Monoaminergic Neurotransmitter Systems Research Articles

Platelet Monoamine Oxidase B Activity in Dementia

Platelet monoamine oxidase B (MAO-B) activity has been found to increase significantly in demented patients. For the first time, a 4-year follow-up of platelet MAO-B activity and Mini-Mental State (MMS) was performed in patients with probable dementia of the Alzheimer type (DAT) and age-matched controls. MAO-B activity of DAT patients increased significantly 2 years after the beginning of the study as compared with controls and remained significantly higher for the entire period of the examinations (p < 0.0001). The decrease of the MMS scores did not correlate with the time course of the increase of platelet MAO-B activity (Spearman rank correlation test). The decline of the MMS scores of DAT patients preceded the elevation of MAO-B activity. Since degenerative processes in brain areas which are responsible for cognitive function and are reflected by the MMS scores rather affect cerebral cholinergic than monoaminergic neurotransmitter systems, degeneration of the latter at late stages of DAT might be reflected by increased platelet MAO-B activity.

Obsessive-compulsive disorder: cerebral calcium deficiency as a possible etiologic/pathogenetic factor — a case study

Obsessive-compulsive disorder (OCD) is briefly characterized, and several of the hypothesized neuroanatomical and neurochemical substrates of this etiologically heterogeneous syndrome are noted. Importantly, alterations in the CNS balance of monoaminergic neurotransmitter systems are probably involved in the pathobiology of OCD. Inasmuch as calcium (Ca) concentration regulates neuronal neurotransmitter release, presynaptic Ca deficiencies can disrupt normal neurotransmission. Supporting this, a case report is presented of a subject with intermittent OCD and comorbid cardiac pathology for whose latter condition a regimen of increasing doses of a Ca channel blocker (CCB) greatly exacerbated the OCD. Upon reducing, then discontinuing the CCB dose, the OCD sympomatology was greatly ameliorated. It is suggested that minimal use of CCBs is indicated for OCD subjects and that, if possible, they be substituted with other drugs. In view of the widespread use of CCBs, this cerebral Ca deficiency hypothesis of OCD etiopathogenesis should be further tested by seeking other OCD subjects, especially from cardiology practices.

Effects of human placental extract on brain monoamines and monoamine oxidase activity in rats.

Human placental extract, an agent clinically used world-wide in a number of physiological anomalies, has been claimed to be effective in children of slow learners. Since the monoaminergic neurotransmitter systems in the brain play an important role in the processes of learning and memory, we examined the effects of human placental extract on the levels of norepinephrine, dopamine and serotonine in rat brain as an attempt to evaluate the possible underlying biochemical mechanism of action of the extract. We also determined the changes of brain monoamine oxidase (MAO) activity following placental extract treatment. The results showed that subchronic (5, 10, 15 or 20) administration of placental extract (2-4 ml/kg/day) had the effect of increasing all the monoamines and decreasing the MAO activity which could be the possible mode of action of the extract in slow learners.

Neuropsychological correlates of l-deprenyl therapy in idiopathic parkinsonism

Finali, Giancarlo, Massimo Piccirilli and Gian Luigi Piccinin: Neuropsychological Correlates of L-Deprenyl Therapy in Idiopathic Parkinsonism. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1994, 18(1): 115–128. 1. 1. Monoaminergic neurotransmitter systems are known to play an important role in neuropsychological functions and they are impaired in dementia of DAT and PD. 2. 2. L-deprenyl is a monoamine—enhancing drug which at low doses selectively inhibits MAO-B, an enzyme whose brain activity has been reported to increase in normal aging and neurodegenerative dementing disorders. 3. 3. The authors studied the effects of L-deprenyl, 10 mg/day, on several cognitive domains in idiopathic parkinsonians without dementia. Ten out-patients, treated with levodopa plus DDI, were tested before receiving L-deprenyl and retested six months after they had been treated with the drug. A control group of ten parkinsonian out-patients treated with only levodopa plus DDI, matched for age, educational level, severity and duration of extrapyramidal disease, was tested by the same neuropsychological battery and retested after a comparable time interval. 4. 4. Statistically significant changes were noted in the verbal and visuospatial learning performances of PD patients treated with the combination of L-deprenyl and levodopa.

Neurobiology of prenatal cocaine exposure effect on developing monoamine systems

Cocaine and crack belong to a broad category of agents that act primarily as central nervous system stimulants at the level of the monoaminergic neurotransmitter system (dopamine, norepinephrine, and serotonin). These neurotransmitters are involved in the regulation of a number of basic psychological functions including attention and arousal and play a crucial role in the defining of brain structure and neuronal formation. This paper outlines what is currently known about the direct effects of cocaine on the mature and developing central nervous system. Three general points are reviewed: (1) Cocaine has differing effects on structural and functional brain development throughout gestation (e.g., there is not a single, all or none effect); (2) No one area of the brain is singularly affected. Areas related by the monoaminergic system are differentially influenced and affecting one area may result in a functional change in another; and (3) Because substantial brain growth, synaptic formation, and remodeling occur in the first months after birth, ongoing postnatal exposure to cocaine also carries risk for direct effects on brain function. Understanding the developmental neurobiological effects of cocaine provides data to guide studies in infants and young children of how prenatal cocaine exposure may contribute to specific, biologically based areas of neurological vulnerability that will be expressed behaviorally and developmentally in the first 3 to 5 years of life. La cocaïne et le crack appartiennent tous deux à la large catégorie des agents qui agissent essentiellement en tant que stimulants du système nerveux central au niveau du système neurotransmetteur monoaminergique (dopamine, norepinephrine, et sérotonine). Ces neurotransmetteurs sont impliqués dans la régulation d'un nombre de fonctions psychologiques de base dont font partie l'attention et la stimulation et jouent un rǒle crucial dans la définition de la structure du cerveau et de la formation neuronale. Cet article fait un bref compte-rendu des connaissances actuelles sur les effets de la cocaïne sur le système nerveux central mǔr et se développant. Trois questions générales sont passées en revue: (I) Durant la gestation, la cocaïne a des effets qui different sur le développement du cerveau structurel et fonctionnel, i.e. il n'existe pas un seul et unique effet; (2) Aucune région du cerveau n'est affectee à elle-seule. Les régions reliées par le système monoaminergique sont influencée différemment et le fait de toucher une région peut résulter en un changement fonctionnel dans une autre région; et (3) A cause du développement considérable du cerveau, la formation et la réorganisation synapsiques a lieu durant les permiers mois après la naissance, l'exposition prolongée postnatale à la cocaïne comporte également des risques pour les effets directs sur la fonction du cerveau. La compréhension des effets neurobiologiques de la cocaïne en matière de développement offre des données qui sont à měme de conduire des études chez les nourrissons et les jeunes enfants sur la façon dont l'exposition prénatale à la cocaïne oeut contribuer à affecter des régions biologiques spécifiques de vulnérabilité neurobiologique qui trouveront leur expression comportementale et dévelop-pementale dans les trois-cinq premières années de la vie.

Effects of nefiracetam, a novel pyrrolidone derivative, on brain monoamine metabolisms in mice.

The effects of acute and chronic administration of nefiracetam, a pyrrolidone derivative, on monoaminergic neurotransmitter systems in the mouse hippocampus, frontal cortex, hypothalamus, and striatum were studied. The levels of monoamines and of their metabolites were measured by high performance liquid chromatography with electrochemical detection on the first, 7th, and 14th days after nefiracetam was given. The neurochemical effects of nefiracetam were compared with those of oxiracetam and indeloxazine. Acute administration of nefiracetam (10 mg/kg, po) and oxiracetam (10 mg/kg, po) had no effect on the levels of noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT), or on the levels of their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in any of the regions examined. In contrast, a single dose of indeloxazine (10 mg/kg, po) decreased the levels of MHPG, DOPAC, and 5-HIAA in all regions examined. After chronic administration of nefiracetam (10 mg/kg, po, once daily), the levels of MHPG, DOPAC, and 5-HIAA were higher than control in all regions on the 14th day only. Oxiracetam (10 mg/kg, po, once daily) similarly increased the levels of MHPG, DOPAC, and 5-HIAA in the hippocampus, frontal cortex, and striatum, but not in the hypothalamus. Conversely, indeloxazine (10 mg/kg, po, once daily) decreased the levels of MHPG and 5-HIAA in all regions and the levels of DOPAC and HVA in the hippocampus and striatum as measured on the 7th and 14th days. These results show that nefiracetam has a delayed effect on brain monoaminergic metabolism, and that its effects are similar to those of oxiracetam, but clearly different from those of indeloxazine.

Co-dergocrine mesylate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in age-related cognitive decline.

Co-dergocrine mesylate is a combination of the mesylated forms of dihydroergocornine, dihydroergocristine, dihydro-alpha-ergocryptine and dihydro-beta-ergocryptine. In animal models and healthy elderly volunteers the compound improves indices of cognitive function such as memory and learning. The mechanism(s) behind such action remains under investigation. Nonetheless, it has been proposed that co-dergocrine mesylate has a dual effect on central monoaminergic neurotransmitter systems, compensating for both hyperactivity and deficits of the adrenergic, serotoninergic and dopaminergic systems. The compound also appears to have a normalising effect on the power of electroencephalogram frequencies, and may improve cerebral metabolism. Results from controlled studies of elderly patients with age-related cognitive decline have established that co-dergocrine mesylate is well tolerated and, in some studies, had statistically significant positive effects on symptoms of cognitive dysfunction. However, there is considerable controversy over the clinical relevance of these results as there was wide variability in the number and type of cognitive and neuropsychological assessments used in individual studies and there may have been considerable overlap in diagnosis of patients with varying degrees of dementia. In addition, the drug has not been compared with most other, more recently developed, centrally active agents. Thus, the specific place of co-dergocrine mesylate in the treatment of age-related cognitive decline remains undetermined, despite many years of clinical use.

A decrease in brain catecholamines prevents oxiracetam antagonism of the effects of scopolamine on memory and brain acetylcholine

The effect of oxiracetam on passive avoidance conditioned response and acetylcholine (ACh) levels in rats with selective lesions of the central monoaminergic pathways was investigated. The lesions were followed by a marked decrease in cortical serotonin (−88%), noradrenaline (−54%) and striatal dopamine (−57%) levels, while neither the performance of a passive avoidance conditioned response nor brain ACh levels were affected. Scopolamine (hyoscine) administration (0.63 mg/kg, s.c.) to lesioned rats exerted the expected amnesic effect, associated with a decrease in hippocampal, cortical and striatal ACh levels. In the rats with degeneration of dopaminergic and noradrenergic but not serotoninergic pathways, oxiracetam (50 and 100 mg/kg, s.c.) was unable to prevent both amnesia and the decrease in brain ACh levels caused by scopolamine. The effect of oxiracetam was prevented by haloperidol (0.2 mg/kg, s.c.). Our findings support the hypothesis that an interaction between monoaminergic and cholinergic neurotransmitter systems may be involved in the actions of nootropic drugs on cognitive functions.

Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide—induced acute liver failure

Functional changes of various neurotransmitter systems have been implicated in the pathogenesis of hepatic encephalopathy. In this study the role of brain monoaminergic neurotransmitter systems in hepatic encephalopathy was investigated in rats with thioacetamide-induced acute liver failure. Concentrations of serotonin, dopamine, noradrenaline and of their metabolites 5-hydroxyindoleacetic acid, dihydroxyphenylalanine (following inhibition of dihydroxyphenylalanine-decarboxylase), dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenyl-glycol, were measured in the cerebral cortex, striatum and hippocampus by high performance liquid chromatography with electrochemical detection. In hepatic encephalopathy concentrations of 5-hydroxyindoleacetic acid were increased in all three brain areas (196%, 204% and 264% of saline-treated controls, p less than 0.01), and concentrations of serotonin were increased in the frontal cortex (121%, p less than 0.01). In the frontal cortex and hippocampus of encephalopathic rats dopamine levels were increased (157% and 289%, p less than 0.05), and levels of noradrenaline (53% and 46%, p less than 0.05) were decreased associated with increased 3-methoxy-4-hydroxyphenylglycol levels (173% and 206%, p less than 0.05). The extent of these changes correlated with the stage of hepatic encephalopathy. In hepatic encephalopathy dihydroxyphenylalanine accumulation was increased in the hippocampus and unchanged in the cerebral cortex. Dopamine, noradrenaline, dihydroxyphenylacetic acid and homovanillic acid concentrations were unchanged in the striatum. The results of this study indicate that hepatic encephalopathy in thioacetamide-induced acute liver failure in rats is associated with neurochemical changes, suggesting an increased activity of the noradrenergic and serotoninergic neurotransmitter systems.

GABAmimetics: A New Class of Antidepressant Agents?

To the Editor.— We report a case study of an antidepressant action of progabide, a ɣ-aminobutyric acid (GABA) agonist, in a patient previously unresponsive to other antidepressant drug therapies. To our knowledge, selective GABA agonists have not been previously pursued as antidepressant therapies. Indeed, manipulation of monoaminergic neurotransmitter systems with tricyclic antidepressants or monoamine oxidase inhibitors has been the traditional therapeutic approach for depression.1However, serious side effects in some depressed patients and nonresponse in others have left many depressed individuals no pharmacological treatment options. In recent years both preclinical and some preliminary clinical studies have focused on the possible role of GABA in depression.2,3Since GABAmimetic therapy might have a different mechanism of neural action from current drugs, it would provide an important alternative treatment approach to depression. Report of a Case.— A 46-year-old woman had an 8-year history of major depressive disorder (DSM-III) associated

Effects of selective monoaminergic reuptake blockade on activity rhythms in developing rats

Developing rats display prominent ultradian rhythms of locomotor activity when separated from the litter. A pharmacological analysis was undertaken to provide preliminary data on the role of monoaminergic neurotransmitter systems in the modulation or manifestation of this fundamental biological rhythm. Twenty-four hour activity profiles were monitored in 15-day-old rats, tested in darkness, after intraperitoneal treatment with desipramine (DMI), zimelidine (ZMI), or GBR-13069 (GBR), selective uptake inhibitors of norepinephrine, serotonin, and dopamine, respectively. Time series data were analyzed by low-resolution variance spectral analysis. DMI significantly diminished ultradian (greater than 1 cycle per day; cpd) rhythmicity, and enhanced the circadian rhythm. Equimolar doses of ZMI had little effect on the ultradian band (7-15 cpd), but slightly reduced the circadian peak. The effects of acute GBR administration were complex, as this agent produced prominent effects on basal activity. In a second study these agents were administered continuously over a 5-day period, using subcutaneously implanted Alzet osmotic minipumps, to avoid the confounding effects of acute administration. Continuously-infused DMI virtually eliminated characteristic ultradian rhythms in the 9-15 cpd bandwidth. ZIM diminished ultradian oscillations only in the 14-15 cpd range, and GBR-12909 had little effect on ultradian rhythms throughout the usually prominent 7-16 cpd domain. All three reuptake inhibitors increased the prominence of slow ultradian rhythms with frequencies of 3-4 cpd. Continuous reuptake blockade had no significant effects on circadian amplitude or phase, as determined by cosinor analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related changes in multiple neurotransmitter systems in the monkey brain

Age-associated changes in cholinergic, monoaminergic and amino acid neurotransmitter systems were analyzed in 14 brain regions of 23 rhesus monkeys that ranged in age from 2 to 37 years. In the frontal pole, the levels of choline acetyltransferase (ChAT) activity, the density of [3H]ketanserin (serotonin type-2) binding sites and endogenous levels of dopamine, homovanillic acid and serotonin, all expressed per milligram of protein, decreased significantly with aging. In precentral motor cortex, ChAT activity decreased; in parietal and occipital cortex, the number of [3H]ketanserin binding sites decreased while the number of Na+-independent [3H]glutamate binding sites increased with age. In the caudate nucleus, endogenous levels of norepinephrine decreased. This descriptive study indicates that the aging monkey may be a very useful model for future investigations of age-associated transmitter abnormalities similar to those that occur in humans.

Effect of ovarian steroids to stimulate region-specific hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats.

Accumulations of 5-hydroxytryptophan (5HTP) and L-dihydroxyphenylalanine (L-DOPA) following decarboxylase inhibition as indices for 5-hydroxytryptamine (5HT) and catecholamine (dopamine and/or norepinephrine) synthesis, respectively, were both increased in the preoptic area-anterior hypothalamus (POA-AH) of ovariectomized rats treated with a combination of 17 beta-estradiol benzoate (E2) and progesterone (P). Similarly, an increased accumulation of L-DOPA was seen in the mediobasal hypothalamus (MBH) and median eminence (ME) of these animals although no change was observed in 5HTP accumulation in the MBH or ME of these rats. Hypophysectomy negated these steroid-induced effects on L-DOPA accumulation. However, hypophysectomy had no apparent effect on steroid-stimulated 5HTP accumulation in the POA-AH of these rats. Under the experimental conditions of our study, the results suggest that the stimulatory effect of ovarian steroids on hypothalamic catecholamine synthesis is dependent on an intact pituitary gland, that the stimulatory effect of ovarian steroids on 5HT synthesis in the POA-AH is not dependent on an intact pituitary gland, and (3) that ovarian steroids do not seem to influence 5HT synthesis in the ME or MBH. The significance of these results may lie in the function of these hypothalamic monoaminergic neurotransmitter systems to regulate gonadotrophin release and subsequent steroid feedback modulation of such central regulatory mechanisms.

The distribution of monoaminergic cells and fibers in a periventricular preoptic nucleus involved in the control of gonadotropin release: Immunohistochemical evidence for a dopaminergic sexual dimorphism

A small, discrete nucleus at the rostral end of the third ventricle, the anteroventral periventricular nucleus (AVPv), has been reported to be involved in the control of gonadotropin release. Since monoaminergic neurotransmitter systems have also been implicated in this function we used an indirect immunohistochemical approach to examine the distribution of 3 monoaminergic neurotransmitter systems in this nucleus. Sections through the AVPv of both colchicine and non-colchicine-treated adult male and female Sprague-Dawley rats were processed for immunohistofluorescence with antisera directed against tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), or serotonin (5-HT), and were subsequently counterstained with the fluorescent Nissl stain ethidium bromide. The distributions of TH-, DBH- and 5-HT-immunoreactive neural elements within the AVPv were evaluated and a comparison was made between males and females. In both sexes, few 5-HT-stained fibers were seen within the borders of the AVPv, in contrast to the relatively high 5-HT-stained fiber density of the surrounding region. A dramatic sexual dimorphism was found in the distribution of TH-immunoreactive fibers and cell bodies. Compared to males, the AVPv in the female contained 3–4 times as many TH-stained perikarya, and a 2- to 3-fold greater density of TH-stained fibers. A low to moderate density of DBH-immunoreactive fibers, and no DBH-stained cell bodies, were seen in the nucleus. A clear sex difference was not found in the density of DBH-stained fibers in the AVPv, indicating that the sexual dimorphism in TH-immunoreactive neural elements in this nucleus is due to a greater density of dopaminergic fibers and a greater number of dopaminergic cell bodies in the female. These results suggest that dopamine may participate in the control of gonadotropin secretion at the level of the AVPv.

Alzheimer's disease.

Significant progress has been made in identifying changes in cholinergic, monoaminergic, and peptidergic neurotransmitter systems in the brains of individuals with Alzheimer's disease. Moreover, neurobiological approaches are beginning to reveal the relationships between these neurotransmitter abnormalities and histological hallmarks of the disease, i.e. neurofibrillary tangles, senile plaques, and loss of specific populations of nerve cells. However, to date, the clinical consequences of these specific neurotransmitter changes remain to be elucidated, the cause of this disorder has not been identified, and no effective therapy is yet available.