal animals 5-MeODMT treatment reproduced both effects. By contrast, zimelidine, which needs functional nerve endings to exert its agonistic action, was ineffective in the spinal rats. This is interpreted to exclude a peripheral mechanism for the effects of the serotonin agonists on penile reflexes of intact animals and makes a strong case for a spinal site of action. We postulate the existence of serotonergic receptors located in the lower segments of the spinal cord which, when stimulated, trigger seminal emission and suppress erection.
Animals↗
Analgesia induced by 5-hydroxytryptamine receptor agonists is blocked or reversed by noradrenaline-depletion in rats.
The antinociceptive effect of acute administration of 5-HT receptor agonists and agents releasing 5-HT from neuronal terminals was studied in rats by using the hot-plate, tail-flick and shock-titration tests. Noradrenaline depletion by the noradrenaline-neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4, 2 X 50 mg/kg) blocked the analgesia induced by the 5-hydroxytryptamine (5-HT) receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and quipazine, as well as that induced by acute release of 5-HT by p-chloroamphetamine (PCA) and increased 5-HT synthesis by 5-hydroxytryptophan (5-HTP). Analgesia in the tail-flick test was partly blocked by both methergoline and mianserin, whereas the analgesic effects of 5-MeODMT in the hot-plate and shock-titration tests were unaffected by the 5-HT antagonists. In the shock-titration test it was found that the DSP4-pretreated animals were made hyperalgesic by acute 5-MeODMT, and this hyperalgesia was blocked by both mianserin and methergoline, implying that this effect was 5-HT receptor mediated. It is therefore concluded that a functional central noradrenergic system is required for eliciting 5-HT receptor mediated analgesia, and that these interactions, at least in part, are probably spinally located.
5-Hydroxytryptophan↗
Spinal noradrenergic neurotransmission and the analgesia induced by brief footshock.
Antinociception induced by brief footshock as well as by 5-methoxy-N,N-dimethyltryptamine was antagonized by lesions of the descending bulbospinal noradrenergic (NA) pathways by intrathecal injections of 6-hydroxydopamine. The alpha 2-adrenoceptor antagonist, yohimbine, injected intrathecally also blocked both types of nociceptive effects in the tail-flick and hot-plate tests. 5-Methoxy-N,N-dimethyltryptamine (1 mg/kg) potentiated shock-induced antinociception and this potentiation was also antagonized by decreased NA neurotransmission. These findings suggest an important role for spinal NA innervation, and possibly alpha 2-adrenoceptors in antinociception induced by brief footshock and serotonergic receptor stimulation induced analgesia in rats.
Afferent Pathways↗
Noradrenaline-serotonin interactions in the control of sexual behavior in the male rat: DSP4-induced noradrenaline depletion antagonizes the facilitatory effect of serotonin receptor agonists, 5-MeODMT and lisuride.
The present communication reports how depletion of central noradrenaline neurons of DSP4 treatment antagonizes the facilitatory actions of 5-MeODMT and lisuride on male rat sexual behavior. In males with intact noradrenaline, 5-MeODMT facilitated sexual behavior by reducing the number of intromissions required for ejaculation; inhibitory actions were also noted, since 5-MeODMT prolonged intromission and ejaculation latencies. In DSP4-pretreated animals the inhibitory effect of 5-MeODMT remained unchanged, whereas its facilitatory action was abolished. Consistent with previous research, lisuride also reduced intromission frequency prior to ejaculation. This facilitation of sexual behavior was not observed in DSP4-treated animals. In the male rat, ejaculations following the first have a lower latency and are preceded by a lower number of intromissions. This naturally occurring facilitation of sexual behavior was not prevented by DSP4-induced noradrenaline depletion. Our results suggest that serotonin and noradrenaline interact in the control of sexual behavior in the male rat.
Animals↗
Ontogenesis of unit activity in the raphe dorsalis of the behaving kitten: its relationship with the states of vigilance.
The relationship between the spontaneous unit activity in the raphe dorsalis (RD), and the sleep-wakefulness cycles, was analyzed in the cat from birth to 40 days of age. Electrodes for polygraphic sleep monitoring were implanted under anesthesia, and unit recordings were obtained from bundles of microwires positioned in the RD area in kittens of different ages. Attention was paid only to units with slow firing in wakefulness (W) (1-6 spikes/s), and two types of discharge patterns during this state were obtained: a 'regular' type, whose discharge in W had the same characteristics of regularity as those described for the adult under the same conditions, was always found inside the RD. An 'irregular' type was always found in sites outside the RD. Injections of different doses of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT i.m.) induced a transient decrease in the firing rate of the regular type of cells, and no change for the units of the irregular type, suggesting that the regular neurons were of serotoninergic nature. Whereas the cells of the irregular type exhibited an increase of discharge frequency in active or paradoxical sleep (AS-PS), those which fired in a clock-like manner during W exhibited a rate of discharge which progressively decreased in quiet or slow wave sleep (QS-SWS) and even more in AS-PS. Such a pattern was qualitatively close to the adult one at all ages, but the discharge rate in AS was significantly higher during the first and second weeks of life than later on. The observation that these serotoninergic neurons exhibited at birth an adult-like pattern of discharge during W, indicates that during ontogenesis there was no direct relationship between the RD activity and the behavioral output. It is proposed that the RD neuronal discharge would be largely under genetic influences, and that the maturation of sleep regulations at the brainstem and mesencephalic levels is achieved only after the second week of postnatal age.
Action Potentials↗
Female rats are more vulnerable than males in an animal model of depression: the possible role of serotonin.
A single 2-h restraint stress reduces locomotion and increases defaecation of male rats placed in an open field 24 h later. After daily 2-h restraints for 5 days these effects were no longer observed. This adaptation was associated with enhanced sensitivity to the serotonin agonist 5-methoxy-N,N-dimethyltryptamine. Female rats were less affected by a single restraint but failed to adapt to the repeated stress procedure and did not exhibit enhanced sensitivity to 5-methoxy-N,N-dimethyltryptamine. Furthermore, females but not males killed 24 h after the final restraint period had decreased brain regional 5-hydroxyindoleacetic acid concentrations particularly in the frontal cortex. No sex differences in hypothalamic and striatal dopamine metabolism were observed. The above differences between male and female rats were unaffected by adult gonadectomy. Similar differences could be involved in the higher incidence of depressive illness in women.
Animals↗
5-HT depletion with 5,7-DHT, PCA and PCPA in mice: differential effects on the sensitivity to 5-MeODMT, 8-OH-DPAT and 5-HTP as measured by two nociceptive tests.
Depletion of 5-hydroxytryptamine (5-HT) in mice was produced by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 80 micrograms) or by systemic injections of p-chloroamphetamine (PCA, 3 X 40 or 4 X 40 mg/kg), p-chlorophenylalanine (PCPA, 5 X 400 or 14 X 400 mg/kg) or combined PCA (3 X 40 mg/kg) + PCPA (11 X 400 mg/kg). Neither of the pretreatments altered nociception in the increasing temperature hot-plate test, whereas hyperalgesia was demonstrated in 5,7-DHT lesioned animals in the tail-flick test. 5,7-DHT-pretreatment enhanced the antinociceptive effect of the 5-HT agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-hydroxytryptophan (5-HTP). This effect was observed after 2, 5 and 8 days in the tail-flick test and after 5 and 8 days in the hot-plate test. However, pretreatment with PCPA or PCA failed to alter the antinociception elicited by the 5-HT agonists, although a tendency towards enhancement of antinociception was found after combined treatment with PCA and PCPA. It is suggested that the injection of 5,7-DHT induces denervation supersensitivity of post-synaptic 5-HT receptors. The lack of such supersensitivity after PCPA-pretreatment which induces similar 5-HT depletion to 5,7-DHT, may suggest that other factors than the absence of 5-HT may contribute to the development of denervation supersensitivity. Alternatively, the three 5-HT depleting agents may produce a qualitatively different reduction of 5-HT.
5,7-Dihydroxytryptamine↗