The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.     

Presynaptic ionotropic glutamate receptors modulate in vivo release and metabolism of striatal dopamine,noradrenaline, and 5-hydroxytryptamine: involvement of both NMDA and AMPA/kainate subtypes

In order to explore further the presynaptic modulation of monoamine release by glutamatergic nerve fibers, we investigated the effects of selective agonists for ionotropic glutamate (GLU) receptors on striatal release of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT). In the striatum of anesthetized Sprague-Dawley rats, in vivo microdialysis was performed to measure the release of monoamines and metabolites, and also to administer GLU agonists locally in the tissue. l-GLU and its selective agonists (N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate (KA)) evoked simultaneous release of striatal DA, NA and 5-HT in a dose-dependent manner. Pretreatment with MK-801 (5 mg/kg i.p.), a noncompetitive NMDA receptor antagonist, selectively suppressed NMDA-evoked monoamine release. The rank order of GLU agonist efficacy in releasing monoamines was different among DA, NA, and 5-HTergic terminals: AMPA = KA > NMDA for DA release, AMPA > NMDA = KA for NA release, and NMDA = AMPA = KA for 5-HT release. In conclusion, presynaptic ionotropic GLU receptors exist extensively on monoaminergic terminals including not only catecholaminergic (DA and NA) but also indoleaminergic (5-HT) terminals in the rat striatum. Their subtypes include both NMDA subtype and AMPA/KA subtype, and show a differential distribution among these three monoaminergic terminals and a differential contribution to facilitating monoamine release.     

Differential effects of -trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with -tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after -tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, -tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.     

Effect of the enterotropic carcinogen 1,2-dimethylhydrazine on the hypothalamic biogenic amine level in rats

Subcutaneous injection of 1,2-dimethylhydrazine (DMH) in a dose of 21 mg/kg into male rats is followed after 24 h by a substantial fall in the hypothalamic levels of noradrenalin (NA), dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). During the first 3–12 h after injection of DMH the NA level was lowered and the intensity of 5-HT metabolism increased in the hypothalamus. The hypothalamic histamine level rose only 30 min after injection of the carcinogen. No significant change took place in the biogenic amine levels in the brain stem and cerebral hemispheres under the influence of DMH. It is suggested that an essential link in the mechanism of the carcinogenic action of DMH in rats is the hormonal metabolic disturbances caused by the selective action of DMH at the level of the hypothalamic biogenic amines.Group for the Study of Mechanisms of Aging and Department of Human Neurophysiology, Institute of Experimental Medicine, Academy of Medical Sciences of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR N. P. Bekhtereva.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 11, pp. 1359–1361, November, 1976.     

The functional significance of biochemical alterations in streptozotocin-induced diabetes.

These experiments examined the effects of restraint stress on dopamine (DA) and 5-hydroxytryptamine (5-HT) and their principal metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, in 4 brain regions, as well as on plasma corticosterone concentration (CORT) and behavior in streptozotocin-induced diabetic rats and nondiabetic controls. Diabetic rats had widespread reductions in DA and 5-HT turnover (DOPAC/DA and 5-HIAA/5-HT ratios). Restraint led to equivalent increases in DA turnover in diabetics and nondiabetics, but attenuated increases in 5-HT turnover in diabetic rats. CORT concentration of diabetics and nondiabetics measured in complete quiet did not differ. Relative to these measures, only diabetics had elevated CORT when either restrained or kept in the same room with restrained rats with food and water removed. Open-field exploration was suppressed by restraint in diabetics only. All diabetic rats showed decreased locomotion in a novel environment which was normalized during a second exposure to the apparatus. Together, these results suggest that diabetes-induced disruptions in open-field activity are related to anxiety rather than to motor or energy deficits, and may be related to impaired 5-HT and CORT systems.     

Effect of long-term caloric restriction on brain monoamines in aging male and female Fischer 344 rats

The present study examines the changes in central monoamines and their metabolites in aged male and female rats after long-term caloric restriction. Fischer 344 rats of both sexes (n = 5-10/group) were maintained on one of two dietary regimens: ad libitum NIH 31 diet or 60% by weight of the ad lib. intake (restricted), supplemented with vitamins and minerals. Animals received these diets from the age of 14 weeks until killed at 22.25 months of age. Caudate nucleus (CN), hypothalamus (HYPO), olfactory bulb (OB) and nucleus accumbens (NA) were assayed for content of norepinephrine (NE), dopamine (DA) and its metabolites (dihydroxyphenylacetic acid, DOPAC, and homovanillic acid, HVA) and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) using HPLC/EC. Relative to the ad lib. group, restricted rats of both sex showed significant decreases in NE content in CN, HYPO and OB. DA and 5-HT content were decreased significantly in the CN and HYPO. No significant changes were found in the levels of DA metabolites in all brain regions studied. While the 5-HIAA level was significantly reduced in the HYPO and NA of the female restricted rats, it was increased several-fold in the OB of the male restricted animals. These preliminary results suggest that long-term caloric restriction alters brain monoamine concentrations, an effect which may in turn modify the normal rate of aging.     

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.     

Effects of whole body microwave exposure on the rat brain contents of biogenic amines

Summary The effects of whole body microwave exposure on the central nervous system (CNS) of the rat were investigated. Rats weighing from 250 to 320 g were exposed for 1 h to whole body microwave with a frequency of 2450 MHz at power densities of 5 and 10 mW·cm^–2 at an ambient temperature of 21–23°C. The rectal temperatures of the rats were measured just before and after microwave exposure and mono-amines and their metabolites in various discrete brain regions were determined after microwave exposure. Microwave exposure at power densities of 5 and 10 mW·cm^–2 increased the mean rectal temperature by 2.3°C and 3.4°C, respectively. The noradrenaline content in the hypothalamus was significantly reduced after microwave exposure at a power density of 10 mW·cm^–2. There were no differences in the dopamine (DA) content of any region of the brain between microwave exposed rats and control rats. The dihydroxyphenyl acetic acid (DOPAC) content, the main metabolite of DA, was significantly increased in the pons plus medulla oblongata only at a power density of 10 mW·cm^–2. The DA turnover rates, the DOPAC:DA ratio, in the striatum and cerebral cortex were significantly increased only at a power density of 10 mW·cm^–2 The serotonin (5-hydroxytryptamine, 5-HT) content in all regions of the brain of microwave exposed rats was not different from that of the control rats. The 5-hydroxyindoleacetic acid (5-HIAA) content in the cerebral cortex of microwave exposed rats was significantly increased at power densities of 5 and 10 mW·cm^–2. The 5-HT turnover rates and the 5-HIAA:5-HT ratio were significantly increased in the cerebral cortex at a power density of 5 mW·cm^–2. Significant increases in the 5-HT turnover rate were observed in the pons plus medulla oblongata and hypopthalamus at a power density of 10 mW·cm^–2. These results indicated that whole body microwave exposure with a frequency of 2450 MHz at power densities of 5 and 10 mW·cm^–2 affected the function of mono-aminergic neurons in the rat brain. It would seem that the effects of whole body microwave exposure on the CNS can be attributed to the hyperthermia characteristic of microwave exposure, although the direct effects of microwave irradiation on the CNS cannot be completely discarded.     

Sexual refractoriness and locomotion effects on brain monoamines in the male rat

Serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and norepinephrine (NE) concentrations in seven brain regions were compared in sexually refractory, physically active, and inactive male rats. Also examined were 5-HIAA/5-HT and DOPAC/DA concentration ratios. Sexually refractory males were permitted uninterrupted copulation with successive receptive females until they failed to mount or ejaculate in a set period. Physically active males ran in motor-driven activity wheels except during the postejaculatory refractory periods of experimental animals, and inactive males remained alone in testing arenas. Significant group differences were found only in monoamine concentrations in the medial preoptic area (MPOA) and the medial forebrain bundle (MFB). In the MPOA, 5-HT concentration was elevated in sexually refractory males, as was DA in both refractory and active animals. In the MFB, 5-HT concentration was increased in active males. MFB DOPAC levels of sexually refractory rats significantly correlated inversely with their ejaculation totals, as did MFB and dorsal raphe (DR) NE levels. The results suggest that the MPOA is a forebrain target for inhibitory influences on male rat sexual behavior of ascending serotonergic fibers and that increased MFB 5-HT and MPOA DA may be associated with general activity.     

Rotational behaviour and neurochemical changes in unilateral N-methyl-norsalsolinol and 6-hydroxydopamine lesioned rats

In earlier studies the tetrahydroisoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) was discovered in lumbar cerebrospinal fluid and brain of patients with Parkinson's disease. To establish whether 2-MDTIQ is toxic to the dopaminergic system, 2-MDTIQ or 6-hydroxydopamine (6-OHDA) were stereotactically injected into the left medial forebrain bundle, and rotational behaviour and neurochemical changes were measured in female Wistar rats. Three weeks after lesioning rotational behaviour was assessed after administration of S(+)-amphetamine (5 mg/kg) and apomorphine (0.1 mg/kg). As expected, after 6-OHDA lesions S(+)-amphetamine as well as apomorphine markedly induced rotations ipsiversive or contraversive, respectively, to the lesion, and dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of the ipsilateral caudate-putamen and accumbens nucleus decreased. Although a decline in the dopamine/DOPAC ratio indicated an enhanced dopamine turnover, striatal monoamine oxidase (MAO) activity remained unchanged when tested in vitro. After a 2-MDTIQ lesion S(+)-amphetamine also caused animals to rotate strongly, ipsiversive to the lesion, but there was no response to apomorphine administration. This 2-MDTIQ effect was not due to a reduction in dopamine metabolism of the ipsilateral caudate-putamen or mesencephalic structures, or, for example, a partial neurodegeneration of dopaminergic neurons, since dopamine metabolites levels and MAO activity were nearly unchanged. Thus, we suggest that 2-MDTIQ interacts with the effect of S(+)-amphetamine and probably leads to an insensitivity of the dopamine uptake/transporter system to S(+)-amphetamine in dopaminergic nigrostriatal neurons. An effect of 2-MDTIQ on presynaptic membranes of dopaminergic synaptosomes has never been reported, but will be an objective of our further studies.     

Aging and haloperidol-induced dopamine turnover in the nigro-striatal pathway of C57BL/6J mice

The responsiveness of male C57BL/6J mice to acute haloperidol (2.5 mg/kg, IP) was studied throughout the average adult lifespan (4, 8, 12, 21, 28 months) by effects on dopamine (DA) turnover, as estimated by DA loss after α-methyl-p-tyrosine (AMPT). Previously, striatal receptors for spiroperidol (a related butyrophenone) decreased progressively after 3 months to a loss of 40% by 28 months [29]. Haloperidol treatment (2 hours) accelerated striatal DA turnover similarly in all age groups, by about 100%. The haloperidol-induced accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) was not significantly impaired in AMPT treated mice with age. These results suggest that the age-related loss of butyrophenone binding sites may not limit acute compensatory responses to blockade of the remaining sites by a large dose of haloperidol. Regional differences in DA metabolism were detected between the substantia nigra (cell bodies and dendrites) and striatum (axonal terminals). Dopamine turnover and DOPAC levels were less in striatum than in substantia nigra; each region had a characteristic DOPAC/DA ratio (nigra, 38%; striatum, 7%); and, DOPAC levels did not precisely covary with DA turnover between regions. The constancy of DOPAC/DA ratios in conrols and after AMPT treatment, in all ages suggests that a constant fraction of DA continued to be released and catabolized to DOPAC despite major decrease of DA after blockade of synthesis of DA.     

Isolation rearing of rats alters release of 5-hydroxytryptamine and dopamine in the frontal cortex: an in vivo electrochemical study

Summary The effects of rearing hooded Lister rats either in groups of seven or singly on 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the frontal cortex were investigated using in vivo voltammetry together with Nafion coated carbon fibre micro-electrodes. The selective detection of basal extracellular levels of 5-HT with this technique (Peak B) was confirmed with parallel experiments using intracranial microdialysis to measure 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in vivo. The DA voltammetric signal (Peak A) was observed in vivo only following pharmacological or electrical stimulation of DA release. Enhanced efflux of cortical DA and 5-HT in response to local application of KCl and that of 5-HT following parentelar fenfluramine were selectively detected by the association: differential pulse voltammetry (DPV) — Nafion coated microbiosensors, supporting the capability of this electrochemical method to selectively monitor release of these amine neurotransmitters in vivo and in situ. The locomotor behaviour data indicated that isolation rearing resulted in augmented locomotor activity in a novel environment. In addition, the in vivo voltammetric results showed that following KC1 or fenfluramine treatment cortical 5-HT release is prolonged while that of DA is increased in rats reared in isolation when compared with socially reared rats. This imbalance between extracellular levels of DA and 5-HT recorded in the frontal cortex of rats exposed to isolated housing conditions may contribute to the behavioural differences reported between isolation and group reared rats.Abbreviations 5-HT 5-hydroxytryptamine - DA dopamine - 5-HIAA 5-hydroxyindoleacetic acid - DPV differential pulse voltammetry - CFE carbon fibre micro-electrode - DOPAC dihydroxy phenilacetic acid - FC frontal cortex - MAO-I monoamine oxidase inhibitor     

Monoamine levels after pilocarpine-induced status epilepticus in hippocampus and frontal cortex of Wistar rats

Pilocarpine-induced status epilepticus (SE) is an useful model to study the involvement of neurotransmitter systems as epileptogenesis modulators. Some researches have shown that pharmacological manipulations in dopaminergic, serotonergic, and noradrenergic systems alter the occurrence of pilocarpine-induced SE. The control group was treated with 0.9% saline (control group, s.c.). Another group of rats received pilocarpine (400 mg/kg, s.c.) and both groups were sacrificed 24 h after the treatment. This work was performed to determine the alterations in monoamine levels (dopamine (DA), serotonin (5-HT) and norepinephrine (NE)) and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA)) after pilocarpine-induced SE in hippocampus and frontal cortex of adult rats. The monoamines and their metabolites were determined by reverse-phase high-performance liquid chromatography with electrochemical detection. DA and 5-HIAA concentrations were not altered in the hippocampus of the pilocarpine group, but in the same group the 5-HT (160%), DOPAC (316%) and HVA (21%) levels increased, whereas, the NE (47%) content declined. For the frontal cortex determinations, there was an increase of 20 and 72% in DA and DOPAC levels, respectively, and a decrease in NE (32%), 5-HT (33%) and 5-HIAA (19%) concentrations, but HVA content remained unaltered. These results indicate that pilocarpine-induced SE can alter monoamine levels in different ways depending on the brain area studied, suggesting that different mechanisms are involved.     

Alteration in hypothalamic monoamine metabolism of freely moving diabetic rat.

Changes in hypothalamic monoamine metabolism were investigated in freely moving streptozotocin (STZ)-induced diabetic rats by using in vivo microdialysis technique. Six weeks later, the animals were implanted with microdialysis probe (molecular weight cut-off index: 12,000-14,000) into the ventromedial portion of the hypothalamus (VMH). The dialysate was collected and loaded onto HPLC to be assayed for norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites (MHPG, DOPAC and 5-HIAA). The concentration of NE was decreased in the dialysate from the VMH of diabetic rats, whereas there was no significant change in MHPG level. The concentrations of 5-HT and 5-HIAA were reduced in diabetic rats. The DA concentration was obviously increased accompanied by the reduction of DOPAC level. The observed changes in hypothalamic monoamine metabolism, especially the reduced NE release, may play an important role in the induction of hyperphagia in freely moving STZ-induced diabetic rats.     

Monoaminc and metabolite levels in the cerebrospinal fluid of hibernating and euthermic marmots

SUMMARY  Cerebrospinal fluid from yellow-bellied marmots, Marmota flaviventris , was analysed for monoamine and monoamine metabolite content during euthermia and deep hibernation. Dopamine (DA) levels were decreased, while DA metabolite levels, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were dramatically increased in hibernating marmots. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels were also greatly enhanced during hibernation while norepinephrine (NE) levels were only moderately increased. These findings demonstrate that cerebrospinal monoamine levels are dynamically altered during hibernation, such that DA versus 5-HT and NE levels undergo opposite changes. Therefore, these data indicate that DA, 5-HT and NE neuronal systems are differentially altered during hibernation in mammals.     

Fate of the catecholamine stores in the rabbit carotid body superfused in vitro

In rabbit carotid bodies (CBs) superfused during 1–5 h, with an air-equilibrated medium containing no tyrosine (TYR), the dopamine (DA) content decreased by approximately 60% after 1 h and remained constant afterwards. TYR and 3,4-dihydroxyphenylacetic acid (DOPAC) decreased with the same time course. Noradrenaline (NA) content exhibited a biphasic decrease of lesser magnitude than that of DA. Superfusions with a TYR-containing medium did not prevent the reduction in DA and TYR. Large amounts of DA and DOPAC were recovered in the effluent during the first hour of superfusion but after 90 min the two substances had declined below the detection limits (i.e. 0.5 and 1 pmol/5 min, respectively). The DA efflux decreased exponentially during the first hour and was not altered by changing the oxygen partial pressure (PO₂) of the medium. The DOPAC efflux declined after 40 min of superfusion and was modulated byPO₂. The DA and the DOPAC effluxes were not suppressed by omitting calcium ions from the superfusing medium. In 4 cat CBs equal amounts of DA and NA were recovered from the effluent during the first hour of superfusion.     

Age-related changes in fear behavior and regional brain monoamines distribution in rats

Differences in fear level assessment based on the time of motionless in the illuminated compartment, time spent in light compartment, number of head dipping from dark to the illuminated compartment and number of returns from dark to the illuminated compartment registered in light/dark transitions test and brain monoamines (NA, DA, 5-HT) and their metabolites (MHPG, DOPAC, 5-HIAA) in the hypothalamus, midbrain, amygdala, hippocampus and pons were examined in 3, 12 and 24 months old Wistar rats. The lowest level of fear was registered in 12 months old rats, a slightly higher level in 3 months old rats and the highest in 24 months old rats. Locomotion activity showed a decreasing tendency within age according to a linear dependence in 3, 12 and 24 months old rats. Neurochemical data showed the decreased activity of NA system and increased activity of DA system in most structures already occurred in 12 months old rats. It remained at the same level in aged rats. The correlation analysis between the behavioral markers of fear level and distribution of monoamines in young, mature and aged rats showed diversified data, only some of them being consistent with the "serotonergic hypothesis" of fear/anxiety. Therefore, we cannot conclude what neurochemical background of fear is.     

Monoamine transmitter activity in lateral hypothalamus during its perfusion with insulin or 2-DG in sated and fasted rat

A unique profile of neurochemical events is proposed to occur in the diencephalon which is contingent upon the nutrient status of the animal. In this first of a series of investigations, we selected the lateral hypothalamus (LH) in order to determine its specific resting profile of monoaminergic neurotransmitters and their principal metabolites. The neuronal pattern of activity was studied during sated and fasted conditions as well as during a local glucoprivic challenge to the LH. After permanent guide cannulae for push-pull perfusion were implanted in female Sprague-Dawley rats, the LH was perfused repeatedly with an artificial CSF, at a rate of 20 microliters/min, in order to collect a series of 5.0 min samples. Aliquots of each perfusate were assayed directly using a high performance liquid chromatography system with electrochemical detection (HPLC-EC) for pg/microliter concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). In comparison to the basal levels of amines during the sated condition, when the rat was food-deprived for 20-22 hr, the release of NE, DA, and 5-HT was significantly lower than that observed under the sated condition. Further, the turnover of NE in the LH was concurrently attenuated as reflected by the lower levels of MHPG in the perfusate, thus demonstrating the modification in catecholamine activity produced in the LH by the condition of hunger. When either 10 micrograms/microliters 2-deoxy-D-glucose (2-DG) or 4.0 mU/microliter insulin was incorporated into the CSF perfused in the LH, the efflux of DA was significantly enhanced independent of the state of satiation. In addition, the proportion of both NE and DA to 5-HT was likewise increased by either of these centrally acting substances, while the turnover of 5-HT was enhanced and NE and DA turnovers were reduced. Perfusion of 2-DG in the LH of the fasted rat caused a significant reduction in catecholamine turnover in terms of MHPG/NE, VMA/NE, DOPAC/DA and HVA/DA ratios. Moreover, 2-DG increased NE/5-HT while lowering the NE/DA ratio, and enhanced simultaneously the 5-HTOL/5-HT ratio. In the sated rat, 2-DG attenuated the release of 5-HT from the animal's LH, whereas insulin caused a shift in the proportions of NE/5-HT and DA/5-HT. Further, the peptide served to reduced the efflux of 5-HT, enhanced the turnover of 5-HT while diminishing DA turnover, and shifted the metabolism of NE from MHPG to VMA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immunoregulatory role of neurotransmitters

The nervous and endocrine systems modulate the immune system functions through releasing neurotransmitters, neuropeptides and endocrine hormones as they regulate the other physiological functions. The immune system in turn communicates with the nervous and endocrine systems through secreting immunocompetent substances. In this report we review our concepts and evidence concerning the immunoregulatory role of acetylcholine (ACh) and monoamine neurotransmitters which include noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA). The immunoregulatory role comprises two aspects, the modulation of immune functions by neurotransmitters and the effect of the immune system on nervous system functions. The inhibition of ACh biosynthesis in the central nervous system (CNS) caused the enhancement of the humoral immune response of rats to sheep red blood cells (SRBC); by contrast, the inhibition of acetylcholinesterase (AChE) activity in the CNS resulted in the suppression of the immune response. It seems that ACh in the brain plays an immunoinhibitory role. The role can be blocked by atropine, a muscarinic antagonist, but not by hexamethonium, a nicotinic antagonist. During the humoral immune response (days 3–6 after SRBC injection), activity of AChE in the hypothalamus and hippocampus was strikingly lower. It is suggested that a functional connection is present in the ACh of the brain and the immune system. In vitro, ACh at 10⁻⁹ to 10⁻⁴ mol/l dose range significantly strengthened the spleen cell proliferation induced by concanavalin (Con A). The action of ACh only occurred either before or just after T lymphocytes were activated through muscarinic cholinergic receptors. In vivo, the depletion of monoamine neurotransmitters or only NA in the CNS caused the impairment of the anti-SRBC response of rats. During the phases of days 2–7 post-immunization, the metabolic alterations of NA, 5-HT and DA emerged in the CNS and the lymphoid organs of rats, which mainly exhibited that in the peak periods of the antibody response, the metabolism of the monoamine neurotransmitters in the hypothalamus and hippocampus was markedly increased, but NA content in the spleen and thymus was significantly decreased. These results provide evidence for the bidirectional information exchange network between the monoamine neurotransmitters and the immune system. Exposure to NA (at 10⁻⁸–10⁻⁵ mol/l concentration range) in vitro was shown to inhibit the Con A-induced proliferation of the rat spleen cells. This effect of NA was related to the early events involved in the initiation of T cell proliferation and was mediated by either alpha- or beta- adrenergic receptors. The evidence that altering 5-HT level in the central or peripheral nervous systems through various ways of administering the drugs to regulate 5-HT biosynthesis led to the variations of the antibody response, and that cyproheptadine, an antagonist of serotoninergic receptors, can block the action of 5-HT show that 5-HT may exert an immunoinhibitory effect, which appears to be mediated via the peripheral mechanism to relate to the 5-HT receptors. However, the antibody response can cause changes in 5-HT metabolism in the CNS. The possible reasons for these results are discussed. Collectively, the antibody response arouses the metabolic variations of ACh, NA, 5-HT and DA in the central and peripheral nervous systems and then, these alterations can in turn influence immune function through neurotransmitter relevant receptors present on the immunocytes. The purpose of this interaction is most likely to maintain the homeostasis of the immune and other physiological functions.     

Behavioral and neurochemical alterations evoked by p-Chlorophenylalanine application in rats examined in the light-dark crossing test

The aim of the present study is to examine the effects of serotonin synthesis inhibition with p-Chlorophenylalanine (p-CPA) in rats on (1) anxiety behavior examined in the light-dark crossing test and, (2) regional brain concentration of monoamines (NA, DA and 5-HT) and their metabolites (MHPG, DOPAC, HVA and 5-HIAA) as well as GABA in the hypothalamus, amygdala, hippocampus, midbrain central gray matter and the frontal cortex. Treatment of animals with p-CPA produced a significant increase in time out from the illuminated part of the chamber and in time of locomotor activity in the illuminated part of the chamber. HPLC analysis showed a significant reduction of 5-HT and 5-HIAA concentration in all examined brain regions with the exception of the frontal cortex. Additionally, a significant decrease in DA and its metabolites, DOPAC and HVA occurred in the hypothalamus and amygdala. Moreover, we observed a significant decrease in frontal cortex NA concentration after p-CPA administration. The results of our study suggest that administration of p-CPA is effective in reduction of anxiety through depletion of 5-HT accompanied by diminution of catecholamines, especially DA and its metabolites in the main emotional brain regions.