Catabolism Of Monoamines Research Articles

The Effect of Chronic Treatment with the Inhibitor of Phosphodiesterase 5 (PDE5), Sildenafil, in Combination with L-DOPA on Asymmetric Behavior and Monoamine Catabolism in the Striatum and Substantia Nigra of Unilaterally 6-OHDA-Lesioned Rats.

The use of phosphodiesterase inhibitors in the treatment of Parkinson's disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra.

Bright side of the MAOA-uVNTR on trait and situational forgiveness

The stress-and-coping theory of forgiveness posits that forgiveness and aggression are alternative ways of coping with stress of interpersonal offences. Inspired by the link between aggression and MAOA-uVNTR (a genetic variant involving in catabolism of monoamines), we investigated the relationship between this variant and forgiveness with two studies. Study 1 examined the relationship between the MAOA-uVNTR and trait forgiveness in students, and study 2 examined the effect of this variant on third-party forgiveness in response to situational offences in male inmates. The results showed that the MAOA-H (a high activity allele) was associated with higher trait forgiveness in male students and greater third-party forgiveness to accidentally committed harm and attempted but failed harm in male inmates than the MAOA-L. These findings highlight the bright side of MAOA-uVNTR on trait and situational forgiveness.

Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain.

LRRK2 gain-of-function is considered a major cause of Parkinson’s disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD.

Benextramine and derivatives as novel human monoamine oxidases inhibitors: an integrated approach.

The two human monoamine oxidase isoforms (namely MAO A and MAO B) are enzymes involved in the catabolism of monoamines, including neurotransmitters, and for this reason are well-known and attractive pharmacological targets in neuropsychiatric and neurodegenerative diseases, for which novel pharmacological approaches are necessary. Benextramine is a tetraamine disulfide mainly known as irreversible α-adrenergic antagonist, but able to hit additional targets involved in neurodegeneration. As the molecular structures of monoamine oxidases contain nine cysteine residues, the aim of this study was to evaluate benextramine and eleven structurally related polyamine disulfides as potential MAO inhibitors. Most of the compounds were found to induce irreversible inactivation of MAOs with inactivation potency depending on both the polyamine structure and the enzyme isoform. The more effective compounds generally showed preference for MAO B. Structure-activity relationships studies revealed the key role played by the disulfide core of these molecules in the inactivation mechanism. Docking experiments pointed to Cys323, in MAO A, and Cys172, in MAO B, as target of this type of inhibitors thus suggesting that their covalent binding inside the MAO active site sterically impedes the entrance of substrate towards the FAD cofactor. The effectiveness of benextramine in inactivating MAOs was demonstrated in SH-SY5Y neuroblastoma cell line. These results demonstrated for the first time that benextramine and its derivatives can inactivate human MAOs exploiting a mechanism different from that of the classical MAO inhibitors and could be a starting point for the development of pharmacological tools in neurodegenerative diseases.

Regulation of Monoamine Oxidase B Gene Expression: Key Roles for Transcription Factors Sp1, Egr1 and CREB, and microRNAs miR-300 and miR-1224

Monoamine oxidase B (MAO-B), a flavoenzyme located in the outer mitochondrial membrane, is involved in the catabolism of monoamines. Altered levels of MAO-B are associated with cardiovascular/neuronal diseases. However, molecular mechanisms of MAO-B gene regulation are partially understood. We undertook a systematic analysis of the MAO-B gene to identify the key transcriptional/post-transcriptional regulatory molecules. Expression of MAO-B promoter–reporter constructs in cultured cells identified the −144/+25-bp domain as the core promoter region. Stringent in silico analysis of this core promoter predicted binding sites for several transcription factors. Over-expression/down-regulation of transcription factors Sp1/Egr1/CREB increased/decreased the MAO-B promoter–reporter activity and endogenous MAO-B protein level. Electrophoretic mobility shift assays and ChIP assays provided evidence for interactions of Sp1/Egr1/CREB with the MAO-B promoter. MAOB transcript level also positively correlated with the transcript level of Sp1/Egr1/CREB in various human tissue samples. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed direct interactions of the microRNAs miR-1224 and miR-300 with MAO-B 3′-UTR. Dopamine dose-dependently enhanced MAO-B transcript and protein levels via increased binding of CREB to MAO-B promoter and reduced miR-1224/miR-300 levels. 8-Bromo-cAMP and forskolin augmented MAO-B expression, whereas inhibition of PKA diminished the gene expression suggesting involvement of cAMP-PKA axis. Interestingly, Sp1/Egr1/CREB/miR-1224 levels correlate with MAO-B expression in rodent models of hypertension/MPTP-induced neurodegeneration, indicating their roles in governing MAO-B gene expression in these disease states. Taken together, this study elucidates the previously unknown roles of the transcription factors Sp1/Egr1/CREB and microRNAs miR-1224/miR-300 in regulating MAO-B gene expression under basal/disease states involving dysregulated catecholamine levels.

Monoamine Oxidase Inhibitors: Perspective Design for the Treatment of Depression and Neurological Disorders

Monoamine oxidase-A and B have been studied over a long period as one of the promising drug targets for the treatment of depression and neurodegenerative disorders. Commonly, MAO-A is associated with depression because of its relation with the control of serotonin levels. On the other hand, MAO-B has been associated with Alzheimer’s and Parkinson’s diseases because this enzyme modulates dopamine levels in the CNS. The major objective of the research in this field is devoted to identify and isolate selective ligands of MAO-A/MAO-B so that the undesirable side effects due to non-selective inhibition of monoamine catabolism by the isoforms can be avoided. This review will give an overview of the inhibition mechanism of MOA and its biochemistry, along with the history and development of MAO inhibitors including the significance of molecular modeling studies for the identification of novel class of MAO inhibitors. Keywords: MAO-A, MAO-B, depression, Parkinson’s disease, cheese effect, docking.

1-Methyl-1,2,3,4-tetrahydroisoquinoline, an Endogenous Neuroprotectant and MAO Inhibitor with Antidepressant-Like Properties in the Rat

Oxidative stress is a major contributing factor in a range of brain pathologies and in the etiology of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which is present in the mammalian brain and exhibits neuroprotective, and monoamine oxidase (MAO)-inhibiting properties. In the present study, in order to investigate the potential role of 1MeTIQ as an antidepressant, we tested antidepressant-like effects of 1MeTIQ in comparison with desipramine (a classic antidepressant) in the forced swimming test (FST), and using HPLC methodology, we measured the concentrations of monoamines (dopamine, noradrenaline, serotonin) and the rate of their metabolism. 1MeTIQ given alone as well as in combination with desipramine produced an antidepressant-like effect and decreased the immobility time in the FST. Neurochemical data have shown that 1MeTIQ like desipramine, activated the noradrenergic system. However, the mechanism of action of 1MeTIQ is broader than the actions of desipramine, and 1MeTIQ inhibits the MAO-dependent oxidation of dopamine and serotonin in all investigated structures. We can conclude that 1MeTIQ exhibits antidepressant-like activity in the FST in the rat. The mechanism of its antidepressant action differs from desipramine and seems to be mostly associated with the inhibition of the catabolism of monoamines and their increased concentrations in the brain. 1MeTIQ seems to be very beneficial from the clinical point of view as a reversible MAO inhibitor with a significant antidepressant effects.

An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia

The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.

A monoamine oxidase from scallop Chlamys farreri serving as an immunomodulator in response against bacterial challenge

Monoamine oxidase (MAO) is an essential enzyme in the catabolism of monoamines, and implicated in the immune response of vertebrates. In the present study, the full-length cDNA encoding monoamine oxidase (designated CfMAO) was cloned from Chlamys farreri by using rapid amplification of cDNA ends (RACE) approaches and expression sequence tag (EST) analysis. The open reading frame of CfMAO cDNA encoded 519 amino acids, which shared 73.9% similarity with that from oyster Crassostrea gigas, and 64.5–66.3% similarity with those from vertebrates. A conserved Amino_oxidase domain and a transmembrane domain were identified in the deduced CfMAO protein. The mRNA transcripts of CfMAO could be detected in all the tested tissues, including haemocytes, hepatopancreas, kidney, adductor muscle, mantle, gill and gonad. The mRNA expression of CfMAO was up-regulated significantly in haemocytes of scallops during 6–48 h after bacteria Vibrio anguillarum challenge, and it reached the peak (25.9-fold, P < 0.05) at 12 h. The cDNA fragment encoding the mature peptide of CfMAO was expressed in the prokaryotic expression system, and 1 mg of the recombinant protein (rCfMAO) could catalyze the deamination of 3665.59 nmol serotonin, 2061.89 nmol norepinephrine, 2104.85 nmol epinephrine or 3040.34 nmol dopamine within 1 min (nmol min −1 mg −1) in vitro. When the reaction mixture was coincubated with 0.1 mmol L −1 MAO inhibitor clorgyline, its catalyzing activity to deaminize serotonin and dopamine was decreased significantly to 1603.69 and 955.39 nmol min −1 mg −1 ( P < 0.05) respectively. These results indicated that CfMAO, as the homologue of monoamine oxidase in scallop C. farreri, could modulate the immune response of scallops through the deamination of monoamines.

Identification of kaempferol as a monoamine oxidase inhibitor and potential Neuroprotectant in extracts of Ginkgo biloba leaves.

The effects of Ginkgo biloba leaf extract on rat brain or livermonoamine oxidase (MAO)-A and -B activity, biogenic amine concentration in nervous tissue, N-methyl-D-aspartate (NMDA)- and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced neurotoxicity and antioxidant activity was investigated to determine the effects of the extract on monoamine catabolism and neuroprotection. Ginkgo biloba leaf extract was shown to produce in-vitro inhibition of rat brain MAO-A and -B. The Ginkgo biloba extract was chromatographed on a reverse-phase HPLC system and two of the components isolated were shown to be MAO inhibitors (MAOIs). These MAOIs were identified by high-resolution mass spectrometry as kaempferol and isorhamnetin. Pure kaempferol and a number of related flavonoids were examined as MAOIs in-vitro. Kaempferol, apigenin and chrysin proved to be potent MAOIs, but produced more pronounced inhibition of MAO-A than MAO-B. IC50 (50% inhibition concentration) values for the ability of these three flavones to inhibit MAO-A were 7 x 10(-7), 1 x 10(-6) and 2 x 10(-6) M, respectively. Ginkgo biloba leaf extract and kaempferol were found to have no effect ex-vivo on rat or mouse brain MAO or on concentrations of dopamine, noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Kaempferol was shown to protect against NMDA-induced neuronal toxicity in-vitro in rat cortical cultures, but did not prevent DSP-4-induced noradrenergic neurotoxicity in an in-vivo model. Both Ginkgo biloba extract and kaempferol were demonstrated to be antioxidants in a lipid-peroxidation assay. This data indicates that the MAO-inhibiting activity of Ginkgo biloba extract is primarily due to the presence of kaempferol. Ginkgo biloba extract has properties indicative of potential neuroprotective ability.

Innovative approaches to treatment - refractory depression: The ketamine story

Byline: T.S. Rao, Chittaranjan. Andrade Antidepressant drugs have traditionally addressed the monoamine triumvirate: serotonin, noradrenaline, and dopamine. There have been predominantly two mechanisms recruited in drug action - inhibition of monoamine reuptake and inhibition of intravesicular monoamine catabolism. Tianeptine, which increases the synaptic reuptake of serotonin, and mirtazapine, which blocks alpha-2 adrenergic autoreceptors and heteroreceptors, are examples of the very few drugs which have other mechanisms of action. Yet, even these two antidepressants target the traditional neurotransmitters in psychiatry.[sup] [1] Recent evidence suggests that glutamate-mediated neuroplasticity may be the final common pathway of antidepressant action;[sup] [2],[3] tianeptine is the best-studied antidepressant in this regard.[sup] [4] If glutamate holds the key to recovery from depression, then treatments that directly address glutamatergic neurotransmission may exhibit greater antidepressant efficiency. Glutamate acts on metabotropic receptors and ionotropic receptors in the brain. Ionotropic receptors surround ion channels and are of three types: N-methyl-D-aspartate (NMDA) receptors, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and kainate receptors.[sup] [5] The glutamatergic system and particularly the NMDA receptor play an important role in the neurobiology of major depressive disorder, and different glutamatergic targets have been considered as treatments for depression.[sup] [6],[7] For example, antagonists of the NR2B subtype of the NMDA receptor are currently under development as potential antidepressant treatments; and traxoprodil, an NR2B antagonist, has demonstrated antidepressant effects in selective serotonin reuptake inhibitor (SSRI)-resistant patients.[sup] [7] Ketamine, the focus of this editorial, is an experimental antidepressant treatment which acts on NMDA receptors.[sup] [5] Ketamine as an Antidepressant Animal studies have shown that ketamine and other NMDA receptor antagonists have antidepressant effects in different animal models of depression.[sup] [8] About a decade ago, Berman et al.[sup] [9] described the first double-blind, placebo-controlled (crossover) study, which showed that an intravenous ketamine infusion (0.5 mg/kg) resulted in significant and rapid but short-lived antidepressant effects in seven patients with major depression. Several years later, Zarate et al.[sup] [8] described the first randomized, double-blind, placebo-controlled (crossover) study of ketamine in 18 patients with treatment-refractory major depressive disorder. Ketamine (0.5 mg/kg) was administered as an intravenous infusion in normal saline across a 40-minute period; placebo comprised normal saline alone. There was significant antidepressant benefit within 110 minutes of the ketamine infusion. One day later, the response and remission rates to ketamine were 71% and 29%, respectively, and the antidepressant effect size was 1.5. However, only six (35%) patients maintained response for one week, by which time the effect size had dropped to 0.7. In contrast, the response rate to saline infusion was 0% after both one day and one week. Adverse effects with ketamine included perceptual disturbances, confusion, euphoria, dizziness, increased libido, and elevated blood pressure; these, however, lasted only for 1-2 hours. Several case reports were subsequently published illustrating the efficacy of ketamine in medication-refractory patients. For example, Goforth and Holsinger[sup] [10] described a patient with severe, recurrent major depressive disorder who markedly improved within eight hours of receiving his first bitemporal electroconvulsive therapy (ECT) treatment under ketamine anesthesia. It is possible; however, that the dramatic response was to ECT and not necessarily to ketamine because such dramatic response to ECT has occasionally been described in literature. …

S11.A Iron deficiency alters monoamine catabolism as well as feedback regulation of DA transporter functioning

S11.A Iron deficiency alters monoamine catabolism as well as feedback regulation of DA transporter functioning

Iron deficiency alters monoamine catabolism as well as feedback regulation of DA transporter functioning

Iron deficiency (ID) causes decreased dopamine (DA) D2 receptor density, decreased DA transporter (DAT) density and alters DA signaling in the brain. We found that post weaning ID results in a 61% decrease in MAO-B activity in striatum. No effect was seen on MAO-A or COMT activity. Direct infusion of 1 μM FeSO4 was found to rescue this deficit indicating iron is vital for proper catecholamine metabolism. We further explored iron’s role on the catecholamine system by using in vivo microdialysis and no net flux. We found that ID increases extracellular dopamine by 26% and decreases extraction fraction (Ed) by 20% implying the DAT function is decreased by ID. Furthermore, stimulation of the D2 system by infusion of 5 μM quinpirole during NNF results in a decrease in basal extracellular DA for both control (CN) and ID animals indicating that the feedback regulation of synthesis and release is intact, although D2 density is decreased. Additionally, quinpirole infusion increased Ed by 45% in CN animals, however there was no change in ID Ed. This lack of response indicates disruption in the signal pathway regulating DAT functionality. Infusion of 1 μM FeSO4 was not able to correct this.

The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons

The enzyme catechol-O-methyl transferase (COMT), identified in the 1950s, is involved in catabolism of monoamines that are influenced by psychotropic medications, including neuroleptics and antidepressants. The COMT gene lies in a chromosomal region of interest for psychosis and bipolar spectrum disorder and a common polymorphism within the gene alters the activity of the enzyme. As a consequence, COMT has been one of the most studied genes for psychosis. On the basis of prior probabilities it would seem surprising if functional variation at COMT did not have some influence either on susceptibility to psychiatric phenotypes, modification of the course of illness or moderation of response to treatment. There is now robust evidence that variation at COMT influences frontal lobe function. However, despite considerable research effort, it has not proved straightforward to demonstrate and characterise a clear relationship between genetic variation at COMT and psychiatric phenotypes. It is of course, possible that COMT will turn out to be an unusually intractable case but it seems more likely that the experiences with this gene will provide a foretaste of the complexity of genotype-phenotype relationships that will be found for psychiatric traits. In this review, we consider the current state of evidence and the implications both for further studies of COMT and more generally for studies of other genes.

Correlates of sleep and waking in Drosophila melanogaster.

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine, a precursor amino acid of norepinephrine, in the brain. Studies by in vivo microdialysis.

The metabolism and the effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) were studied in the rat brain striatum by in vivo microdialysis. In the brain L-threo-DOPS was metabolized by 3 different enzymes; aromatic L-amino acid decarboxylase, catechol-O-methyltransferase, and DOPS-aldolase. DOPS-aldolase was the main enzyme which metabolizes L-threo-DOPS. The amounts of the metabolites by L-amino acid decarboxylase (norepinephrine and its metabolites) were 0.4% of the total amounts of metabolites detected in the dialysate, while those by catechol-O-methyltransferase, 2.1%, and by DOPS-aldolase, 97.5%, after 100 min perfusion of L-threo-DOPS. L-threo-DOPS was found to increase extracellular levels of dopamine and serotonin, and to inhibit monoamine catabolism in the brain. Inhibition of DOPS-aldolase should improve its effectiveness as the supplement therapy of norepinephrine.

Effect of antidepressant drugs on monoamine synthesis in brain in vivo

The activity of tryptophan and tyrosine hydroxylase were estimated in vivo by measuring the accumulation during 30 min of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA), respectively, after inhibition of aromatic amino acid decarboxylase by administration of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). Whereas the activity of tyrosine hydroxylase in the dopamine-rich striatum was sensitive to haloperidol, which caused a significant increase in accumulation of DOPA, there was no effect of haloperidol in the predominantly noradrenergic frontoparietal cortex, confirming that the activity of tyrosine hydroxylase, measured in the frontoparietal cortex, is essentially localized in noradrenergic neurones. In the frontoparietal cortex of the rat the in vivo activity of tryptophan and tyrosine hydroxylase were equipotently attenuated by imipramine, while the selective Mocker of the uptake of noradrenaline, desipramine and the selective blocker of the uptake of serotonin, citalopram, reduced only tyrosine or tyrosine hydroxylase respectively. Milnacipran, an antidepressant which inhibits the uptake of both monoamines to a similar extent, decreased the synthesis of both monoamines equipotently. The monoamine oxidase inhibitor, clorgyline, also reduced the synthesis of both monoamines. Thus, the in vivo inhibition of the synthesis of monoamines would appear to be mediated by an increase in synaptic concentration of monoamines, resulting from the inhibition of the uptake or catabolism of monoamines. Chronic administration of citalopram led to a significant increase of the basal synthesis of 5-hydroxytryptamine (5-HT). Milnacipran, given chronically, significantly enhanced the basal synthesis of both 5-HT and noradrenaline (NA). However in both cases, the inhibition of the respective monoamine, induced by an additional acute administration of citalopram or milnacipran, respectively, remained similar in control and treated groups. Mechanisms of action of antidepressant drugs are discussed in the light of these results.

Relationship of Gonadal Hormone Administration, Sex, Reproductive Status and Age to Monoamine Oxidase Activity Within the Hypothalamus

Abstract Activity of Type A monoamine oxidase (MAO) was measured in microdissected samples from preoptic-hypothalamic and hindbrain areas of young male and female rats, and aged female rats. Administration of estradiol and progesterone, in doses sufficient to facilitate lordosis behavior and induce a luteinizing hormone surge in ovariectomized, but not castrated rats, was associated with sexually dimorphic changes of MAO activity within the hypothalamus. Forty-two h following estradiol benzoate administration, increased MAO activity was measured in the ventromedial nucleus (VML) and midbrain central gray of females, while decreased MAO activity was measured in the VML and arcuate-median eminence (ArME) of males. Progesterone administration to estradiol benzoate-primed rats was associated with decreased MAO activity in the VML and medial preoptic nucleus (mPOA) of females and decreased activity in the dorsal raphe nucleus of males. Activity of MAO on diestrus, proestrus and estrus was assessed in ten preoptic-hypothalamic and hindbrain sites. Differences between days of the cycle were limited to the mPOA, ArME and VML. While activities were generally lowest at estrus, these areas exhibited different patterns of activity across the cycle. Activity was highest at proestrus in the mPOA and highest at diestrus in the VML and ArME. Activity of MAO in some areas of 25-month old, diestrus rats was altered as compared to young, cycling rats; however, ageing was not associated with widespread changes in MAO activity. In the suprachiasmatic nucleus, aged rats showed approximately 30% less activity than young rats. In the mPOA, VML and ArME, activity in aged females was different from some, but not all, days of the estrous cycle. These results show that MAO activity changes within specific hypothalamic sites when the neuroendocrine axis is altered. Since the changes are present in areas where activity of rnonoaminergic systems is critical for initiating gonadotrophin surges and inducing lordosis behavior, these results provide initial evidence that catabolism of monoamines by MAO may contribute to rnonoaminergic regulation of reproductive function.

Analysis of monoamines and their metabolites by high performance liquid chromatography with coulometric electrochemical detection

High performance liquid chromatography with coulometric electrochemical detection has been used to achieve simultaneous determination of norepinephrine, epinephrine, 5-hydroxytryptophan, normetanephrine, dopamine, metanephrine, 3,4-dihydroxyphenylacetic acid, N-acetyldopamine, tyramine, tryptophan, 5-hydroxyindoleacetic acid, 5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, homovanillic acid, tyrosine, p-octopamine, N-acetyl-p-octopamine, and p-synephrine. The procedure has been applied to study monoamine degradation in the insect brain and to demonstrate that N-acetylation rather than oxidative deamination is the primary route of monoamine catabolism in insects.

Effect of amezinium on the release and catabolism of 3H-monoamines in brain slices

Occipitocortical slices of rats were preincubated with [ 3H]noradrenaline or [ 3H]serotonin; striatal slices were preincubated with [ 3H]dopamine. The outflow of 3H-compounds was studied. In slices preincubated with [ 3H]noradrenaline, 1 nM amezinium diminished the outflow of deaminated metabolites (mainly [ 3H]-3,4-dihydroxyphenylglycol). Higher concentrations in addition released [ 3H]noradrenaline. The effects were antagonized by cocaine. In slices preincubated with [ 3H]dopamine, 1 nM amezinium caused no change, but 10 nM amezinium decreased the outflow of deaminated products (mainly [ 3H]-3,4-dihydroxyphenylacetic acid). Higher concentrations in addition released [ 3H]dopamine. The effects were antagonized by nomifensine. In experiments with [ 3H]serotonin, 1 nM amezinium caused no change, but 10 nM amezinium reduced the outflow of [ 3H]-5-hydroxyindoleacetic acid. Higher concentrations in addition released [ 3H]serotonin. The effects were antagonized by paroxetine. When amezinium was injected in vivo 1 hr before sacrifice, up to 10 mg/kg did not change the deamination of [ 3H]noradrenaline in cortical cubes; amezinium (50 mg/kg) caused slight inhibition. The results indicate that amezinium, added in vitro, is a very potent inhibitor of the MAO inside cerebral noradrenergic neurones. It is less potent at dopaminergic and serotonergic neurones. When injected systemically in vivo, however, amezinium at moderate doses has no effect on central monoamine catabolism, probably because of exclusion from the brain by the blood-brain barrier.