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PubMed1980

5-Methoxy-N,N-dimethyltryptamine: spinal cord and brainstem mediation of excitatory effects on acoustic startle.

The effects of different doses (0.03, 0.06, 0.12, 0.25, 1.0, 2.0, 4.0, and 8.0 mg/kg body weight) of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) were tested on the acoustic startle reflex in rats. Beginning at 0.12 mg/kg, 5-MeODMT increased startle monotonically up to the highest dose used. 5-MeODMT still increased startle in acutely decerebrate rats or when infused directly onto the spinal cord. The excitatory effects of a high systemic dose of 5-MeODMT were completely blocked by cinanserin, cyproheptadine, and propranolol, but not by parachlorophenylalanine, alpha-methyl-p-tyrosine, haloperidol, sotalol, or phenoxybenzamine. The results were discussed in terms of a new theory, which suggests that stimulation of serotonin receptors in the spinal cord enhance startle whereas serotonin receptors in the forebrain inhibit startle.

Acoustic Stimulation↗
PubMed1989

The role of 5HT1A receptors in the modulation of the acoustic startle reflex in rats.

The modulatory role of serotonin (5-HT) on the acoustic startle reflex was studied using 5-HT receptor agonists and antagonists. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1,2 and 4 mg/kg, SC) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (1,2 and 4 mg/kg, IP), putative 5-HT1a receptor agonists, increased the magnitude of the startle reflex, while quipazine (5, 10 and 20 mg/kg, SC), an agonist with mixed 5-HT2 and 5-HT1b receptor activity, decreased startle responsiveness. Pretreatment of rats with ketanserin (1, 2 and 4 mg/kg, SC), a 5-HT2 receptor antagonist, had no significant effect on the activity of 8-OHDPAT, 5-MeODMT, or quipazine. Metergoline (0.25, 0.5, 1 and 2 mg/kg, SC), a mixed 5-HT1/5-HT2 receptor antagonist attenuated the augmentation of the reflex by 8-OHDPAT and 5-MeODMT and the suppression produced by quipazine. At the doses used, metergoline produced a non-dose-dependent increase in startle, while ketanserin had no effect. None of the agents specifically affected the ability of a prepulse stimulus to inhibit the acoustic startle response. These data suggest that 5-HT1a and 5-HT1b receptors play opposite roles in the modulation of the acoustic startle response and that 5-HT plays little, if any, role in the prepulse inhibition of the acoustic startle response.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1982

Prevention of the serotonin syndrome in rats by repeated administration of monoamine oxidase inhibitors but not tricyclic antidepressants.

The serotonin syndrome, a behavioral response produced by the activation of serotonin receptors, and 3H-serotonin binding were examined after repeated treatment of rats with different types of antidepressant drugs. The serotonin syndrome was produced by the direct-acting serotonin receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeDMT) or d-lysergic acid diethylamide (LSD). Repeated, but not acute treatment of rats with monoamine oxidase inhibitors (nialamide, pargyline, and phenelzine) prevented the serotonin syndrome in response to either 5-MeDMT or LSD and also reduced 3H-serotonin binding in the brain stem and spinal cord. Pretreatment of rats with p-chlorophenylalanine blocked the ability of nialamide treatment to inhibit the serotonin syndrome caused by 5-MeDMT. By contrast, neither the serotonin syndrome or 3H-serotonin binding was affected significantly by the repeated administration of tricyclic antidepressants (amitriptyline, desmethylimipramine, and chlorimipramine) or iprindole. Repeated monoamine oxidase inhibitor treatments may prevent the serotonin syndrome by causing a reduction of 3H-serotonin receptor binding sites in the brain stem and/or spinal cord.

Animals↗
PubMed1984

In vivo increase in hypothalamic cyclic AMP following 5-hydroxytryptophan administration in rats.

The administration of 5-hydroxytryptophan (5-HTP, 100 mg/kg, i.p.) consistently increased hypothalamic cyclic AMP levels in rats treated 10 days earlier with the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to produce 5-HT receptor supersensitivity. However 5-HTP (100 mg/kg), failed to cause an increase in hypothalamic cyclic AMP in rats not pretreated with 5,7-DHT. The 5-HTP-induced increase in cyclic AMP was blocked by the decarboxylase inhibitor, benserazide (RO 4-4602, 800 mg/kg) and by the 5-HT antagonist metergoline (5 mg/kg). Other treatments that caused a significant elevation of hypothalamic cyclic AMP included: (a) L-Tryptophan plus the monoamine oxidase inhibitor, tranylcypromine, and (b) the serotonin agonist, 1-(m-trifluromethylphenyl)-1-piperazine. The 5-HT antagonist, methysergide, blocked the serotonin receptor mediated behavioral syndrome, but failed to prevent the increase in hypothalamic cyclic AMP. Moreover, the 5-HT agonist, 5-methoxy-N, N-dimethyltryptamine, (5-Me-DMT), induced a strong behavioral syndrome but failed to significantly increase hypothalamic cyclic AMP. These findings suggest that activation of 5-HT receptors somewhere in the brain causes an increase in hypothalamic cyclic AMP, but further studies will be needed to determine whether this is a direct result of activation of the 5-HT receptors in the hypothalamus.

5,7-Dihydroxytryptamine↗
PubMed1980

The effects of 5-HT uptake- and MAO-inhibitors on L-5-HTP-induced excitation in rats.

The behavioural syndrome caused by L-5-HTP in rats was used for the study of effects of selective 5-HT uptake inhibitors and inhibitors of MAO on central 5-HT receptors. A good correlation was found between the relative potencies of drugs in inhibiting the 5-HT uptake in the rat brain and in intensifying L-5-HTP-induced behavioural stimulation. The potentiation of the L-5-HTP syndrome by the MAO inhibitors correlated with the inhibition of the A- but not of the B-form of the brain monoamine oxidase. In rats treated with the maximally inhibiting dose of a 5-HT uptake inhibitor, MAO inhibitors were still able to increase the intensity of the L-5-HTP syndrome, while the combination of maximal doses of two 5-HT uptake inhibitors did not produce a more intense syndrome than that produced by one 5-HT uptake inhibitor alone. The L-5-HTP-induced behavioural syndrome in rats seems to afford an experimental model allowing the quantification and characterization of the interaction of drugs with serotonin metabolism in the brain.

5-Hydroxytryptophan↗
PubMed1987

Modulation of the vestibulo-ocular reflex by serotonin in the rat.

The effects of intraventricular injection of serotonin (5-HT) and its agonists and antagonists on the amplitude of the vestibulo-ocular reflex were studied in chronic implanted rats. 5-HT (10(-5) M) triggers an increase of the amplitude of the reflex which lasts 30 min. Similar results are obtained when N,N-dimethyl-5-methoxytryptamine (10(-3) M) is introduced into the ventricular cannula. The increasing effects observed both with 5-HT and N,N-dimethyl-5-methoxy-tryptamine are abolished by methiothepin, a potent antagonist of 5-HT receptors. Injection of indirect agonists like pargyline, a monoamine oxidase inhibitor, or fluoxetine, a potent inhibitor of 5-HT reuptake, is followed by an increase of the amplitude of the vestibulo-ocular reflex. These results indicate that 5-HT can modulate the activity of the vestibulo-ocular pathway and muscular tone of extraocular muscles. Location and involvement of various modulating 5-HT sites are discussed.

Animals↗
PubMed1987

The interoceptive discriminative stimuli induced by the novel putative anxiolytic TVX Q 7821: behavioral evidence for the specific involvement of serotonin 5-HT1A receptors.

TVX Q 7821 is active in several behavioral models of anxiety in animals and has a high selective affinity for brain serotonin 5-HT1A receptors in binding assays. In order to determine if interaction with 5-HT1A receptors is important for some of the behavioral effects of this compound, 11 rats were trained to reliably discriminate the interoceptive stimuli induced by TVX Q 7821 (10 mg/kg, IP) from those of saline. Following discrimination acquisition, TVX Q 7821 administration resulted in drug-appropriate responding with an ED50 of 1.5 mg/kg, as did other substances with high affinity for the 5-HT1A receptor: 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, ED50 = 0.16 mg/kg), 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, ED50 = 2.5 mg/kg), and buspirone (ED50 = 5.4 mg/kg). Anxiolytics not acting via the 5-HT1A receptor, like diazepam and pentobarbital, did not induce full TVX Q 7821-appropriate responses. In addition, non-selective 5-HT agonists and antagonists such as bufotenin, quipazine, and methysergide, as well as substances with high affinity for the 5-HT1B receptor (m-trifluoromethylphenylpiperazine, TFMPP; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate, RU 24969) did not substitute for TVX Q 7821. These data support a selective 5-HT1A mechanism of action in vivo for TVX Q 7821 and indicate the suitability of TVX Q 7821 for the investigation of behavioral correlates of the 5-HT1A receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Intrathecal noradrenaline restores 5-methoxy-N,N-dimethyltryptamine induced antinociception abolished by intrathecal 6-hydroxydopamine.

Intrathecal administration of 6-hydroxydopamine (6-OHDA) abolished the antinociceptive effects of acute administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 mg/kg, s.c.) in the hot-plate, tail-flick and shock titration tests of nociception. The antinociceptive effects of 5-MeODMT, abolished by the prior intrathecal 6-OHDA treatment, were restored by intrathecal administration (2 or 1 microgram) of noradrenaline (NA), immediately prior to 5-MeODMT, in all three tests of nociception. Biochemical analysis confirmed severe NA depletions (95 percent loss) in the lumbar and thoracic regions of the spinal and much lesser dopamine depletions (25-35 percent loss). Intrathecal 5,7-dihydroxytryptamine (5,7-DHT) attenuated 5-MeODMT induced antinociception in the tail-flick test and combined NA + 5-MeODMT induced antinociception in the hot-plate and tail-flick tests. Intrathecal administration of 5,7-DHT caused a severe depletion of 5-hydroxytryptamine in the lumbar region of the spinal cord. The present findings demonstrate further the modulatory role of NA upon serotonergic systems in nociception and indicate the necessity of NA availability for induction of 5-MeODMT analgesia.

5,7-Dihydroxytryptamine↗
PubMed1989

Subsensitivity of serotonin and substance P receptors involved in nociception after repeated administration of a serotonin receptor agonist.

The antinociceptive effects of subcutaneous 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the responses to intrathecal (i.th.) serotonin (5-HT) and substance P (SP) were examined in mice after repeated administration of 5-MeODMT (3 mg/kg every 30 min for 4 hours). Ninety min after the last injection of 5-MeODMT the basal tail-flick and hot-plate response latencies were unaltered, but the antinociceptive effects of 5-MeODMT (3 mg/kg) in the tail-flick and hot-plate tests and the antinociceptive effect of 8-OH-DPAT (0.5 mg/kg) in the hot-plate test were markedly reduced. The behavioral responses to i.th. 5-HT (4.0 micrograms) and SP (2.5, 5, and 10 ng) which include vigorous biting, licking and scratching of the caudal part of the body, were attenuated 90-120 min after withdrawal of 5-MeODMT treatment. It is suggested that repeated administration of 5-MeODMT downregulates the function of the 5-HT receptors mediating the antinociceptive effects of 5-MeODMT and 8-OH-DPAT. The rapid desensitization to the behavioral responses both to 5-HT and SP by 5-MeODMT pretreatment may reflect a functional interaction between 5-HT and SP in the spinal modulation of nociception.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

5-HT agonist induced analgesia modulated by central but not peripheral noradrenaline depletion in rats.

The antinociceptive effect elicited by the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was reversed or blocked in animals which had previously sustained severe spinal noradrenaline (NA) depletion via either systemic N-2-chlorethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP 4), neonatal 6-hydroxydopamine (neon. 6-OHDA), or intrathecal 6-OHDA treatment. Biochemical analysis of the lumbar spinal cord samples confirmed severe central NA depletions. Animals were tested with nondamaging heat pain (tail-flick test, hot-plate test) and electric footshock titration to determine the amount of antinociception or nociception. Peripheral NA depletion following intravenous (i.v.) 6-OHDA injection to adult rats had no effect on the antinociception induced by 5-MeODMT, but did cause severe NA depletions in the left heart atrium. These results suggest a modulatory effect of central and not peripheral noradrenergic system upon 5-HT agonist induced analgesia, and also give evidence that this effect is spinally mediated.

5,7-Dihydroxytryptamine↗
PubMed1991

Effect of isolation rearing on 5-HT agonist-induced responses in the rat.

Rats were reared from weaning (21 days of age) either in isolation or in social groups of five for 30 days and were then tested for spontaneous locomotor activity and 7 days later for 5-hydroxytryptamine (5-HT) agonist-induced behaviour. Isolation-reared animals displayed locomotor hyperactivity when placed in a novel environment. 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg IP) and 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) (0.32 mg/kg SC) elicited various components of the "5-HT behavioural syndrome" in both groups of animals, with forepaw treading and flat body posture being significantly more pronounced in isolation-reared animals. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg IP), a 5-HT2 selective agonist, produced a significantly greater number of back muscle contractions in isolation-reared animals but there was no difference between the two groups in the number of wet-dog shakes produced. Forepaw treading and flat body posture are thought to be mediated by 5-HT1A receptor activation, and stimulation of this receptor by either 5-MeODMT or 8-OH-DPAT produced greater responding in isolation-reared rats, suggesting supersensitivity of the post-synaptic 5-HT1A receptor. Wet-dog shakes are thought to be mediated by 5-HT2 and other (none-5-HT) receptors while back muscle contractions have been shown to be mediated by 5-HT2 receptors, indicating that there is also an increase in 5-HT2 receptor responsiveness in the socially-isolated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Effects of oxotremorine on inhibitory avoidance behaviour in two inbred strains of mice: interaction with 5-methoxy-NN-dimethyltriptamine.

The effects of the cholinergic muscarinic agonist, oxotremorine (0.005, 0.01, 0.02 and 0.04 mg/kg), the serotonergic agonist, 5-methoxy-NN-dimethyltriptamine (5-MeODMT) (0.5, 1 and 2 mg/kg), and their combination, were investigated in C57BL/6 and DBA/2 mice using a one-trial inhibitory avoidance task, drug treatment being given immediately after the acquisition trial. Post-trial administration of oxotremorine facilitated, while post-trial administration of 5-MeODMT inhibited memory retention of both strains in a dose-dependent fashion. The DBA/2 strain was more affected by oxotremorine than the C57BL/6 mice; no strain-dependent sensitivity to serotonergic agonist administration was observed. In both strains, the combination of oxotremorine plus 5-MeODMT inhibited the performance improvement shown by the administration of the cholinergic agonist alone. The facilitatory role of cholinergic stimulation on retention performance was confirmed and an inhibitory action of the serotonergic system on memory processes was suggested. Moreover, the present results support a functional interaction between cholinergic and serotonergic systems on memory consolidation.

Animals↗
PubMed1990

An investigation of the role of 5-hydroxytryptamine in the attenuation of presynaptic alpha 2-adrenoceptor-mediated responses by antidepressant treatments.

Changes in the function of presynaptic alpha 2-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 micrograms ICV) or administration of p-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11-15 days produced 62-77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT2 receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this alpha 2-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic alpha 2-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.

5,7-Dihydroxytryptamine↗
PubMed2006

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats.

RATIONALE: The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. OBJECTIVES: A series of interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg), the 5-HT(2A) antagonist M100907 (1.0 mg/kg), and the 5-HT(2C) antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. RESULTS: 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. CONCLUSIONS: While the prevailing view was that the activation of 5-HT(2) receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT(1A) receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

Animals↗
PubMed1987

Study of metabolism of psychotomimetic indolealkylamines by rat tissue extracts using liquid chromatography.

The use of a series of liquid chromatographic techniques involving cation-exchange, reverse-phase and normal-phase chromatography has permitted the separation and characterisation of a number of metabolites of the psychotomimetic indolealkylamines N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine which were isolated following incubation of these compounds with rat tissue extracts. In liver, kidney and brain tissue extracts the routes of metabolism identified included oxidative deamination, N-demethylation, O-demethylation and N-oxidation. The quantitative significance of individual routes of metabolism in these tissues was assessed using N,N-dimethyltryptamine as a substrate.

Animals↗
PubMed1987

In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat.

Following intraperitoneal administration, 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine are subject to both a very rapid uptake into, and clearance from, all tissues examined. The current studies in vivo confirm previous in vitro observations that the routes involved in the metabolism of these compounds include oxidative deamination, N-demethylation, O-demethylation, and N-oxidation. The analysis of metabolic profiles in various tissues led to the identification of the N-oxides as major metabolites. The successful inhibition and redirection of metabolism away from the indole acids towards the parent compounds and their structurally unique metabolites were demonstrated in animals pretreated with iproniazid.

Adrenal Glands↗
PubMed1990

Observations on the metabolism of the psychotomimetic indolealkylamines: implications for future clinical studies.

Although the psychotomimetic indolealkylamines N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and 5-hydroxy-N,N-dimethyltryptamine have been unequivocally identified in human body fluids, evidence relating their concentration to the presence of psychotic illness in humans remains controversial. A series of studies on the metabolism of the compounds in the rat have highlighted the rapidity and with which these are metabolized and renally excreted. The implications of our observation for the interpretation of past clinical studies and the design of future ones is discussed.

Animals↗