L-5-Hydroxytryptophan-induced myoclonus in guinea pigs: a model for the study of central serotonin-dopamine interactions.

Myoclonic responses produced in guinea pigs by systemic administration of l-5-hydroxytryptophan (l-5-HTP), or of l-tryptophan plus a monoamine oxidase inhibitor, were recorded and analysed quantitatively. l-5-Hydroxytryptophan-induced myoclonus involves 5-hydroxytryptamine (5-HT) neurones and receptors, and appears to be an all-or-none response due to a spill-over phenomenon, rather than to impulse released 5-HT. The myoclonus was antagonized by the 5-HT receptor blockers, cyproheptadine and methergoline. Quipazine, an agent which releases 5-HT and inhibits its reuptake, produced a low rate of myoclonic jerks. Injection of the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, resulted in intense myoclonus as well as a behavioural syndrome characterized by writhing, turning and hyperactivity. The dopamine (DA) receptor agonists, apomorphine and N-n-propyl-N-n-butyl-β-(3,4-dihydroxyphenyl)-ethylamine-HCl (PBD), antagonized the l-5-HTP induced myoclonus. The DA receptor blockers, haloperidol and pimozide, had no appreciable effect on l-5-HTP-induced myoclonus, but antagonized the suppression of myoclonus by DA agonists, indicating a modulation of the L-5-HTP-induced myoclonus by DA neurones. It is proposed that l-5-HTP-induced myoclonus in guinea pigs represents a useful model by which to study interactions between DA and 5-HT neuronal systems. Using the recording system described, the relative 5-HT and DA agonist and antagonist properties of new compounds may be determined. Furthermore, suppression of myoclonus by DA agonists may be employed as a method for screening potential anti-Parkinsonian agents.     

Myoclonus in the rat induced by p,p'-DDT and the role of altered monoamine function

Administration of p,p'-DDT to rats produced myoclonus, but unlike previous studies in mice, this was not decreased by administration of clonazepam. Precursors of 5-hydroxytryptamine (5-HT) (l-tryptophan and l-5-HTP) reduced the intensity of myoclonus, but the 5-HT agonists, quipazine and Org 6582 did not. Antagonists of 5-HT (methergoline, methysergide and cinanserin) did not potentiate the myoclonus induced by p,p'-DDT. Drugs altering the function of dopamine and noradrenaline (apomorphine, clonidine or phenoxybenzamine) also had no effect on this myoclonus. Administration of monoamine oxidase inhibitors (MAOIs; pargyline, nialamide and tranylcypromine) markedly attenuated the myoclonus, an effect that could not be attributed to an action on any one monoamine system. No observable changes in cerebral biochemical parameters of 5-HT occurred at the onset of myoclonus, although tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in brain were increased following periods of prolonged myoclonus. Electrophysiological analysis of the myoclonus in the rat induced by p,p'-DDT revealed changes in EEG and EMG activity which suggested an origin for the myoclonus in the brainstem. Although this was similar to electrophysiological findings in some human patients with post-anoxic action myoclonus, the pharmacological studies suggest that the myoclonus induced by p,p'-DDT in the rat is not a suitable model for screening potential drugs to be used in the treatment of this disorder.     

Analgesia induced by brief footshock is inhibited by 5-hydroxytryptamine but unaffected by antagonists of 5-hydroxytryptamine or by naloxone

Exposure to footshock (1 mA) for 30 sec induced a marked analgesia that was enhanced by pretreatment with the 5HT synthesis inhibitor, p-chlorophenylalanine, and attenuated by the 5HT releasing drugs p-chloroamphetamine and fenfluramine, by the 5HT re-uptake inhibitor, fluoxetine and by the 5HT agonists, 5-methoxy-N,N-dimethyltryptamine and MK212. However, agonists, quipazine and trifluoromethylphenylpiperazine, with greated reported affinities for 5HT binding sites on rat brain membranes than MK212 were without effect as were the antagonists metergoline, methysergide, cyproheptadine, mianserine and methiothepin. The specific opioid antagonist naloxone was also without effect. The results in general indicate that analgesia induced by brief footshock (1 mA, 30 sec) is inversely related to 5HT availability but thereis little evidence of involvement of known 5HT receptors.     

"Wet-dog" shake behaviour in the rat: a possible quantitative model of central 5-hydroxytryptamine activity.

The ‘Wet-Dog’ shake (WDS) response has been investigated in the rat as a possible animal model to quantify central 5-hydroxytryptamine (5-HT) activity. The behaviour occurs in a dose-dependent manner following systemic administration of the 5-HT precursor. 5-hydroxytryptophan (5-HTP). It is also seen after injection of L-tryptophan and the proposed 5-HT agonists 5-methoxy-NN'-dimethyltryptamine, lysergic acid diethylamide and quipazine. Potential 5-HT uptake blocking compounds (chlorimipramine. ORG 6582. femoxetine) only weakly and intermittently induced the phenomenon. The putative 5-HT antagonists methysergide and cyproheptadine were effective at blocking 5-HTP-induced WDS. Concomitant dopamine receptor stimulation with amphetamine and apomorphine also markedly decreased the 5-HTP-induced WDS response. However manipulation of central cholinergic and noradrenergic mechanisms was without effect on 5-HTP-induced WDS behaviour. Biochemically, regional increases in cerebral 5-HT concentrations paralleled the WDS response seen after systemic administration of 5-HTP. From lesioning and brain sectioning experiments it is concluded that the WDS reflex originates in the brain stem but can be greatly facilitated by the presence of diencephalic structures. It is proposed that the WDS response in rats may provide a quantitative model of central 5-HT activity. It is possibly related to head twitches and jerks described in other animal species.     

Receptor mechanisms in increased sensitivity to serotonin agonists after dihydroxytryptamine shown by electronic monitoring of muscle twitches in the rat

Muscle twitches and autonomic changes were induced by systemic injections of L-5-hydroxytryptophan (5-HTP) or the serotonin agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats previously lesioned with intracranial 5,7-dihydroxytryptamine (5,7-DHT) after desmethylimipramine. Movements were recorded sensitively and continuously by an electronic activity monitor. Spontaneous locomotor activity was strongly reduced after 5-HTP in both intact and lesioned rats, so that electronically recorded activity correlated very closely with disordered jerking movements scored by a behavioral rating scale. This myoclonus was dependent on the doses of 5-HTP and of 5,7-DHT and was strongly inhibited by serotonin antagonists. In lesioned rats, myoclonus occurred with unaltered activity of monoamine oxidase (MAO) and after only small increases in serotonin levels after 5-HTP, but even large increases in availability of serotonin in intact rats, or strong inhibition of serotonin uptake failed to induce myoclonus unless MAO was first inhibited. The response to 5-HTP in lesioned rats was attenuated by repeated injections of 5-HTP or 5-MeO-DMT. This decreased response was in turn blocked by repeated doses of a serotonin antagonist, but appeared not to be due to altered metabolism of 5-HTP or of serotonin; repeated pretreatment with cyproheptadine potentiated the myoclonic response to 5-HTP after DHT. Changes in postsynaptic receptors may be important in the behavioral supersentivity following 5,7-DHT, and restitution of serotonin or stimulation of its receptors after presynaptic denervation may suppress an evolving supersensitivity at receptive postsynaptic membranes.     

p,p′-DDT-Induced Myoclonus in Mice: The Effect of Enhanced 5-HT Neurotransmission

The acute behavioural consequences of intragastric p,p′-DDT in high doses to mice are stimulus sensitive abrupt muscle jerks (myoclonus). The serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) ameliorated in contrast to the natural precursor tryptophan, the neurotoxin-induced myoclonus. The extracerebral decarboxylase inhibitor carbidopa and the selective 5-HT reuptake inhibitor paroxetine both enhanced the antimyoclonic action of 5-HTP. The effect was reversed by the 5-HT receptor blockers cinanserine and methysergide. The data add further evidence to a central serotonergic mechanism involved in p,p′-DDT induced myoclonus.     

Clomipramine enhances the cortisol response to 5-HTP: implications for the therapeutic role of 5-HT2 receptors

We measured the cortisol response to the 5-HT precursor, 5–hydroxytryptophan, (5-HTP) in seven patients with major depression before and after 8 weeks treatment with the tricyclic antidepressant, clomipramine. The cortisol response to 5-HTP was significantly increased following clomipramine treatment, suggesting that clomipramine, like selective serotonin re-uptake inhibitors (SSRIs), enhances this 5-HT₂ receptor mediated response. Because other tricyclic antidepressants do not increase 5-HTP-mediated cortisol release, it seems unlikely that enhancement of 5-HT₂ receptor function is a critical mechanism for antidepressant action. However, facilitation of neurotransmission at 5-HT₂ receptors could account for the efficacy of clomipramine and SSRIs in the treatment of obsessive compulsive disorder and also for their liability to cause orgasmic dysfunction. Received: 20 May 1998/Final version: 5 July 1998     

Responses of developing rats to l-tryptophan plus an MAOI—I. Monitoring changes in behaviour,brain 5-HT and tryptophan

The behavioural responses of developing (21-day-old) and adult (40–50 days) rats to tranylcyprornine (an MAOI) plus l-tryptophan were monitored. The concomitant changes in whole brain 5-HT levels and tryptophan concentration were also measured. Following tranylcypromine (TCP) (10 mg/kg i.p.), l-tryptophan (l-TP) administration (0–100 mg/kg) produced a characteristic hyperactivity syndrome in both adult and 21-day-old rats. Measurement of activity using LKB Animex Activity Meters showed a progressive increase in activity with l-TP dosage in both adults and pups. However, differences in brain 5-HT and tryptophan accumulation between adults and pups were noted following l-TP injection. The 21-day rat brain tryptophan accumulation was greater than that of adult brain at all doses of l-TP, the difference becoming greater as the l-TP dose was increased. In contrast, 21-day brain 5-HT accumulation plateaued at a lower dose of l-TP and a lower total brain tryptophan concentration than the adult brain, whose accumulation continued to increase up to doses of 100 mg/kg, as previously observed. No difference in sensitivity post-synaptie to the 5-HT neurones was found between adult and immature rats using the putative 5-HT receptor agonists 5-rnethoxy-N,N-dimethyltryptamine (5-MeODMT) or quipazine. Prevention of the peripheral decarboxylation of l-tryptophan to tryptamine using benserazide (50 mg/kg) drastically reduced the activity of 21-day rats to TCP plus l-TP administration (35 and 70 mg/kg). Whether the predominant participation of tryptamine in the immature rat behavioural responses to l-TP administration can explain the increasing activity without an increase in brain 5-HT accumulation, or whether some other factor can explain this discrepancy remains to be determined.     

Dual action of methadone on 5-HT synthesis and metabolism

Summary The main purpose of these experiments was to compare the effects of methadone and morphine on cerebral 5-hydroxytryptamine (5-HT) synthesis and 5-hydroxyindoleacetic acid (5-HIAA) formation. In addition the rate of catecholamine synthesis and the concentrations of tyrosine and tryptophan in the brain were measured, as well as the effects of naloxone were investigated.Morphine (34 mg/kg, 2h) increased the synthesis of 5-HT and catecholamines, determined by measuring the accumulation of 5-hydroxytryptophan (5-HTP) and dopa in the whole brain of rats treated with an inhibitor of the aromatic l-amino acid decarboxylase (3-hydroxybenzylhydrazine hydrochloride, NSD 1015). Morphine also increased the cerebral 5-HIAA concentration both in rats treated with NSD 1015 or probenecid. Naloxone antagonized all these effects of morphine. A lower dose of naloxone was needed to antagonize the effect of morphine on 5-HT than on catecholamine synthesis, Similarly to morphine methadone (9 mg/kg, 2 h) increased the cerebral 5-HIAA concentration, but methadone alone did not alter the rate of formation of 5-HTP. However, in combination with naloxone methadone decreased the concentration of 5-HIAA and the accumulation of 5-HTP depending both on the dose of methadone and that of naloxone. Similarly to morphine, methadone stimulated and never reduced the catecholamine synthesis; naloxone antagonized this effect. Both morphine and methadone increased the cerebral concentrations of tryptophan and tyrosine and naloxone antagonized these effects. In addition naloxone alone (2+2 mg/kg, 1+2h) decreased the cerebral tyrosine concentration significantly suggesting that the opiate receptors are involved in the control of cerebral tyrosine concentration.Our results suggest that methadone similarly to morphine stimulates the cerebral 5-HT and catecholamine synthesis, and that these effects are most probably mediated via opiate receptors. However, when opiate receptors are blocked, methadone is able to decrease the cerebral 5-HT synthesis and cerebral 5-HIAA concentration probably via a feedback mechanism produced by blockade of 5-HT reuptake.     

Pharmacology of a novel selective 5-hydroxytryptamine1B receptor antagonist, AR-A000002

The terminal 5-HT_1B autoreceptors have attracted great pharmacological interest since they are potential targets for compounds modifying serotonergic neurotransmission. In the present work the in vivo biochemical properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel selective 5-HT_1B receptor antagonist, are reported.The effects of AR-A000002 on: 5-HT metabolism was measured as the ratio between 5-HIAA and 5-HT concentrations in different brain regions; 5-HT synthesis was measured as the accumulation of 5-HTP after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD1015); 5-HT release was measured using the microdialysis technique. 5-HT, 5-HIAA and 5-HTP concentrations were analyzed using high power liquid chromatography (HPLC) with electrochemical detection. AR-A000002 significantly enhanced 5-HT metabolism (5-HIAA/5-HT ratio) and 5-HT synthesis in guinea pig brain in the dose range 0.9–18 mg/kg s.c. (ED₅₀=1 mg/kg s.c. in the four brain regions examined) with maximal effect seen after 2–4 h. AR-A000002 (9 mg/kg s.c.) significantly increased the extracellular concentrations of 5-HT and 5-HIAA by 20% in the guinea pig frontal cortex, measured with the in vivo microdialysis technique in freely moving guinea pigs. AR-A000002 (9 mg/kg s.c.) in combination with the 5-HT uptake inhibitor citalopram (5 mg/kg s.c.) increased the extracellular 5-HT concentration in guinea pig frontal cortex from 250 to 400% of the basal level. Citalopram alone decreased the extracellular 5-HIAA levels to 70% of the basal value. AR-A000002 counteracted the citalopram-induced decrease in 5-HIAA. Since the basal level of extracellular 5-HIAA was 160 times higher than that of 5-HT the 20% increase in 5-HIAA concentrations indicates that only a few percent of the exocytotically released 5-HT from the nerve terminals reached the extracellular space when the re-uptake mechanism was intact. The results also show that the terminal 5-HT_1B autoreceptors are tonically activated under drug-free as well as citalopram conditions. The increase in plasma level of cortisol after AR-A000002 administration may indicate stimulation of post-synaptic 5-HT receptors. AR-A000002 also blocked 5-HT_1B agonist-induced (CP-135,807) decrease in 5-HT metabolism and hypothermia (ED₅₀=1 mg/kg s.c.), thus indicating competition between these two drugs.It is concluded that AR-A000002 is a 5-HT_1B receptor antagonist that enhances the serotonergic neurotransmission in guinea pig brain.     

Evidence for the involvement of central 5-HT1A receptors in the mediation of lordosis behavior in the female rat

5-Hydroxy-L-tryptophan (5-HTP), 25 mg kg^-1 IP, in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg kg^-1 IP, and the selective inhibitor of neuronal 5-hydroxytryptamine (5-HT) re-uptake, zimeldine, 10 mg kg^-1 IP, suppressed lordosis in ovariectomized female rats, treated with estradiol benzoate (EB) or with EB plus progesterone (P). The suppression of lordosis produced by 5-HTP was antagonized by the -receptor blocker (-)pindolol, which also is a selective 5-HT₁ receptor antagonist, but not by the 5-HT₂ receptor antagonists metitepine or pirenperone, nor by the -receptor blocker betaxolol. The EB-or EB plus P-activated lordosis was also suppressed by administration of the selective 5-HT_1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Together, these observations indicate an important role of central 5-HT_1a receptors in the mediation of lordosis behavior in the female rat.     

p,p'-DDT-induced myoclonus in mice: the effect of enhanced 5-HT neurotransmission

The acute behavioural consequences of intragastric p,p'-DDT in high doses to mice are stimulus sensitive abrupt muscle jerks (myoclonus). The serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) ameliorated in contrast to the natural precursor tryptophan, the neurotoxin-induced myoclonus. The extracerebral decarboxylase inhibitor carbidopa and the selective 5-HT reuptake inhibitor paroxetine both enhanced the antimyoclonic action of 5-HTP. The effect was reversed by the 5-HT receptor blockers cinanserine and methysergide. The data add further evidence to a central serotonergic mechanism involved in p,p'-DDT induced myoclonus.     

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

Summary 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.     

Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists

The effect of the selective 5-HT₃ receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by l-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced l-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by l-5-HTP are mediated by 5-HT₂ receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT₂ receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.     

Effects of the chronic ingestion of therapeutic doses of chlorimipramine on the behavioral action of agonists and antagonists of serotonin in male rats

Locomotor activity and hole-board exploration (frequency and time spent head-dipping) were impaired in male rats by injecting IP the 5-HT agonists, fluoxetine and 5-HTP. This treatment produced also myoclonus and increased the time spent resting during trials. The chronic ingestion of chlorimipramine (CIM) or the injection of the 5-HT receptor blocker, methysergide (15 mg/kg) prevented the action of the 5-HT agonists on locomotion and resting and blocked the appearance of myoclonus. Both CIM and methysergide prevented to a minor degree the fluoxetine-5-HTP-induced decrease of exploration. The chronic ingestion of CIM clearly potentiated the effects of methysergide on hole-board exploration. Results suggest that the chronic treatment with therapeutic doses of CIM reduces the functional activity of some 5-HT systems in the brain of the rat, probably by blockade of post-synaptic 5-HT receptors. This does not preclude, however, that CIM may also alter some NA systems.     

Dual agonist-antagonist effects of 5-hydroxytryptamine (5-HT) in the guinea pig ileum: evidence for a selective receptor desensitization effect

The application of 5-HT to strips of whole ileum or the longitudinal muscle-myenteric plexus preparation from guinea pigs caused dose-dependent muscle contractions that were followed by relaxation to baseline tension without washing off the drug (fade). The contractile effect of a subsequent addition of 5-HT, 4 min after a priming dose of 5-HT, was markedly reduced. Increasing priming doses of 5-HT caused proportional increases in the 5-HT Emax50, up to a priming dose that completely abolished the contractile effects caused by further additions of 5-HT. The auto-blockade of the 5-HT responses was selective to drugs acting on serotonergic receptors. 5-HT did not antagonize the effects of acetylcholine, dimethylphenylpiperazinium, nicotine, histamine, prostaglandin E2, substance P or angiotensin II. N-methyl-5-HT was the most potent analogue in mimicking the effects of 5-HT to produce auto-blockade and fade of the contractile responses. Other structural analogues of 5-HT that shared the 5-HT blocking effect were 5-methoxytryptamine, 5,6-dihydroxytryptamine, and N,N-dimethyltryptamine although these compounds were considerably less potent than 5-HT as blockers or as agonists. Results suggest that fade and the auto-blockade are part of a common effect and are discussed in relation to a model of drug-induced selective receptor desensitization.     

The effects of lesions produced by 5,7-dihydroxytryptamine on 5-hydroxytryptamine-mediated behaviour induced by amphetamine in large doses in the rat

The role of 5-hydroxytryptamine (5-HT)-containing terminals in the spinal cord and basal ganglia in behavioural responses induced by amphetamine in large doses have been investigated using the neurotoxin for 5-HT, 5,7-dihydroxytryptamine (5,7-DHT). The effects of pretreatment with 5,7-DHT were also examined using the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). d-Amphetamine (25 mg/kg) induced several classical 5-HT-dependent behavioural responses (head weaving, forepaw treading, hind limb abduction, “wet dog” shakes, Straub tail), together with some classical dopamine (DA)-dependent behaviour and backward locomotion which requires both transmitters. Pretreatment with 5,7-DHT, given into the striatum significantly decreased “wet dog” shakes and virtually abolished backward walking. Pretreatment with 5,7-DHT in the nucleus accumbens or substantia nigra did not significantly alter behaviour. Pretreatment with 5,7-DHT intraspinally did not significantly alter behaviour induced by amphetamine, although a decrease of Straub tail just failed to reach significance (P = 0.056). Similar pretreatment in rats given 5-MeODMT (8 mg/kg) significantly enhanced both Straub tail and tremor but did not alter the other behavioural responses induced by this drug (limb abduction, forepaw treading, head weaving). The results in general suggest that behavioural responses induced by 5-HT can be classified into 3 groups (a) those requiring striatal 5-HT (“wet dog” shakes and backward locomotion), (b) those requiring spinal 5-HT (Straub tail, tremor) and (c) those requiring neither spinal nor striatal 5-HT (hind limb abduction, head weaving and forepaw treading).     

Evidence for a peripheral effect of serotonin or metabolites in 5-hydroxytryptophan-induced hypothermia

The effects of l-5-hydroxytryptophan (l-5-HTP) on the body temperatures of restrained rats were studied alone and following pretreatment with the central and peripheral decarboxylase inhibitor, benserazide (R04-4602), the peripheral decarboxylase inhibitor, carbidopa (MK-486), or the peripheral serotonergic antagonist, xylamidine tosylate. l-5-Hydroxytryptophan alone (25–200 mg/kg, i.p.) decreased body temperature in a dose-dependent manner. Pretreatment (1 or 4 hr) with benserazide (25–400 mg/kg) produced a dose- and time-dependent blockade of the hypothermic effects of 25 mg/kg and 200 mg/kg of l-5-HTP. Pretreatment with carbidopa (12.5–50 mg/kg) or xylamidine tosylate (1 and 3mg/kg) also produced dose- and time-dependent antagonism of the hypothermic effects of 25 mg/kg of l-5-HTP. Serotonin (5-HT) creatinine sulfate (5–20 mg/kg, i.p.), produced a dose-related hypothermic effect similar to l-5-HTP. Pretreatment with xylamidine tosylate (1 and 3 mg/kg) produced a dose- and time-dependent blockade of the temperature decrease produced by 5 mg/kg of 5-HT. These results suggest that the hypothermic effect produced by systemic l-5-HTP administration in the rat is entirely the result of an effect of serotonin (or metabolites) outside the blood-brain barrier.     

Plasma Accumulation and Metabolism of Orally Administered Single Dose L-5-Hydroxytryptophan in Man

Abstract: Single oral doses of L-5-hydroxytryptophan (5-HTP) were administered in combination with L-aromatic amino acid decarboxylase inhibitors. The time courses of plasma concentrations of 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and the concentrations of 5-HT in blood platelets were measured. Carbidopa enhanced the rise in plasma concentrations of 5-HTP 5–15 fold and counteracted the increase in plasma 5-HIAA levels induced by 5-HTP alone. A single dose of the decarboxylase inhibitor was equipotent to 14 days' pretreatment. Plasma or platelet concentrations of 5-HT failed to reflect the metabolism of 5-HTP. The ratio of 5-HTP to carbidopa influenced the systemic bioavailability of single dose administered 5-HTP indicating dose dependent absorption kinetics. Co-administration of L-dopa with 5-HTP and decarboxylase inhibitors had no effect on gastrointestinal absorption of 5-HTP in six parkinsonian patients.     

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-HT₂ 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.