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PubMed1989

Slow fluctuations of single unit activities of hippocampal and thalamic neurons in cats. II. Role of serotonin on the stability of neuronal activities.

A series of experiments was carried out both in the hippocampal pyramidal and thalamic ventrobasal neurons to investigate the effect of serotonin level in the brain on slow fluctuations of neuronal discharges. Single neuronal activities were recorded in the following two pharmacologically treated states: (1) a 5-hydroxytryptamine depleted state by p-chlorophenylalanine administration (PCPA phase) and (2) a 5-methoxy-N,N-dimethyltryptamine administered state under the PCPA pretreatment (5-MeODMT phase). The slow fluctuations of neuronal activities in the frequency range of 0.02-1.0 Hz in both nuclei were prominent during the PCPA phase and were similar to those during the paradoxical sleep. In contrast, slow fluctuations were suppressed during the 5-MeODMT phase and neuronal activities during this phase were similar to those during slow wave sleep (SWS). The results show that serotonin in the brain definitely plays a role in stabilizing single neuronal activities.

Action Potentials↗

PubMed1990

The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex.

The role of the 5-hydroxytryptamine (5-HT) receptor subtypes in the spinal cord in the regulation of nociception is unknown. This study examined whether administration of different 5-HT1 receptor agonists into the spinal subarachnoid space of mice modulates the nociceptive tail-flick reflex, and whether effects on the tail-flick reflex involve changes in tail skin temperature. The tail-flick latencies (the time needed to evoke the tail-flick reflex by noxious radiant heat) were significantly increased after intrathecal (i. th.) injection of 5-HT (10-20 micrograms), the 5-HT1A/5-HT1B receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 10-20 micrograms), the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 20 micrograms) and after i.th. injection of 1(m-chlorophenyl)piperazine (mCPP, 5-20 micrograms) and 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 5-20 micrograms) which have high affinity for the 5-HT1B receptors. None of the 5-HT1 receptor agonists had the ability to change the tail skin temperature. The results show that in the mouse i.th. injection of both 5-HT1A and 5-HT1B receptor agonists has the ability to inhibit the tail-flick reflex without interfering with the tail skin temperature.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

The effects of serotonergic drugs on the locomotor pattern and on cutaneous reflexes of the adult chronic spinal cat.

The effects of serotonergic substances on the locomotor pattern and cutaneous reflexes were studied in 3 adult chronic spinal cats trained for 1-3 months to walk with their hindlimbs on a treadmill. The 5-hydroxytryptamine (5-HT) precursor, 5-hydroxytryptophan (5-HTP), and two 5-HT agonists, 5-methoxy-N,N-dimethyltryptamine and quipazine, were found to generally increase the step length and augment the amplitude of hindlimb extensors and flexors as well as axial muscles. Correspondingly, the excursion of the hip, the knee and the ankle joints was increased, mainly in the flexion direction. Cyproheptadine, a 5-HT antagonist, partially or completely antagonised these effects. The threshold current needed to elicit a flexion reflex by stimulating the dorsum of the paw through implanted wires, was lower after the injection of 5-HT agonists than in the immediately preceding control period. Fast paw shaking initiated by dipping the paw in water was unchanged after quipazine and was not abolished by cyproheptadine. In accordance with others, our results suggest that serotonergic drugs may increase the excitability of several types of spinal neurones, including motoneurones, and consequently influence the locomotor pattern as well as the reflex responsiveness. The changes observed with serotonergic agonists were different in many respects from those obtained with noradrenergic agonists and these differences are discussed. This may indicate specific roles for these classes of substances on locomotor function and reflex activity and also provide a basis for further clinical investigations.

5-Hydroxytryptophan↗

PubMed1991

Acute and chronic effects of intrathecal galanin on behavioural and biochemical markers of spinal motor function in adult rats.

The spinal motor effects of galanin, which co-exists with 5-hydroxytryptamine (5-HT) and thyrotrophin-releasing hormone (TRH) in bulbospinal raphe neurones innervating spinal motoneurones, were examined by administering this neuropeptide through indwelling intrathecal cannulae to conscious adult Wistar rats. The acute effect of intrathecal galanin on spontaneous motor behaviour and the motor behaviours (back muscle contractions and wet-dog shakes) elicited by intrathecal injection of the non-selective 5-HT receptor agonist, 5-methoxy-N, N'-dimethyltryptamine (5-MeODMT) or the TRH analogue, RX 77368 analogue, RX 77368 (pGlu-His-3,3'-dimethyl-ProNH2), respectively, and the chronic effect of galanin on neurochemical markers for bulbospinal raphe neurones and spinal motoneurones were determined. Intrathecal galanin (0.1 to 10 micrograms) did not produce any notable motor behaviours when given alone, but pretreatment with the neuropeptide (0.1 micrograms) significantly attenuated both the number of wet-dog shakes and the amount of forepaw-licking induced by RX 77368, without affecting 5-MeODMT-induced back muscle contractions. Repeated intrathecal galanin administration (1 microgram, twice daily for 5 d) significantly elevated 5-HT (but not 5-hydroxyindoleacetic acid) and substance P-like immunoreactive (LI) levels and choline acetyltransferase (ChAT) activity in the dorsal, but not in the ventral, portion of the thoraco-lumbar spinal cord. In contrast, chronic intrathecal galanin did not alter the TRH- or calcitonin gene-related peptide (CGRP)-LI levels in either spinal cord region.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1991

Pharmacological characterization of medullary serotonin neurons.

In the present study we investigated the characteristics of medullary raphe serotonergic neurons. Specifically, we sought to examine further the similarities between medullospinal 5-HT neurons and the more extensively studied neurons of the dorsal raphe. Intravenous administration of 5-methoxy-dimethyltryptamine (5-MeODMT) produced a dose-related inhibition of the firing of midline medullary 5-HT neurons. Microiontophoretically applied 5-MeODMT also inhibited medullary 5-HT neurons. The inhibitory potency of 5-MeODMT was nearly identical to that observed for dorsal raphe 5-HT neurons. Microiontophoretic or intravenous administration of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) did not alter the firing rate of medullary 5-HT neurons. Intravenous administration of the alpha 1-receptor antagonist prazosin resulted in an inhibition of the medullary 5-HT neuronal firing. The discharge of medullary 5-HT neurons increased during iontophoresis of norepinephrine. These data are discussed in relation to the identification and characterization of medullary 5-HT neurons. In addition, the data suggest that the firing rate of medullary 5-HT neurons is regulated in part by a tonic excitatory noradrenergic input.

Amphetamines↗

PubMed1992

Serotonergic influence on cholinergic-induced analgesia: differences in two inbred strains of mice.

C57BL/6 (C57) and DBA/2 (DBA) inbred mice showed different analgesic responses to cholinergic stimulation. The simultaneous administration of muscarinic and serotonergic agonists, oxotremorine and 5-methoxy-NN-dimethyltryptamine (5-MeODMT), lowered the antinociceptive effect of the cholinergic drug in DBA mice, while no effects were detectable in the C57 strain. These results suggest a strain-dependent behavioural effect of the interaction of cholinergic and serotonergic neuronal systems.

Acetylcholine↗

PubMed1994

The excitability and rhythm of medullary respiratory neurons in the cat are altered by the serotonin receptor agonist 5-methoxy-N,N, dimethyltryptamine.

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) is an indolealkylamine which has agonist activity at 5HT receptors. In the present investigation, 5-MeODMT had two types of effects on medullary respiratory neurons of the cat. Iontophoretic administration or i.v. doses (43 +/- 8.9 micrograms/kg) of 5-MeODMT hyperpolarized respiratory neurons and severely reduced action potential discharges. Cinanserin, a 5HT-2/1 c receptor antagonist, when injected i.v. reduced the inhibition produced by i.v. injection of 5-MeODMT. Iontophoresis of cinanserin did not antagonize inhibition produced by iontophoresis of 5-MeODMT or 5-HT. The depression of respiratory discharge by i.v. injection of 5-MeODMT is attributed to presynaptic effects (network depression) and post-synaptic activation of 5HT-1A receptors on respiratory neurons. 5-MeODMT (27 +/- 2.78 micrograms/kg i.v.) also increased discharge frequency of inspiratory and expiratory neurons. Inspiratory neuron discharges were briefer and expiratory neuron discharges occurred earlier in relation to phrenic nerve activity. It is suggested that the effects of the smaller doses are due to binding of 5-MeODMT to 5HT-1A receptors on early inspiratory neurons of the medulla.

Animals↗

PubMed1979

Repeated administration of 5-methoxy-N,N-dimethyltryptamine to male rats potentiates stimulation of prolactin secretion by serotonin agonists.

Repeated administration of 5-methoxy-N,N-dimethyltryptamine (5MeODMT, 5 mg/kg, a serotonin agonist, every 3 h for a total of 4 injections) potentiated its prolactin (PRL)-releasing effect and that of two other serotonin agonists, quipazine and N,N-dimethyltryptamine. This pretreatment schedule had no effect on PRL response to anti-dopaminergic drugs. The onset of enhanced PRL response to serotonin agonists was gradual and appears to be due to sensitization of the serotonergic mechanism involved in the regulation of PRL secretion. The possible mechanisms underlying this phenomenon are discussed.

Animals↗

PubMed1980

Unilateral 5,7-dihydroxytryptamine lesions of the dorsal raphe nucleus (DRN) and rat rotational behaviour.

A unilateral lesion in the dorsal raphe nucleus (DRN) resulted in a decreased concentration of 5-hydroxytryptamine (5-HT) in the ipsilateral striatum (CS), anterior cortex and substantia nigra (SN), a loss of [3H]5-HT uptake sites in the cortex and striatum and a selective reduction in 5-HT turnover in the substantia nigra. The directly acting 5-HT agonist 5-methoxy-N,N-dimethyltryptamine induced contralateral turning behaviour in the lesioned animals, whilst the 5-HT releasing agent, p-chloroamphetamine, induced ipsilateral rotation. All rotational behaviour was blocked by haloperidol and the turning behaviour in response to 5-MeODMT was blocked by methysergide. The data presented suggest that the DRN innervates the SN and CS differentially and that nigral 5-HT receptors become supersensitive after denervation of the DRN-SN pathway.

5,7-Dihydroxytryptamine↗

PubMed1981

Behavioral properties of psychoactive phenylisopropylamines in rats.

Rats were trained to discriminate injections of 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT, 3.0 mg/kg) a hallucinogenic agent for which a serotonergic mechanism has been implicated, from saline in a two-lever drug discrimination task. After reliable levels of accuracy (greater than or equal to 85%) were attained, the ability of the 5-OMe DMT cue to generalize to 36 substituted phenylisopropylamines (or their optical isomers) was assessed. The results reveal that, in general, the challenge compounds could be differentiated into three broad categories: Those that produced 5-OMe DMT-appropriate responding (generalization), those that produced partial 5-OMe DMT-appropriate responding (partial generalization) and those that produced negligible 5-OMe DMT-appropriate responding. It is concluded that certain of the substituted phenylisopropylamines, unlike amphetamine itself, can produce effects in rats similar to those produced by the training dose of 5-OMe DMT, and that a serotonergic mechanism might be involved.

Amphetamines↗

PubMed1982

Intracellular studies on the effects of systemic administration of serotonin agonists on rat facial motoneurons.

Intracellular recordings were made from facial motoneurons of anesthetized rats during systemic administration of 5-methoxy-N,-N-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA), drugs which elicit the behavioral serotonin syndrome. Both drugs caused a slow depolarization, increased input resistance, and increased excitability of facial motoneurons. These changes are identical to those caused by direct microiontophoretic application of serotonin to these neurons, and probably underlie some of the components of the behavioral serotonin syndrome.

Animals↗

PubMed1982

Medullary serotonergic neurons are insensitive to 5-MeoDMT and LSD.

A comparison was made of the effects of 5-MeoDMT or LSD on serotonergic unit activity in the dorsal raphe nucleus (DRN) and nucleus raphe pallidus (NRP) of freely moving cats. NRP neurons were substantially less responsive than DRN neurons to both drugs. NRP neurons were unresponsive to behaviorally effective low doses of these drugs whereas the activity of DRN neurons was strongly depressed. These data are discussed in terms of autoregulatory control of serotonergic neurons.

Animals↗

PubMed1982

Withdrawal from chronic treatment with metergoline, dl-propranolol and amitriptyline enhances serotonin receptor mediated behaviour in the rat.

Acute treatment of rats with metergoline (2 mg/kg), a serotonin antagonist, prevented the behavioural syndrome produced by the serotonin agonist 5-methoxy-N',N'-dimethyltryptamine (2.5 mg/kg, 5MEODMT). dl-Propranolol (15 mg/kg) and amitriptyline (15 mg/kg) also inhibited the behavioural syndrome. The 5MEODMT behavioural syndrome was attenuated when metergoline or amitriptyline were administered daily for 14 days and 5MEODMT administered 30 min after the injection on day 14. This attenuation was not seen with chronic dl-propranolol treatment. When 5MEODMT was administered 72 h after the last injection of metergoline, amitriptyline or dl-propranolol on day 14, the behavioural syndrome was enhanced. The results suggest that withdrawal from chronic treatment with serotonin antagonists results in functional supersensitivity of serotoninergic neurones.

Amitriptyline↗

PubMed1983

Raphe neurons: firing rate correlates with size of drug response.

Significant negative correlations were obtained between the spontaneous discharge rate during waking and the neural response to systemic injections of either 5-MeODMT or LSD for serotonergic neurons in the dorsal raphe nucleus, nucleus centralis superior, and nucleus raphe pallidus of unanesthetized and unrestrained cats. These data are discussed in terms of an hypothesis which accounts for both the rate of spontaneous activity of serotonergic neurons and the magnitude of their response to serotonin agonist drugs in terms of autoreceptor density on individual neurons.

Animals↗

PubMed1983

Inhibitory effect of 5-methoxy-N,N-dimethyltryptamine on the synaptosomal uptake of 5-hydroxytryptamine.

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) in concentrations of 0.5-500 microM produced a significant inhibition of [14C]5-hydroxytryptamine [14C]5-HT) uptake in striatal, hippocampal and hypothalamic crude synaptosomes from rat brain. Higher concentrations of 5-MeODMT (10 microM) also inhibited the uptake of [3H]dopamine [3H]DA) and induced the release of [14C]5-HT and [3H]DA from preloaded synaptosomes. It appears that the 5-HT agonist properties of 5-MeODMT may involve reuptake inhibition in addition to the previously documented direct receptor stimulation.

Animals↗

PubMed1983

Regional differences in the response of serotonergic neurons in rat CNS to drugs.

In vivo rates of 5-hydroxytryptophan accumulation (following administration of the decarboxylase inhibitor R04/4602/1) and levels of 5-HT in the nucleus raphe dorsalis (DR), nucleus centralis superior (NCS), nucleus septalis lateralis (LS), nucleus suprachiasmaticus (SCN), nucleus hypothalamicus anterior (AH), and nucleus amygdaloideus centralis (AG) were determined following administration of fluoxetine, 5-methoxy-N,N-dimethyltryptamine, methiothepin, L-tryptophan and reserpine. Fluoxetine and 5-methoxy-N,N-dimethyltryptamine inhibited 5-hydroxytryptophan synthesis in all nuclei, although inhibition of synthesis in the DR was resistant to fluoxetine. Methiothepin inhibited 5-HT synthesis in the DR, NCS, LS and AG, but not in the SCN or AH. L-Tryptophan greatly increased 5HT synthesis in all areas, but this increase was not uniform, being fourfold greater in the NCS than in the LS. Reserpine, while greatly depleting 5HT did not increase 5-hydroxytryptophan synthesis in any nucleus. In no region could changes in brain tryptophan account for the observed drug effects on serotonin metabolism. We conclude that not all CNS serotonergic structures respond to the same drug in a uniform manner.

5-Hydroxytryptophan↗

PubMed1983

Effects of chronic antidepressant treatment on serotonin receptor activity in mice.

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.

Amitriptyline↗

PubMed1983

Hyponeophagia in the Roman rat strains: effects of 5-methoxy-N,N-dimethyltryptamine, diazepam, methysergide and the stereoisomers of propranolol.

The effects of 5-MeODMT (2.5 mg/kg), diazepam (1 mg/kg), methysergide and the stereoisomers of propranolol (6 mg/kg) on hyponeophagia were studied in both sexes of the Roman strains of rats, selectively bred for acquisition of a two-way conditioned avoidance response. Diazepam, methysergide and 1-propranolol increased feeding in a novel environment whilst 5-MeODMT decreased it and d-propranolol was inactive. Several strain differences in drug responsiveness occurred, the Roman Low Avoidance subjects being most sensitive to all drugs tested as well as being most neophobic. A sex difference in 5-MeODMT sensitivity was also found, female rats of the Roman High and Control Avoidance strains being more sensitive than males. The findings are discussed in connection with differences in arousal and biochemical parameters between these strains.

Animals↗