Non-selective Monoamine Oxidase Research Articles

Linezolid and Serotonergic Drug Interactions: A Retrospective Survey

Linezolid is a reversible, nonselective monoamine oxidase inhibitor. There are currently 11 published case reports of serotonin syndrome being associated with linezolid and selective serotonin reuptake inhibitors (SSRIs). Controversy exists regarding whether linezolid and SSRIs can be given concomitantly. The purpose of this study was to report the incidence of serotonin syndrome in patients receiving linezolid and SSRIs. This study was a retrospective chart review of inpatients at the Mayo Clinic (Rochester, MN) with concomitant orders or therapy within 14 days for linezolid and an SSRI from 2000 to 2004. The Sternbach criteria and Boyer criteria for diagnosis of serotonin syndrome were used to identify clinical features of serotonin syndrome. Seventy-two patients received linezolid and an SSRI or venlafaxine within 14 days of each other. Fifty-two patients (72%) received concomitant therapy with linezolid and an SSRI or venlafaxine, and 20 patients (28%) did not receive concomitant therapy but received linezolid and an SSRI within a 14-day period. Overall, only 2 patients (3%) had a high probability of serotonin syndrome. In both patients with high probability, symptoms reversed rapidly on discontinuation of serotonergic therapy. The Boyer criteria were much more specific than the Sternbach criteria for identification of serotonin syndrome. On the basis of our experience, we suggest that, if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome. Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected.

Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive Medications

Demethylation of histone H3 lysine 4 is carried out by BHC110/LSD1, an enzyme with close homology to monoamine oxidases (MAO). Monoamine oxidase A or B are frequent targets of selective and nonselective small molecular inhibitors used for treatment of depression. Here we show that in contrast to selective monoamine oxidase inhibitors such as pargyline, nonselective monoamine oxidase inhibitors potently inhibit nucleosomal demethylation of histone H3 lysine 4. Tranylcypromine (brand name Parnate) displayed the best inhibitory activity with an IC50 of less than 2 microM. Treatment of P19 embryonal carcinoma cells with tranylcypromine resulted in global increase in H3K4 methylation as well as transcriptional derepression of two BHC110 target genes, Egr1 and the pluripotent stem cell marker Oct4. These results attest to the effectiveness of tranylcypromine as a small molecular inhibitor of histone demethylation.

Effects of monoamine oxidase inhibitors on cocaine discrimination in rats

This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, intraperitoneal) from saline using a two-lever choice methodology. The nonselective monoamine oxidase inhibitors tranylcypromine (0.01-5 mg/kg) and phenelzine (1-25 mg/kg), the monoamine oxidase-A selective compound clorgyline (1-25 mg/kg), and the monoamine oxidase-B selective compounds pargyline (0.005-50 mg/kg) and selegiline (1-25 mg/kg) were tested for substitution 15 min or 24 h following administration, and in combination with 10 mg/kg of cocaine 24 and 48 h after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 h, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 h than at 15 min. When cocaine was administered 24 h after clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 h, the effects of all compounds except phenelzine were markedly reduced. Selectivity for monoamine oxidase-A or monoamine oxidase-B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that monoamine oxidase inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 h, and may be useful for treatment of cocaine abuse.

Isolation and characterization of a monoamine oxidase B selective inhibitor from tobacco smoke

It is well established that tobacco smokers have reduced levels of monoamine oxidase activities both in the brain and peripheral organs. Furthermore, extensive evidence suggests that smokers are less prone to develop Parkinson’s disease. These facts, plus the observation that inhibition of monoamine oxidase B protects against the parkinsonian inducing effects of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have prompted studies to identify monoamine oxidase inhibitors in the tobacco plant and tobacco cigarette smoke. Our previous efforts on cured tobacco leaf extracts have led to the characterization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-selective monoamine oxidase inhibitor, and farnesylacetone, a selective monoamine oxidase B inhibitor. We now have extended these studies to tobacco smoke constituents. Fractionation of the smoke extracts has confirmed and extended the qualitative results of an earlier report [ J. Korean Soc. Tob. Sci. 1997, 19, 136] demonstrating the inhibitory activity of the terpene trans, trans-farnesol on rat brain MAO-B. In the present study, K i values for the inhibition of human, baboon, monkey, dog, rat, and mouse liver MAO-B have been determined. Noteworthy is the absence of inhibitory effects on human placental MAO-A and beef liver MAO-B. A limited structure–activity relationship study of analogs of trans, trans-farnesol is reported. Although the health hazards associated with the use of tobacco products preclude any therapeutic opportunities linked to smoking, these results suggest the possibility of identifying novel structures of compounds that could lead to the development of neuroprotective agents.

The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms

Objective: To synthesise results from investigations reporting on the effect of antidepressants on glucose–insulin homeostasis. Method: The authors conducted a MedLine search of all English language articles from 1966 to October 2005 using the keywords: bipolar disorder, major depressive disorder, diabetes mellitus, glucose homeostasis, and the name of each antidepressant that has been indicated for major depression in Canada and the US up to October 2005. The search was supplemented with a manual review of relevant references. Both preclinical and clinical investigations were reviewed. Results: Some serotonergic antidepressants (e.g., fluoxetine) reduce hyperglycaemia, normalise glucose homeostasis and increase insulin sensitivity, whereas some noradrenergic antidepressants (e.g., desipramine) exert opposite effects. Dual-mechanism antidepressants (e.g., duloxetine and venlafaxine) do not appear to disrupt glucose homeostatic dynamics, whereas nonselective hydrazine monoamine oxidase inhibitors (e.g., phenelzine) are associated with hypoglycaemia and an increased glucose disposal rate. Conclusion: Some antidepressants exert a clinically significant effect on metabolism relevant to both therapeutic outcome and adverse events.

Synthesis of Novel N-Substituted Imidazolecarboxylic Acid Hydrazides as Monoamine Oxidase Inhibitors

Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides ( 15a,b) were synthesized as analogues of isocarboxazide, which is a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the compounds showed any inhibition of MAO B activity up to a high concentration of 100 μM. An MAO A activity was only slowly inhibited at this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.

Neurobiologie et pharmacothérapie de la phobie sociale

Resume Bien que Marks ait propose des 1970 une classification des phobies comprenant la phobie sociale, l’apparition de l’entite diagnostique phobie sociale est encore plus recente. Elle a lieu en 1980 avec le DSM III, 3e edition de la nomenclature de l’American Psychiatric Association, qui etablit des criteres operationnels pour son diagnostic. De ce fait, les recherches visant a identifier les facteurs genetiques, familiaux et temperamentaux, les correlats neurochimiques et neuroendocriniens ainsi que les structures cerebrales s’inscrivant dans la pathogenie de ce trouble en sont a leur debut. Neanmoins, elles ont permis d’apprecier l’intervention des influences genetiques, du milieu familial, et de traits temperamentaux, comme l’inhibition comportementale face a l’inconnu, dans le risque d’apparition d’une phobie sociale. Elles ont egalement contribue a mettre en evidence des perturbations du fonctionnement des systemes de neurotransmission monoaminergique dans la phobie sociale. Parallelement, les progres realises dans l’analyse des relations structure-fonction, et notamment l’apport recent de la neuro-imagerie, ont souligne l’importance des voies cortico-limbiques dans la physiopathologie de la phobie sociale, avec la participation de regions et structures cerebrales comme le cortex prefrontal, l’hippocampe, l’amygdale et le striatum. Ceci n’a rien de surprenant si l’on considere leur role essentiel dans la signification attribuee aux informations emanant de l’environnement, les processus emotionnels, mnesiques et de conditionnement contextuel, ainsi que dans la programmation des comportements dont on peut supposer l’alteration a la lumiere des symptomes caracteristiques de la maladie. La demarche pharmacotherapique aujourd’hui proposee repose sur l’efficacite demontree d’agents medicamenteux, au premier rang desquels figurent les inhibiteurs selectifs de la recapture de la serotonine dont l’emploi peut aujourd’hui prevaloir sur celui d’autres produits egalement actifs, comme les inhibiteurs de la monoamine oxydase non selectifs et irreversibles ou les benzodiazepines, de par la simplicite de leur utilisation et leur tres bonne tolerance.

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and behavioral profile.

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one] is a new, nonselective, and reversible monoamine oxidase (MAO) inhibitor, belonging to a oxazoloquinolinone series. In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki values of 3.3 and 4.2 nM, respectively. In ex vivo conditions, the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED50 values of 0.67 and 0.52 mg/kg, respectively. In the rat brain, duodenum, and liver, the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible, and the recovery of MAO-A and MAO-B activities was complete 16 h after administration. SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA), norepinephrine, and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid. In mice, SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. In addition, when coadministered with L-DOPA, SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity. The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-lesioned rats was also increased. The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed, potent, and reversible MAO-A/B inhibitor in vitro, in vivo, and ex vivo. SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.

Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. The present study was undertaken to demonstrate that nervous systems other than the 5-HT system also participate in the pathophysiology of 5-HT syndrome. Concentrations of 5-HT, dopamine (DA) and glutamate in the hypothalamus were measured in two different 5-HT syndrome animal models using a microdialysis technique. The first model was induced by tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor (3.5 mg/kg) and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (10 mg/kg). The second model was induced by clorgyline, an MAO-A inhibitor (1.2 mg/kg) and 5-hydroxy- l-tryptophan, a precursor of 5-HT (5-HTP) (80 mg/kg). In the first model, the levels of 5-HT and DA increased by 40-fold and 44-fold, respectively, compared with the preadministration levels. In the second model, the concentrations of 5-HT increased by up to 140-fold, whereas DA levels increased by only 10-fold, of the preadministration levels. Although the level of glutamate in the second model barely changed, a delayed increase in the glutamate level was observed in the first model. These findings suggest that not only hyperactivity of the 5-HT system, but also hyperactivity of the DA system, are present in 5-HT syndrome, and that the glutamatergic system is influenced in some 5-HT syndrome cases in which the DA concentration markedly increases.

Features of this month's Journal

Features of this month's <i>Journal</i>

Inhibition of monoamine oxidase modulates the behaviour of semicarbazide-sensitive amine oxidase (SSAO).

The specific activity and kinetic behaviour of semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) towards benzylamine, in the rat heart, is affected by in vivo treatment with the non-selective monoamine oxidase (MAO) inhibitor tranylcypromine, but not by the selective MAO-A and -B inhibitors, clorgyline and lazabemide. SSAO activity was increased to 178% of control activity after 7 days of treatment with tranylcypromine. This increase appears to represent an increase in the limiting velocity (V(max)) for benzylamine oxidation with no significant change in the K(m) at that time-point. However, the K(m) for benzylamine oxidation was found to decrease in both controls and treated groups, in a time-dependent manner, during the treatment regime. These findings suggest a link between SSAO and cellular stress and may have importance in the context of the recent finding that tissue-SSAO is identical to a vascular adhesion protein (VAP1), involved in the process of inflammation.

Novel Monoamine Oxidase Inhibitors, 3-(2-Aminoethoxy)-1,2-benzisoxazole Derivatives, and Their Differential Reversibility

Although possible usefulness of non-selective monoamine oxidase (MAO) inhibitors for Parkinson's disease therapy has been suggested in the literature, MAO inhibitors whose inhibition is reversible and have dual action to both MAO-A and -B subtypes is not available yet. Subtype selectivity and reversibility of a series of novel MAO inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, were studied. Several dual MAO inhibitors, which inhibit both MAO-A and -B, were obtained. When administered to mice, their effects were generally reversible. Among the derivatives, RS-1636 and RS-1653 had much longer duration of brain MAO-B inhibition than that of MAO-A. In vitro, the inhibited MAO-A activity by these compounds was partially recovered by buffer change at 4 degrees C, while little MAO-B activity was recovered. Although it is not fully elucidated yet, the reversibility of these inhibitors is probably determined primarily by this dissociation profile. This unique differential reversibility indicates that optimization of the balance of actions can be achieved by differentiating reversibility to each target molecule.

Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular γ-aminobutyric acid levels in the striatum

Phenelzine (PLZ) is a non-selective monoamine oxidase inhibitor (MAOI) commonly used to treat depression and panic disorder. As expected, PLZ increases brain levels of dopamine, norepinephrine, and serotonin. Interestingly, PLZ also elevates brain levels of γ-aminobutyric acid (GABA), and previous studies have suggested that these increases may also contribute to the anxiolytic effects of PLZ. Using in vivo microdialysis in conscious, freely moving rats, combined with high performance liquid chromatography, the present experiments determined that PLZ (15 or 30 mg/kg, free base weight) increases extracellular levels of GABA in the caudate-putamen and nucleus accumbens. The results also indicated that phenylethylidenehydrazine (PEH; 29.6 mg/kg, free base weight), a putative intermediate metabolite of PLZ that is not an MAOI, also significantly increases extracellular GABA levels in the caudate-putamen. These findings provide further evidence that GABA may play an important role in the actions of PLZ and suggest that PEH should be pursued further as a GABAergic drug in its own right.

Changes in Vesicular Monoamine Transporter (VMAT2) and Synaptophysin in Rat Substantia nigra and Prefrontal Cortex Induced by Psychotropic Drugs

We investigated the regulatory effect of the dopaminergic agent L-dopa, the mood stabilizer lithium and the nonselective monoamine oxidase inhibitor phenelzine on brain vesicular monoamine transporter (VMAT2) expression. Rats were treated chronically (21 days) with the three psychoactive drugs. VMAT2 gene expression at the protein level was assessed in the prefrontal cortex and striatum by autoradiography with high-affinity [³H]dihydrotetrabenazine ([³H]TBZOH) binding and at the mRNA level in the substantia nigra pars compacta by in situ hybridization. In addition, the effect of various treatments on the synaptophysin mRNA level was determined in the substantia nigra by in situ hybridization. Chronic administration of L-dopa resulted in a significant decrease (28%, p < 0.05) in the density of [³H]TBZOH binding in the prefrontal cortex but had no effect on VMAT2 and synaptophysin mRNA levels in the substantia nigra. Lithium treatment increased [³H]TBZOH-specific binding in the prefrontal cortex (23%, p < 0.05) but had no effect on VMAT2 and synaptophysin mRNA levels. Phenelzine did not modulate VMAT2 gene expression but reduced the synaptophysin mRNA level (19%, p < 0.05). The modulatory activities of these drugs, although relatively weak, may be relevant to the drug-induced synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of monoamine-related neuropsychiatric disorders.

Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats

The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1–10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-( m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.

Possible mediation of quinolinic acid-induced hippocampal damage by reactive oxygen species.

Several differences exist between quinolinic acid and N-methyl-D-aspartate (NMDA) in the potency and pharmacology of their neurotoxic actions in the brain, suggesting that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors, possibly involving lipid peroxidation. In the present review, studies are considered which have attempted to determine whether free radicals might contribute to the neuronal damage induced by quinolinic acid. Following Injections into the hippocampus of anaesthetised rats, quinolinic acid induced damage is prevented by melatonin, by an action not blocked by the melatonin receptor blocker luzindole. Deprenyl, but not the non-selective monoamine oxidase inhibitor nialamide, also prevent quinolinic acid-induced damage. In vitro, several groups have shown that quinolinic acid can induce lipid peroxidation of brain tissue The results suggest that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and γ-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague–Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.

Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.

1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

The influence of mirtazapine on memory and other behavioural functions in rats: E. Nowakowska, A. Chodera, K. Kus, A. Massakowska. Department of Pharmacology University of Medical Sciences Poznañ, Poland

The question of whether serotonin is deaminated by MAO before it can be released or after release has occured was investigated by studying the 5-HT behavioral syndrome in acutely reserpinized rats. The release of serotonin from vesicles by reserpine does not produce the serotonin behavioral syndrome which is an in vivo index of serotonin release and receptor activation. However, if rats are first pretreated with a nonselective monoamine oxidase inhibitor (e.g., tranylcypromine), the injection of reserpine is followed by symptoms which are characteristic of the behavioral syndrome including forepaw treading, hindlimb abduction and head weaving. Neither selective MAO-A or -B inhibition with clorgyline or deprenyl, respectively, nor inhibition of serotonin reuptake with fluoxetine prior to reserpine produced the serotonin behavioral syndrome. However, the combination of clorgyline and deprenyl followed by reserpine does so. These behavioral data along with neurochemical analyses of serotonin and 5-hydroxyindoleacetic acid levels lead to the conclusion that serotonin does not have to be released before it is metabolized to 5-hydroxyindoleacetic acid. Consequently, the levels of 5-hydroxyindoleacetic acid in brain reflect MAO activity and not serotonin release or utilization.

New functional agonists and antagonists of 5-HT 1A receptors : A. Szclejewska-Wożniakowska, M. Cybulski, Z. Chilmonczyk, K. Krajewski, J. Cybulski, E. Chojnacka-Wójcik 1. Pharmaceutical Research Institute, 8 Rydygiera St., 01–793 Warsaw; 1Institute of Pharmacology Polish Academy of Sciences, 12 Sm [formula omitted]tna St., 31–343 Kraków, Poland

The question of whether serotonin is deaminated by MAO before it can be released or after release has occured was investigated by studying the 5-HT behavioral syndrome in acutely reserpinized rats. The release of serotonin from vesicles by reserpine does not produce the serotonin behavioral syndrome which is an in vivo index of serotonin release and receptor activation. However, if rats are first pretreated with a nonselective monoamine oxidase inhibitor (e.g., tranylcypromine), the injection of reserpine is followed by symptoms which are characteristic of the behavioral syndrome including forepaw treading, hindlimb abduction and head weaving. Neither selective MAO-A or -B inhibition with clorgyline or deprenyl, respectively, nor inhibition of serotonin reuptake with fluoxetine prior to reserpine produced the serotonin behavioral syndrome. However, the combination of clorgyline and deprenyl followed by reserpine does so. These behavioral data along with neurochemical analyses of serotonin and 5-hydroxyindoleacetic acid levels lead to the conclusion that serotonin does not have to be released before it is metabolized to 5-hydroxyindoleacetic acid. Consequently, the levels of 5-hydroxyindoleacetic acid in brain reflect MAO activity and not serotonin release or utilization.