Brain Monoaminergic Systems Research Articles

Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain.

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 x 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity.

Melatonin attenuates methamphetamine‐induced toxic effects on dopamine and serotonin terminals in mouse brain

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 × 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity. Synapse 30:150–155, 1998. © 1998 Wiley-Liss, Inc. This article is a US government work and, as such, is in the public domain of the United States of America.

327 Brain monoaminergic system and adaptation of rat's circadian rhythm activity in changes of light: dark cycle

327 Brain monoaminergic system and adaptation of rat's circadian rhythm activity in changes of light: dark cycle

Superoxide radicals are mediators of the effects of methamphetamine on Zif268 (Egr-1, NGFI-A) in the brain: evidence from using CuZn superoxide dismutase transgenic mice

Administration of methamphetamine (METH) to mammals is known to cause deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. Acute administration of METH causes activation of immediate-early genes (IEGs) such as c- fos and Zif268 mRNA in rodent brains. However, the exact mechanisms involved in these changes have not been completely clarified. As a first step towards assessing a possible role for free radicals in METH-induced changes in IEGs, we have used CuZn superoxide dismutase (SOD) transgenic (Tg) mice and have quantified the effects of METH on c- fos and Zif268 mRNAs by in situ hybridization techniques. Mice were injected with 25 mg/kg of METH and sacrificed at various time points afterwards. There were significant METH-induced increases in both c- fos and Zif268 mRNAs in the frontal cortex and striatum of both strains of animals. Interestingly, the increases in Zif268 were markedly attenuated in the CuZn SOD-Tg mice; the increases in c- fos were also attenuated, but to a significantly lesser degree. These results indicate that superoxide radicals might play an important role in the activation of Zif268 after METH administration. Because IEGs are modulators of gene expression, these results also raise the possibility that oxidative mechanisms might be important factors in neuroadaptive changes caused by stimulant drugs.

The role of monoaminergic brain systems in the mechanisms of individual resistance to emotional stress

The role of monoaminergic brain systems in the mechanisms of individual resistance to emotional stress

Short- and Long-Term Memory Are Differentially Regulated by Monoaminergic Systems in the Rat Brain

Rats with cannulae implanted in the dorsal CA1 region of the hippocampus or in the entorhinal cortex (EC) were trained in one-trial step-down inhibitory avoidance and tested 1.5 or 24 h later, in order to measure short-term memory (STM) and long-term memory (LTM) respectively. Several drugs infused immediately post-training inhibited STM without altering LTM: the D1 receptor agonist SKF38393 (7.5 μg) given into either CA1 or EC, the β blocker timolol (0.3 μg) given into EC, the 5HT1A receptor agonist 8-HO-DPAT (2.5 μg) given into CA1, and the 5HT1A antagonist NAN-190 (2.5 μg) given into EC. These findings indicate that STM is not a necessary step toward LTM. Intraentorhinal 8-HO-DPAT enhanced STM and depressed LTM. The D1 antagonist SCH23390 (0.5 μg) enhanced STM without affecting LTM when given into CA1, and blocked LTM without affecting STM when given into EC. Intraentorhinal norepinephrine (0.3 μg) enhanced both STM and LTM, and the same drug when given into CA1 enhanced LTM selectively. None of the drugs had any effect on retrieval of either STM or LTM when given prior to testing. The data indicate that STM and LTM are differentially modulated by D1, β, and 5HT1A receptors in CA1 and EC.

Synthetic derivative of tuftsin recovers cognitive functions disturbed by antenatal hypoxia

Intraperitoneal injection of synthetic derivate of tuftsin in a dose 300 μg/kg to animals exposed to antenatal hypoxia recovers directed attention and processes of learning and normalizes emotional behavior and the balance between the activities of brain monoaminergic systems. The peptide can be used for compensation of behavioral disorders caused by antenatal hypoxia.

Methamphetamine-induced serotonin neurotoxicity is attenuated in p53-knockout mice

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. The tumor suppressor gene, p53, is thought to play an important role in cell death. In the present study, we have assessed the participation of p53 in METH-induced serotonergic neurotoxicity, by using the mice lacking the gene for p53 protein. Three dosages (2.5, 5.0 and 10.0 mg/kg×4) of METH were administered to wild-type (p53 +/+), heterozygous (p53 +/−) and homozygous (p53 −/−) p53-knockout mice. The two lower doses caused no significant changes in serotonin (5-HT) transporters in any of the groups. The highest dose (10.0 mg/kg) caused significant decreases in striatal 5-HT transporters in wild-type (−31%) and heterozygous (−18%) mice. In contrast, 5-HT transporters were not significantly decreased in homozygous mice. These results suggest that the tumor suppressor, p53, plays an important role in METH-induced serotonergic neurotoxicity in mice brain. These data provide further evidence for a role of p53 in the neurotoxic effects of METH.

Role of serotonin in fish immunomodulation

In the recent past, the importance of the fish brain monoaminergic system in aggression, mating and feeding has been documented. There are several apparent similarities between the functioning of the fish and mammalian monoaminergic systems. In fish, the hypermetabolism of catecholamines (norepinephrine and dopamine) and indoleamine (serotonin, 5-hydroxytryptamine, 5-HT) has been found to be associated with stressful conditions. In contrast to the situation in mammals, these monoamines can pass through the blood­brain barrier in teleost fishes, contributing to the high levels of biogenic amines in the periphery. Hence, high levels of serotonin in the peripheral circulation, during different stressful conditions, may influence the functioning of other physiological systems, notably the immune system. Serotonin is also stored in considerable amounts by mast cells and platelets, and can be synthetized by chromaffin cells. In mammals, it has been established that 5-HT modulates immune function at a variety of levels. However, little is known about the role of serotonin in the functioning of the immune system in fish. In this perspective article, we will discuss our results and the findings of other laboratories, although meagre on this subject, on the possible role of serotonin in the functioning of immunocompetent cells in fish.

Monoamine transporter gene expression in the central nervous system in diabetes mellitus.

Diabetic animals exhibit altered neurotransmission in brain monoaminergic systems. By means of in situ hybridization, we have investigated the expression of dopamine, noradrenaline, and serotonin transporter (DA-T, NA-T, and 5-HT-T, respectively) mRNAs in the brains of alloxan- and streptozotocin-diabetic rats. The expression of DA-T mRNA is decreased in 1- (-11%) and 4- (-17%) week alloxan-diabetic and 4- (-9%) and 8- (-20%) week streptozotocin-diabetic rats in the ventral medial bundle. The expression of NA-T mRNA is decreased in the locus coeruleus of 8- (-26%) week streptozotocin-diabetic rats, in the noradrenergic A1 cell group of 4- (-27%) week alloxan- and 8- (-25%) week streptozotocin-diabetic rats, and in the noradrenergic A2 cell group of 1- (-21%) and 4- (-28%) week alloxan-diabetic and 4- (-27%) and 8- (-25%) week streptozotocin-diabetic animals. The expression of 5-HT-T mRNA in the dorsal raphe nucleus is increased in 1- (+14%) and 4- (+44%) week alloxan- and 4- (+28%) and 8- (+44%) week streptozotocin-diabetic rats. The expression of each of the three monoamine transporter genes may be differentially regulated in diabetes and dependent on the duration of diabetes. Altered monoamine transporter gene expression may possibly contribute to the observed dysfunctions in brain monoamine transmission in chronic diabetes.

Amantadine in the treatment of neuroleptic-induced obesity in rats: behavioral, endocrine and neurochemical correlates.

The efficacy of the antiviral agent Amantadine (AM, 5-100 mg/kg/sc, ip or intrahypothalamically, 12.5-100 micrograms bilaterally) in influencing body weight and food intake in drug-free rats, and in preventing neuroleptic-induced weight gain, was assessed in adult female rats. In drug-free rats, acute administration of systemic AM or directly injected in the lateral hypothalamus (LH) displayed a significant dose-dependent anorectic effect (p < 0.001). This effect could be mediated by the brain monoaminergic system, because systemic or local injections of AM increased dopamine and serotonin overflow in the nucleus accumbens and in the LH. Chronic administration of AM significantly decreased body weight gain in drug-free rats only at the dose of 100 mg/kg/sc. Similarly, obesity induced by the neuroleptic drug sulpiride (SUL, 20 mg/kg/ip for 21 days) was prevented by AM only at the dose of 100 mg/kg. AM did not prevent SUL-induced hyperprolactinemia, disruption of the vaginal cycle and a decrement in the weight of the uterus and ovaries at any dosage. This lack of efficacy of AM contrasts with that of bromocriptine, which completely prevented SUL-induced weight gain and hyperprolactinemia. The results show that despite a potent acute anorectic effect, AM displays a weak antagonistic action on SUL-induced obesity in rats, in contrast to the preliminary results obtained in humans. As AM metabolism differs in humans and rats, additional research is needed before its systematic testing in counteracting neuroleptic-induced obesity in patients with mental disorders.

Effect of social rank on brain monoaminergic activity in a cichlid fish.

In Haplochromis burtoni, an African cichlid fish, male sexual maturation is regulated via social interactions, and these effects are mediated by gonadotropin-releasing-hormone (GnRH)-containing neurons in the preoptic area of the brain. Since brain monoaminergic systems are known to be involved in the regulation of GnRH release, and the activity of these systems is influenced by agonistic interactions, we analyzed the effect of social status on brain monoaminergic activity in H. burtoni. Animals were either (1) in normal social groups consisting of two males and four females or (2) in groups of one male and five females. Quantitative behavioral observations were made on each group of animals and, following sacrifice several physiological measurements were made. Concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA, the main 5-HT metabolite) and tryptophan (TRP, the amino acid precursor of 5-HT), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC, the main DA metabolite) were measured. The 5-HIAA/5-HT and DOPAC/DA ratios were calculated and used as indexes of 5-HT and DA activity, respectively. In addition, the gonadosomatic index was calculated from body and gonadal weights and used as an index of reproductive status. Concentrations of 5-HIAA as well as 5-HIAA/5-HT ratios were significantly higher in the brainstem of non-territorial males than in that of territorial males, and similar trends were seen in the telencephalon and hypothalamus. Moreover, TRP concentrations in the telencephalon and brainstem were significantly lower in non-territorial males. In this species, sexual maturation in females is not socially regulated, and there was no significant correlation between measured antagonistic behavior and biochemical indices. These results suggest a fundamental difference in the neurochemical responses between male and female H. burtoni.

Effect of neonatal thyroid hormone alterations on CNS ethanol sensitivity in adult LS and SS mice

LS and SS mice develop their differential sensitivity to the motor-incoordinating and hypothermic effects of ethanol at 10–16 days after birth, when thyroid hormones (T 4) show a transient peak. This rise in thyroid hormones is an important element in the normal development of monoaminergic systems and thyroid hormones reach a significantly higher level in the less ethanol-sensitive SS mice than in the more ethanol-sensitive LS mice. Previous investigations have suggested the differential ethanol response of brain monoaminergic neuronal systems in adult LS and SS mice may be related to this development difference in thyroid status. To test the hypothesis that neonatal thyroid status can influence adult. CNS ethanol sensitivity, LS and SS mice were treated neonatally with thyrotropin-releasing hormone (TRH) and propylthiouracil (PTU) to enhance of diminish, respectively, thyroid status at this critical developmental period. The subsequent effect on adult CNS ethanol sensitivity was then determined. Contrary to expectations, both PTU and TRH administration attenuated the transient rise in plasma T 4 levels at postnatal days 10–16 in LS mice and in both instances this was associated with decreased CNS ethanol sensitivity (sleep time and hypothermia) in adults. In SS mice, PTU treatment attenuated the postnatal rise in T 4 levels as expected, whereas TRH treatment had no significant effect. However, neither neonatal treatment altered CNS ethanol sensitivity in adult SS mice. The decrease in ethanol-induced sleep times and hypothermia of neonatally treated LS mice was associated with an attenuation of ethanol-induced decreases in in vivo tyrosine and tryptophan hydroxylase activity that was not seen in the SS mice. These findings are consistent with the notion that the response of monoaminergic neuronal systems to ethanol is an important determinant of behavioral intoxication. However, the observation that neonatal administration of both TRH and PTU blunted the postnatal rise in thyroid levels in LS mice, yet both treatments resulted in a decrease in adult ethanol sensitivity in LS mice, that the relationship between postnatal thyroid development and CNS ethanol sensitivity is more complex than originally hypothesized.

Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals

Methamphetamine (METH) causes deleterious effects in brain monoaminergic systems. Evidence has accumulated to suggest that these effects may be mediated via the overproduction of the superoxide radicals. We have recently shown that METH-induced dopamine (DA) depletion is attenuated in copper-zinc superoxide dismutase (CuZnSOD) transgenic (Tg) mice. In the present study, we have used receptor autoradiographic studies of [ 125I]RTI-55 labeled serotonin (5-HT) uptake sites to evaluate the effect of a two dosing schedule (5 mg/kg or 10 mg/kg×4) of METH on striatal 5-HT uptake sites in nontransgenic (Non-Tg), heterozygous (Hetero) and homozygous (Homo) SOD-Tg mice. The low dose caused no significant changes in striatal 5-HT uptake sites in any of the groups. The high dose caused marked decreases (−74%) in striatal 5-HT uptake sites in Non-Tg mice. In contrast, 5-HT uptake sites showed only a 31% decrease in homozygous SOD-Tg mice whereas heterozygous SOD-Tg mice showed 63% depletion. These results show that increased SOD activity can protect against METH-induced neurotoxicity in striatal serotonergic terminals. These data provide further evidence for a role of oxidative stress in the neurotoxic effects of METH.

Psychoemotional stress and brain monoaminergic systems

Psychoemotional stress and brain monoaminergic systems

Alterations of lidocaine and pentylenetetrazol-induced convulsions by manipulation of brain monoamines.

The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.

Neonatal desipramine treatment alters free-running circadian drinking rhythms in rats

Neonatal treatment with monoamine reuptake inhibitors results in a constellation of neurobehavioral alterations in adult rats that may model human depression. Since alterations in circadian rhythmicity have been reported in both depressed patients and in animal depression models, the present study examined the effects of neonatal desipramine treatment (5.0 mg/kg SC from postnatal day 7 through 22) on free-running circadian drinking rhythms. Rhythmicity was examined in constant darkness (DD), constant light (LL), and during adult desipramine treatment (0.25 mg/ml via the drinking water). Compared with saline-treated controls, neonatal desipramine lengthened free-running period in DD, blunted the period-altering effect of LL, and potentiated the period-altering effect of adult desipramine treatment. Neonatal desipramine treatment also increased circadian amplitude and spectral magnitude, but did not modify the effects of light or adult desipramine on these parameters. These results provide further evidence that behavioral depression is associated with alterations in circadian rhythmicity, and are consistent with the hypothesis that such relationships are mediated by brain monoaminergic systems.

Changes in extracellular PVN monoamines and macronutrient intake after idazoxan or fluoxetine injection

Norepinephrine (NE) and serotonin (5-HT) in the paraventricular nucleus (PVN) have opposite effects on feeding, with NE stimulating carbohydrate intake through α 2 noradrenergic receptors and 5-HT inhibiting carbohydrate intake. This study examined the action of drugs that affect brain monoaminergic systems, in terms of their impact on nutrient intake and on PVN monoamines measured using microdialysis. The drugs studied were idazoxan, a blocker of α 2 receptors, or fluoxetine, a 5-HT reuptake blocker. In rats maintained on pure macronutrient diets, idazoxan (1 mg/kg) and fluoxetine (10 mg/kg), 120 min after injection both reduced total food intake, and specifically carbohydrate intake. In dialysis experiments, successive 20-min dialysate samples were taken, three samples before and seven samples after intraperitoneal injection of idazoxan (5 and 20 mg/kg), fluoxetine (10 mg/kg), or vehicle. Idazoxan increased NE, homovanillic acid, and hihydroxyphenylacetic acid in the PVN. Fluoxetine induced a significant increment of 5-HT in PVN, while producing a smaller increase in NE, dopamine, and homovanillic acid. These results support the conclusion that the impact of these drugs on macronutrient intake may be a consequence of their action on endogenous monoamine systems in the PVN. Thus, in this nucleus, the blockade of α 2-noradrenergic receptors, like stimulation of 5-HT receptors, attenuates normal ingestion of carbohydrate.

A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs

A human vesicular monoamine transporter cDNA has been identified by screening a human brainstem library using sequences from the rat brain synaptic vesicle monoamine transporter (SVMT) [(1992) Cell 70, 539-551; (1992) Proc. Natl. Acad. Sci. USA 89, 10993-10997]. The hSVMT shares 92% amino acid identity with the rat sequence, but displays one less consensus site for asparagine N-linked glycosylation and one more consensus site for phosphorylation by protein kinase C. The human SVMT gene maps to chromosome 10q25 using Southern blotting analysis of human/rodent hybrid cell lines and fluorescent in situ hybridization approaches. The cDNA, and a subclone, recognize TaqI polymorphisms that may prove useful to assess this gene's involvement in neuropsychiatric disorders involving monoaminergic brain systems.

Neurotoxicity of an MPTP analogue, 2'CH3-MPTP, on monoaminergic systems in the mouse brain.

Neurotoxicity of an MPTP analogue, 2'CH3-MPTP, on monoaminergic systems in the mouse brain.