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PubMed1985

Indoleamine-sensitive adenylate cyclase in rabbit retina: characterization and distribution.

Previous histological, electrophysiological, and biochemical reports have addressed the hypothesis that serotonin functions as a neurotransmitter in mammalian retinas. We have tested the effect on the levels of cyclic AMP of the application of exogenous serotonin, 5-methoxytryptamine, melatonin, and 5-methoxydimethyl-tryptamine to isolated, incubated rabbit retinas. All indoleamines tested significantly elevated intracellular levels of cyclic AMP in both light- and dark-adapted, incubated, intact retinas, provided a phosphodiesterase inhibitor was present. In homogenates of rabbit retina, all indoleamines tested also markedly increased adenylate cyclase activity over basal levels. Maximal activity was observed with 50 microM indoleamine; addition of GTP augmented this increase. The increase in enzyme activity persisted in the presence of known antagonists of dopamine and serotonin 5-HT2-receptors, but was blocked by the mixed 5-HT1, 5-HT2-antagonist lysergic acid diethylamide. The retinal locations of this response have also been identified using layer microdissection techniques on freeze-dried samples obtained from rabbit eyecups suprafused with indoleamine plus phosphodiesterase inhibitor. Cyclic AMP levels were measured in discrete retinal layers of both light- and dark-adapted suprafused eyecups, and increased levels were observed primarily in the inner and outer plexiform layers, which contain the synapses of the retinal neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Studies on the oxidation of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase B.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a chemical that, after injection into experimental animals, including mice and monkeys, causes a degeneration of the nigrostriatal pathway. We carried out experiments designed to study the in vitro oxidation of MPTP by mouse brain mitochondrial preparations. MPTP was actively oxidized by the mitochondrial preparations, with Km and Vmax values very similar to those of benzylamine, a typical substrate for MAO-B. MPTP was oxidized considerably better than many of its analogs, even those with relatively minor structural changes. Several monoamine oxidase inhibitors (MAOI) were potent inhibitors of MPTP oxidation, and there was a highly significant correlation between the capacity of the MAOI tested to inhibit MPTP oxidation and benzylamine oxidation. There was no correlation between the capacity of the MAOI to inhibit MPTP oxidation and their capacity to inhibit the oxidation of tryptamine, a substrate for MAO-A. In other experiments, MPTP was an excellent substrate for pure MAO-B, prepared from bovine liver. All of these data, combined with the fact that MAO-B inhibitors can protect against MPTP-induced dopaminergic neurotoxicity in vivo, point to an important role for MAO-B in MPTP metabolism in vivo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Differential postnatal development of monoamine oxidases A and B in the blood-brain barrier of the rat.

We studied the monoamine metabolizing mitochondrial enzyme, monoamine oxidase (MAO), in cerebral microvessels obtained from postnatally developing rats by measuring the specific binding of [3H]pargyline, an irreversible inhibitor of MAO, and the rate of oxidation of three known MAO substrates: benzylamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and tryptamine. MAO activity increased postnatally, with the greatest increase occurring in the second week and reaching a peak at 3 weeks of age. A concomitant increase in MAO of the cerebral cortex also occurred, but was several-fold less than that of cerebral microvessels. Using clorgyline and deprenyl, relatively specific inhibitors of MAO-A and MAO-B, we showed that cerebral microvessels contain both forms of MAO at all ages, but there was a major preponderance in the postnatal development of MAO-B. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses of rat microvessels after [3H]pargyline binding also showed two distinct bands of radioactivity at all ages. These two bands corresponded to molecular weights of approximately 65,000 for MAO-A and approximately 60,000 for MAO-B. SDS-PAGE results of brain microvessels obtained from 1-, 14-, and 42-day-old rats confirm the differential postnatal development of MAO-B in rat brain microvessels.

Aging↗
PubMed1989

Evidence for the presence of serotonin receptors negatively coupled to adenylate cyclase in the rabbit iris-ciliary body.

Serotonin has no obvious effect on basal cyclic AMP levels but reduces the forskolin-, isoproterenol-, and vasoactive intestinal peptide-induced stimulation of cyclic AMP levels in a dose-dependent manner. Serotonergic, cholinergic, muscarinic, alpha-adrenergic, and dopaminergic antagonists have no effect on the serotonin response. Topical application of a serotonin/pargyline solution to the living eye causes desensitisation of the serotonin response in the iris-ciliary body, an observation confirming the presence of specific serotonergic receptors linked to adenylate cyclase. The 5-HT1A [5-hydroxytryptamine (serotonin) type 1A] receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone mimic the serotonin response in reducing the forskolin-stimulated cyclic AMP levels, as do the indole derivatives 5-methoxytryptamine, 5-hydroxtryptophan, and tryptamine. However, the ineffectiveness of the 5-HT1A agonist ipsapirone and the inability of spiroxatrine to block the serotonin response show that classical 5-HT1A receptors are not involved. The serotonin response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor theophylline, which indicates the involvement of an inhibitory guanine regulatory protein in the coupling of the serotonin receptor to the adenylate cyclase catalytic unit.

5-Hydroxytryptophan↗
PubMed2004

Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators.

The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

Amphetamines↗
PubMed1960

The responses of the Venus heart to catechol amines and high concentration of 5-hydroxytryptamine.

The catechol amines excite the isolated heart of Venus mercenaria in a characteristic manner. This response was not obtained with phenethylamine, tyramine, ephedrine, or mescaline, nor with histamine, nor with the basic n-alkylamines. 5-Hydroxytryptamine had a distinctive effect at high concentrations (above 3x10(-6) M) different from that at lower doses. The response to high concentrations was dominated by an increase in muscle tone. Hearts exposed to high concentrations of 5-hydroxytryptamine and other tryptamine analogues for long periods became tachyphylactic to low doses of these substances. However, high doses of 5-hydroxytryptamine (about 2x10(-5) M) still excited the tachyphylactic heart, but the response was then like that to the catechol amines. When high bath temperatures rendered the heart insensitive to 5-hydroxytryptamine, high concentrations of this compound again had the catechol amine effect. The possibility of a physiological role for the catechol amines or high 5-hydroxytryptamine concentrations is discussed.

Amines↗
PubMed1961

Effect of L-tryptophan on diuresis and 5-hydroxyindoleacetic acid excretion in the rat.

Oral administration of L-tryptophan to rats produced two main biochemical and pharmacological effects: a marked increase in urinary 5-hydroxyindoleacetic acid excretion, and a significant reduction in the urine flow after a water load. Urinary 5-hydroxyindoleacetic acid excretion reached its maximum 2 to 6 hr after the administration of tryptophan, and it increased with the dose of the amino acid. Antidiuresis was seen after the administration of L-tryptophan, 200 mg/kg, or more. The effect appeared promptly and it was roughly proportional to the dose of the amino acid administered. Both antidiuretic effect and increase in urinary 5-hydroxyindoleacetic acid excretion were more intense after oral than after parenteral administration of L-tryptophan. D-Tryptophan, in oral doses up to 1,000 mg/kg, produced neither an increase in urinary 5-hydroxyindoleacetic acid nor a reduction of diuresis. Available evidence suggests that reduction of urine flow is a consequence of biosynthesis and release of 5-hydroxytryptamine by the gastrointestinal mucosa. Tryptamine produced by direct decarboxylation of L-tryptophan does not seem to play any important role.

Administration, Oral↗
PubMed1963

Actions of certain amines on cerebral cortical neurones.

A number of derivatives of tryptamine and phenethylamine, and certain other compounds, were tested on neurones in the cerebral cortex of cats by iontophoretic release from micro-pipettes. The characteristic action of many of these compounds was a depression of the neuronal discharge initiated by synaptic activity or by the application of L-glutamate; imidazolylacetic acid, dopamine, ephedrine and ergometrine were particularly effective. Catechol amines, hydroxytryptamines and imidazolylacetic acid had a relatively quick and rapidly reversible action, not unlike that of gamma-aminobutyric acid, whereas ephedrine and derivatives of lysergic acid diethylamide caused a slower and more prolonged depression of the amplitude of spikes, rather like atropine. Several compounds, including 5-hydroxytryptamine, adrenaline and ergometrine, could also excite the same neurone when larger amounts were applied. A few substances, such as dopa and methylergometrine, had a predominantly excitant action.

Amines↗
PubMed1971

Protection against burn, tourniquet and endotoxin shock by histamine, 5-hydroxytryptamine and 5-hydroxytryptamine derivatives.

1. 5-Hydroxytryptamine (5-HT), tryptamine, 5-methyltryptamine, 5-methoxytryptamine, N-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine, and histamine markedly protect mice subjected to burn, tourniquet and endotoxin shock. All of these compounds protect when given 30 min before the production of shock, but not when administered afterwards.2. The above compounds, as well as purines and purine derivatives have a similar chemical structure. Protection requires the compounds to contain a 5-membered ring with one unsubstituted N atom and a side chain with a basic N atom three atoms from the ring.3. All other biological amines tested without this chemical structure did not protect.4. Since the simplest compounds containing all the prerequisites for protection is histamine, this compound may play the key role in protection, for both 5-HT and purines release histamine from tissues.5. Protective doses of 5-HT and histamine prevent swelling of the injured area after tourniquet trauma and produce an increased bleeding volume and lower haematocrit value after burning. These actions of the drugs on the circulation may account for the increased survival after thermal trauma.

Animals↗
PubMed1972

Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues.

1. The specificity of platelet receptor sites for 5-HT uptake and for the rapid morphological change and aggregation was investigated with 5-hydroxy-tryptamine (5-HT) and seventeen analogues as well as with some antagonists of 5-HT.2. The analogues, with the exception of 5-hydroxy-N'N'-dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0.05-2.0 muM), these analogues themselves inhibited competitively the shape change caused by 5-HT.3. The velocity of change in shape caused by 5-HT was reduced in low Na media.4. Ten analogues produced platelet aggregation; three of these, viz. 5-methoxy-alpha-methyltryptamine, 5-hydroxy-alpha-methyltryptamine and 5-hydroxy-N'N'-diisopropyltryptamine), were approximately equipotent with 5-HT. Six analogues did not induce platelet aggregation.5. All the analogues which prevented the initial change in shape of platelets caused by 5-HT also inhibited its aggregating effect, apparently competitively with low K(i) values (0.02-1.6 muM).6. As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site.7. Methysergide was a potent inhibitor of shape change and aggregation (K(i) approximately 0.03 muM); imipramine was much less inhibitory (K(i) approximately 5-10 muM).8. Only one analogue (5-hydroxy-alpha-methyltryptamine) was taken up like 5-HT by platelets. All the other analogues inhibited the uptake of 5-HT by platelets (K(i)=0.2-2.7 muM).9. Methysergide was a weak inhibitor of 5-HT uptake (K(i) approximately 125 muM) whereas imipramine was very effective (K(i) approximately 0.3 muM).10. Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5-HT appears low whereas the uptake mechanism is a highly specific one. The uptake probably proceeds through more than one step, the relationship between the steps is not yet clear.

Blood Coagulation↗
PubMed1978

The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats.

1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour.

Animals↗
PubMed1979

The sites of action of 5-hydroxytryptamine in nerve-muscle preparations from the guinea-pig small intestine and colon.

1 The sites of action of 5-hydroxytryptamine (5-HT) were examined in isolated segments of guinea-pig intestine. Mechanical records were taken from the longitudinal muscle of the ileum and proximal colon and from the circular muscle of the ileum and distal colon.2 In order to examine direct actions of 5-HT, nerve-mediated responses were blocked with tetrodotoxin (0.2 mug/ml). There was a gradient in the responsiveness of the longitudinal muscle of the ileum; in the proximal ileum it was usually unresponsive, whereas in the distal ileum about 30% of the amplitude of contraction was caused by a direct effect on the muscle. In the circular muscle from all parts of the ileum, direct effects on the muscle were weak or absent. In the distal colon, the circular muscle was almost always unresponsive to direct effects of 5-HT even when concentrations of 5-HT as great as 100 mug/ml were used. All direct actions of 5-HT on intestinal muscle were blocked by methysergide (1 mug/ml), which itself did not affect nerve-mediated responses.3 Excitatory cholinergic nerves and excitatory and inhibitory nerves which released unidentified substances were all stimulated by 5-HT. The contractions mediated through cholinergic nerves were blocked by hyoscine (0.6 mug/ml).4 Tachyphylaxis to the action of 5-HT occurred both for effects mediated through nerves and for direct effects on the muscle. Responses returned promptly after 5-HT was washed from the organ bath.5 While 5-HT blocked its own action on neural receptors, it did not antagonize the stimulation of nicotinic receptors on cholinergic neurones by 1-1 dimethyl-4-phenylpiperazinium iodide (DMPP). Moreover, pentolinium markedly reduced contractions caused by DMPP without significantly affecting responses to 5-HT. In contrast, (+)-tubocurarine, another nicotinic receptor antagonist, was effective in reducing contractions caused by 5-HT.6 Phenyldiguanide, which has been reported to antagonize the stimulant action of 5-HT on cholinergic neurones in the mouse small intestine, did not cause any significant reduction in the action of 5-HT on cholinergic neurones in the guinea-pig ileum unless a concentration of 1 mg/ml was used. However, contractions elicited by carbachol and DMPP were antagonized to a similar extent by phenyldiguanide at this concentration. Antagonism of the action of 5-HT at neural receptors by bromolysergic acid and by tryptamine was found but it was not specific, these drugs causing comparable decreases in responses to 5-HT, carbachol and DMPP.7 The present results, which show that 5-HT has little or no direct effect on the circular muscle of the ileum and colon, imply that, if 5-HT is a transmitter in enteric reflexes, it must be released from interneurones.

Animals↗
PubMed1995

Enhancement by 5-hydroxytryptamine and analogues of desensitization of neuronal and muscle nicotinic receptors expressed in Xenopus oocytes.

1. The action of 5-hydroxytryptamine (5-HT) on neuronal and muscle nicotinic acetylcholine receptors (nicotinic AChR) expressed in Xenopus oocytes was studied. 2. 5-HT enhanced the rate of desensitization of the acetylcholine (ACh) current response in all receptor subtypes investigated (muscle, alpha beta 2 gamma delta and alpha 4 beta 2), acting in a dose-dependent manner. 3. 5-HT also reduced the peak current elicited by ACh in a dose-dependent manner. The IC50 value for the muscle type receptor was 227 +/- 0.44 microM, and 166 +/- 0.47 microM and 283 +/- 0.28 microM for the combinations alpha beta 2 gamma delta and alpha 4 beta 2 respectively. 4. The effect of 5-HT on the responses to ACh (10 microM) was found to be independent of membrane voltage over the range tested (-80 to -10 mV), and to be readily reversed by washout. 5. The action of 5-HT could be mimicked by structurally similar molecules. The homologue tryptamine was less potent than 5-HT in blocking the ACh current, with an IC50 of 1.0 +/- 0.02 mM. Ketanserin, a 5-HT2 receptor antagonist, was more potent than 5-HT, the IC50 being 49.0 +/- 1.4 microM. 6. We postulate that a highly conserved portion of the tertiary structure of nicotinic AChRs, which includes some part of the ACh binding site, has affinity for 5-HT and structural analogues.

Acetylcholine↗
PubMed1985

An investigation of demethylation in the metabolism of methoxytryptamine and methoxytryptophol.

Though melatonin is primarily metabolised to 6-hydroxy-melatonin, we have recently shown that it can also be demethylated to form N-acetyl-serotonin. The question therefore arises as to whether demethylation is a general metabolic pathway that can apply to other pineal methoxyindoles. To investigate this possibility we administered deuterated methoxy-tryptophol (dML) and deuterated methoxy-tryptamine (dMT) to rats and analysed the urine for the presence of deuterated methoxyindole acetic acid (dMIAA) and deuterated hydroxyindole acetic acid (dHIAA). The method of analysis was gas chromatography mass spectrometry (GCMS), where the relevant molecular ion and fragment ions were monitored. The results showed that the major metabolite in all cases was dMIAA. There was no evidence to suggest that the compounds had been demethylated to form dHIAA. The study therefore indicates that the demethylation of melatonin is a specific metabolic pathway that does not apply to other methoxyindoles.

5-Methoxytryptamine↗
PubMed2005

Products of tryptophan catabolism induce Ca2+ release and modulate the cell cycle of Plasmodium falciparum malaria parasites.

Intraerythrocytic malaria parasites develop in a highly synchronous manner. We have previously shown that the host hormone melatonin regulates the circadian rhythm of the rodent malaria parasite, Plasmodium chabaudi, through a Ca2+-based mechanism. Here we show that melatonin and other molecules derived from tryptophan, i.e. N-acetylserotonin, serotonin and tryptamine, also modulate the cell cycle of human malaria parasite P. falciparum by inducing an increase in cytosolic free Ca2+. This occurs independently of the extracellular Ca2+ concentration, indicating that these molecules induce Ca2+ mobilization from intracellular stores in the trophozoite. This in turn leads to an increase in the proportion of schizonts. The effects of the indolamines in increasing cytosolic free Ca2+ and modulating the parasite cell cycle are both abrogated by an antagonist of the melatonin receptor, luzindole, and by the phospholipase inhibitor, U73122.

Animals↗
PubMed1982

Equine immunology 3: immunopharmacology--anti-inflammatory and antihypersensitivity drugs.

This article reviews anti-inflammatory and antihypersensitivity drugs under these 4 headings: Functional or physiological antagonists; Selective pharmacological inhibitors; Broad spectrum anti-inflammatory drugs; Miscellaneous inhibitors. The compounds considered include sympathomimetic amines, anticholinergic drugs, antihistamine drugs, tryptamine antagonists and dopamine antagonists, glucocorticosteroids and non-steroidal anti-inflammatory drugs, disodium cromoglycate and diethylcarbamazine citrate. The relationship of the pharmacological actions of these compounds is considered in the context of clinical conditions. The potential for immunomodulatory pharmacology is discussed using levamisole as an example.

Animals↗
PubMed1984

Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane.

Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1984

Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic.

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.

5-Hydroxytryptophan↗