DA), 3,4-dihydroxyphenylacetic Acid Levels Research Articles

Disturbance of neurotransmitter metabolism in drug-naïve, first-episode major depressive disorder: a comparative study on adult and adolescent cohorts.

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.

Effect of the 5-HT2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study.

The effects triggered by serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of a neurochemical database on monoamines obtained after the intraperitoneal administration of the preferential 5-HT2C receptor agonist WAY-163909 (0.3 and 3 mg/kg) in 29 distinct rat brain regions. We focused on the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the index of the turnovers 5-HIAA/5-HT and DOPAC/DA. WAY-163909 increased and decreased 5-HIAA tissue levels in the amygdala and dorsolateral orbitofrontal cortex, respectively, and decreased the 5-HT turnover in the infralimbic cortex. It enhanced HVA levels in the medial orbitofrontal cortex and DOPAC levels in the amygdala. WAY-163909 increased and decreased DA turnover in the medial orbitofrontal cortex and the anterior insular cortex, respectively. The correlative analysis of the turnovers between pairs of brain regions revealed low levels of correlations across the brain but presented a distinct pattern of correlations after WAY-163909 was compared to saline-treated rats. WAY-163909, notably at 0.3 mg/kg, favored cortico-cortical and cortico-subcortical correlations of both turnovers separately, and frontal DOPAC/DA ratio with cortical and subcortical 5-HIAA/5-HT ratios at 3 mg/kg. In conclusion, the qualitative, but not the quantitative analysis shows that WAY-163909 alters the pattern of correlations across the brain, which could account for its multiple behavioral influences.

Inhibition of microRNA-200a Upregulates the Expression of Striatal Dopamine Receptor D2 to Repress Apoptosis of Striatum via the cAMP/PKA Signaling Pathway in Rats with Parkinson’s Disease

Parkinson's disease (PD) is a neurodegenerative movement disease with a high annual incidence. Accumulating evidence demonstrates that microRNAs play important roles in the pathogenesis of multiple neurological disorders, including PD. This study aims to investigate how microRNA-200a (miR-200a) regulates striatal dopamine receptor D2 (DRD2) to affect apoptosis of striatum in rats with PD and to explore the associated mechanism. After successfully establishing a PD model by 6-hydroxydopamine injections, PD rats were mainly treated with miR-200a mimics, inhibitors, Forskolin or a combination of miR-200a inhibitors and Forskolin. High-performance liquid chromatography-electrochemical detection (HPLC-ECD) was employed to detect the levels of dopamine, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and chemistry colorimetric methods were applied to detect the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). A TUNEL assay and immunocytochemical staining were performed to observe apoptosis and tyrosine hydroxylase (TH)-positive cells in the striatum. The expression of miR-200a, DRD2, Bad, Bax, Bcl-2, cAMP and PKA was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot assays. In the cellular experiments, after transfection with the inhibitor of miR-200a, decreased levels of Bax, GSH-Px, SOD, dopamine, DOPAC and HVA but increased levels of MDA and Bcl-2 were found along with a reduced apoptosis rate and increased TH-positive cell number. In addition, downregulating miR-200a resulted in lower expression of AKT, cAMP and PKA but higher expression of DRD2 and CREB, indicating that the downregulation of miR-200a increases DRD2 expression, which blocks the cAMP/PKA signaling pathway. This study provides evidence that the inhibition of miR-200a can repress apoptosis in the striatum via inhibition of the cAMP/PKA signaling pathway by upregulating DRD2 expression in PD rats.

β-asarone and levodopa co-administration increase striatal dopamine level in 6-hydroxydopamine induced rats by modulating P-glycoprotein and tight junction proteins at the blood-brain barrier and promoting levodopa into the brain.

Levodopa (L-dopa) is widely considered as one of the most effective drug constituents in the treatment of Parkinson's disease (PD), but the blood-brain barrier (BBB) permeability of L-dopa is <5%, which causes low efficacy. Neuroprotective effects of β-asarone on 6-hydroxydopamine (6-OHDA)-induced PD rats were demonstrated by our previous studies. Co-administration of β-asarone and L-dopa has not been explored until being investigated on PD rats in this study. PD rats were divided into four groups: untreated, L-dopa-treated, β-asarone-treated and co-administered-treated groups. All of the treatments were administered to the rats twice per day for 30days. The L-dopa, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), S100β and neuron-specific enolase (NSE) levels were subsequently determined. The P-glycoprotein (P-gp), zonula occludens-1 (ZO-1), claudin-5, occludin and actin expression was also assessed in cortex. Changes in BBB ultrastructure were observed using transmission electron microscopy. Our results showed that the co-administered treatment increased levels of L-dopa, DA, DOPAC and HVA in striatum, and S100β in plasma, but down-regulated NSE, P-gp, ZO-1, occludin, actin and claudin-5 in cortex. Crevices were observed between capillary endothelial cells at intercellular tight junction of the striatum in co-administered-treated group, while the endothelial cells in untreated group were tightly jointing each other. In addition, the correlations of L-dopa or DA and P-gp or tight junction proteins respectively were significantly negative in co-administered- and β-asarone-treated groups. These findings suggest that co-administered treatment may enhance the L-dopa BBB permeability and attenuate brain injury, which may be beneficial to PD treatment.

Methylglyoxal increases dopamine level and leads to oxidative stress in SH-SY5Y cells.

More and more studies have suggested that methylglyoxal (MGO) induced by type-2 diabetes is related to Parkinson's disease (PD). However, little is known about the molecular mechanism. In this study, we explored the MGO toxicity in neuroblastoma SH-SY5Y cells. Neurotoxicity of MGO was measured by mitochondrial membrane potential, malondialdehyde, and methylthiazoletetrazolium assays. The levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and 1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (salsolinol) were detected by liquid chromatography-mass spectrometry/mass spectrometry. The expressions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) were detected by reverse transcriptase polymerase chain reaction and western blot analysis. The results showed that MGO induced an increase in TH and DAT expressions in SH-SY5Y neuroblastoma cells, while the levels of dopamine, DOPAC, and endogenous neurotoxin salsolinol also increased. Aminoguanidine (AG) is an inhibitor of MGO. It was found that AG could decrease the reactive oxygen species (ROS) level induced by MGO, but could not inhibit an increase of TH, DAT and dopamine. The increase of dopamine, DOPAC and salsolinol levels could lead to high ROS and mitochondrial damage. This study suggests that ROS caused by dopamine could contribute to the damage of dopaminergic neurons when MGO is increased during the course of diabetes.

Counteraction by Nitric Oxide Synthase Inhibitor of Neurochemical Alterations of Dopaminergic System in 6-OHDA-Lesioned Rats Under l-DOPA Treatment

Nitric oxide synthase inhibitors reduce L-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, 2005) 4-dihydroxyphenylalanine (L-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3weeks, rats were treated during 21days with L-DOPA/benserazide (30mg/kg/7.5mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before L-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. L-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. L-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of L-DOPA-induced dyskinesia with potential utilization of nitric oxide synthase inhibitors for treatment.

Selenium partially reverses the depletion of striatal dopamine and its metabolites in MPTP-treated C57BL mice

Oxidative stress and inflammation have been implicated in idiopathic Parkinson's disease as well as in the mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Selenium possesses both antioxidant and anti-inflammatory properties; thus we studied the effect of selenium supplementation on MPTP-induced dopaminergic neurotoxicity in mice. C57BL male mice were treated with MPTP (30mg/kg, i.p.), daily for 4 days. Sodium selenite (Se) was administered in the doses of 0, 1, 2 and 3mg/kg, 30min prior to the administration of MPTP. One group of animals served as control (saline only) and another group as Se alone (3mg/kg). The animals were sacrificed at 24h after the last dose of MPTP. The striata were isolated and analyzed for dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Administration of MPTP significantly depleted striatal DA (6.78±0.80μg/g) as compared to control animals (19.32±0.77μg/g) which was significantly prevented by co-treatment with 3mg/kg dose of Se (12.28±0.97μg/g). MPTP caused significant reduction in striatal DOPAC but the decrease in HVA levels was not significant. Although Se dose-dependently reversed MPTP-induced decreases in DOPAC and HVA levels, these effects were statistically not significant. These findings indicate a significant impairment of dopaminergic neurotransmission by MPTP which is partially reversed by Se treatment.

Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson's disease model mouse

Ethnopharmacological relevance Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine, used over 4000 years in India, shown to have effect on neural growth and locomotor function. Although catecholamines and oxidative stress resulting in neurodegeneration and locomotor disorder are the main events in Parkinson's disease (PD), efficacy of the drug on these molecules and physiological abnormality are not clear. Aim of the study The objective of the study was to examine effect of Ws on catecholamines and physiological abnormalities seen in PD using PD model mouse. Materials and methods Mouse were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days to show biochemical and physiological abnormalities similar to patients with PD. PD mice were treated with Ws 100 mg/kg body weight for 7 or 28 days. Catecholamines: dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA); antioxidants: glutathione (GSH) and glutathione peroxidase (GPx); and lipid peroxidation marker (TBARS) were analyzed in the Ws treated and untreated PD mouse striatum. Results Mouse treated with MPTP showed reduced levels of DA, DOPAC, HVA, GSH and GPx and induced thiobarbituric acid reactive substance (TBARS) level compared to the control. Physiological abnormalities were seen in the mouse as determined by hang test and rotarod test. Oral treatment of PD mouse Ws root extract (100 mg/kg body weight) for 7 days or 28 days increased DA, DOPAC and HVA levels and normalized TBARS levels in the corpus striatum of the PD mouse. The 7 days Ws treated mice showed improved motor function as determined by hang test and rotarod test. Treatment with Ws for 28 days increased GSH and GPx levels in the striatum compared to the Ws untreated PD mouse striatum. Conclusion These data suggest that Ws is a potential drug in treating catecholamines, oxidative damage and physiological abnormalities seen in the PD mouse.

Alteration of Brain Neurotransmitters in Female Rat Offspring Induced by Prenatal Administration of 16 and 64 mg/kg of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153)

PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl), a non-coplanar PCB and the congener most widely distributed in the environment, was orally administered to pregnant Sprague-Dawley (Crj: CD (SD) IGS) rats from gestation day 10 through 16 at doses of 0 (control), 16 and 64 mg/kg body weight. Female pups were sacrificed at 1, 3, 6, and 9 wk, and at 1 yr of age to evaluate the differences in brain neurotransmitters and their metabolites between PCB153-exposed and control groups. Brain levels of norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), acetylcholine (ACh), and choline (Ch) in discrete brain regions or in whole brain were measured. At 1 to 3 wk after birth, brain levels of DA, DOPAC, HVA, 5HT and 5HIAA in PCB-exposed groups were higher than those of the control group. At 9 wk after birth, DA turnover was reduced in half of the four brain areas examined (forebrain and hindbrain), and 5HIAA levels were increased in all brain areas in the PCB-treated group compared to those of the control group. At 1 yr after birth, the levels of DA, DOPAC, and HVA in the hippocampus, hypothalamus, and medulla oblongata were lower in the PCB-exposed groups than in the control group. Prenatal exposure to PCB153 stimulated the turnover of 5HT neurons in the brain of female offspring at early stages (1 to 9 wk) of development. On the other hand, the turnover of DA neurons in the PCB-exposed groups was reduced in late stages (9 wk to 1 yr) of development compared with that of the control group. The brain neurotransmitters of dams treated with PCB were assayed at 3 wk after delivery (15 wk old), and decreases in DA, DOPAC, and HVA were observed. PCB153 reduced the activity of DA neurons in the brain of dams. These results are discussed in relation to health effects observed in humans exposed to PCBs.

Comparison of the Effects of Deramciclane, Ritanserin and Buspirone on Extracellular Dopamine and Its Metabolites in Striatum and Nucleus Accumbens of Freely Moving Rats

In the present study, we assessed the effect of single graded doses of a putative anxiolytic compound, the 5-HT(2A/C )antagonist, deramciclane fumarate (EGIS-3886), on the dopamine efflux and metabolism in nucleus accumbens and striatum and thus evaluated the dose window for deramciclane to cause adverse effects related to the brain dopaminergic system. Dual probe in vivo microdialysis in freely moving rats was used to compare the effects of graded doses of deramciclane fumarate (3, 10 and 30 mg/kg), 5-HT(2A/C )antagonist ritanserin (1 mg/kg) and a partial 5-HT(1A) agonist buspirone hydrochloride (5 mg/kg) on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens and striatum assayed by high performance liquid chromatography with electrochemical detection. The indirect dopamine agonist, D-amphetamine sulfate (2 mg/kg), was used as a positive control. Ritanserin, buspirone and deramciclane 3 and 10 mg/kg had no significant effects on the extracellular dopamine levels in either brain area but deramciclane 30 mg/kg significantly increased accumbal dopamine as well as DOPAC and HVA in both brain areas. As expected, the positive control D-amphetamine significantly increased both striatal and accumbal dopamine levels. The effects of buspirone or the highest deramciclane dose and D-amphetamine on DOPAC and HVA levels were opposite; buspirone and deramciclane increased while D-amphetamine decreased the metabolite levels in both brain areas. The results indicate that a single high dose of deramciclane has the neuroleptic- or buspirone-like effect, particularly in mesolimbic regions. There is at least a 5-fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat.

Echinacoside prevents the striatal extracellular levels of monoamine neurotransmitters from diminution in 6-hydroxydopamine lesion rats

We investigated the effects of echinacoside, a phenylethanoid glycoside isolated and purified from the stems of Cistanche salsa, a Chinese herbal medicine, on the striatal extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in 6-hydroxydopamine (6-OHDA) lesion rats. Seven days after 6-OHDA was injected into the right striatum of rats, the striatal extracellular levels of DA, DOPAC and HVA fell significantly ( P < 0.01 vs. vehicle), as demonstrated by the method of cerebral microdialysis and high performance liquid chromatography with electrochemical detection. However, simultaneous treatment with echinacoside (7.0, 3.5 mg/kg) attenuated the diminution of them ( P < 0.01 vs. model). The results implied that echinacoside could protect the striatal dopaminergic neurons from injury induced by 6-OHDA and may be useful in the prevention and treatment of Parkinson's disease (PD).

Association between the levels of biogenic amines and superoxide anion production in brain regions of rats after subchronic exposure to TCDD

The effects of TCDD on the distribution of biogenic amines and production of superoxide anion (SA) in different brain regions of rats have been studied after subchronic exposure. Groups of females Sprague–Dawley rats were administered daily dose of 46 ng TCDD/(kg day) (treated groups), or the vehicle used to dissolve TCDD (control group), for 90 days. The rats were sacrificed at the end of the exposure period and their brains were dissected into different regions including, hippocampus (H), cerebral cortex (Cc), cerebellum (C), and brain stem (Bs). The levels of different biogenic amines and some of their metabolites, including, norepinephrine (NE), dopamine (DA), 3,4-dihydroxy phenyl acetic acid (DOPAC), 4-hydroxy-3-methoxy-phenyl acetic acid (HVA), 5-hydroxy tryptamine (5-HT), and 5-hydroxy indole 3-acetic acid (5-HIAA), were determined in those brain regions, using a high performance liquid chromatography (HPLC) system with an electrochemical detector. SA production was also determined in those regions, using the cytochrome c reduction method. Results of analyses indicate significant increases in the levels of DA, NE and DOPAC in H, NE and HVA in Cc, NE and DA in Bs and NE in C. SA production was significantly increased in H and Cc, but not in Bs or C. The results also indicated strong correlations between DA and DOPAC, and SA and NE in all of the brain regions, and also between SA and 5-HT/HIAA in H and Cc. These results may indicate the contribution of biogenic amines, especially NE and 5-HT/HIAA to SA overproduction in some brain regions and may also indicate the potential of long term neurotoxic effects of those biogenic amines, in response to subchronic exposure to TCDD.

Novel dopamine releasing response of an anti-convulsant agent with possible anti-Parkinson's activity.

We used cerebral microdialysis to assess the ability of the anticonvulsant drug Zonisamide (ZNS) to release striatal dopamine in 6-hydroxydopamine nigrotomized rats. Following exogeneously administered ZNS we measured dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in striatal dialysates obtained from the ipsilateral side of the nigrotomy. ZNS administration alone had no effect on levels of DA and its metabolites or rotational behavior. Administration of carbidopa-levodopa alone led to small but insignificant increases in rotational behavior contralateral to the side of the nigrotomy but no corresponding increases in indices of striatal catecholamine release. In contrast, if animals were preloaded with carbidopa and ZNS was co-administered with levodopa 30 minutes later significant increases in contralateral rotational behavior occurred within 20 minutes of ZNS-levodopa injection that lasted for at least 90 minutes. In contrast to the uniform rotational behavioral responses observed in all our nigrotomized animals, less than half demonstrated neurochemical evidence of DA release. In these "responder" animals DOPAC levels increased 300% following carbidopa-levodopa-ZNS administration. We conclude that these results support previously reported findings and provide additional evidence that the anticonvulsant ZNS appears to possess anti-Parkinson's properties. ZNS could therefore be a novel agent for the treatment of PD that could delay the use of or reduce the amount of levodopa needed to treat patients with PD.

Pineal melatonin and brain transmitter monoamines in CBA mice during chronic oral nicotine administration

The effects of chronic oral nicotine administration on the pineal melatonin and brain transmitter monoamines were studied in male CBA mice, which possess a clear daily rhythm of melatonin secretion. On the 50th day of nicotine administration, pineal melatonin as well as cerebral dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined at various times. The chronic nicotine treatment did not alter the timing of the pineal melatonin peak, which occurred at 10 h after the light offset. However, in mice drinking nicotine solution, the nocturnal pineal melatonin levels were lower than in control mice drinking tap water. The chronic nicotine treatment increased the striatal DA, DOPAC, HVA and 5-HIAA levels, the hypothalamic NE, MHPG and 5-HIAA and the cortical MHPG. Most prominent effects of nicotine were found at 8 h after the light offset, when the striatal levels of DA and HVA, hypothalamic NE and MHPG as well as cortical MHPG were significantly elevated in the nicotine-treated mice compared with the control mice. No direct correlation between nicotine’s effects on brain transmitter monoamines and on pineal melatonin levels was apparent. The results suggest that chronic nicotine treatment slightly suppresses the melatonin production but does not alter the daily rhythm of pineal melatonin in mice maintained on a light–dark cycle. However, the results indicate that nicotinic receptors might be involved in the regulation of pineal function.

Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice

The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na + channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease.

Neuroprotective effect of riluzole in MPTP-treated mice

The neuroprotective effects of riluzole, a Na + channel blocker with antiglutamatergic activity, and MK-801, a blocker of N-methyl- d-aspartate (NMDA) receptors, were compared in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed 1, 3 and 7 days after the treatment. Dopamine and DOPAC levels were significantly decreased in the striatum from 1 day after MPTP treatment. A severe depletion in dopamine and DOPAC levels was found in the striatum 3 and 7 days after MPTP treatment. Riluzole antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. On the other hand, MK-801 prevented the MPTP-induced decrease in DOPAC levels, but not in dopamine levels in the striatum. An immunohistochemical study indicated that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.

BIA 3-202, a novel catechol- O-methyltransferase inhibitor, enhances the availability of l-DOPA to the brain and reduces its O-methylation

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202) is a new long-acting catechol- O-methyltransferase (COMT) inhibitor with limited access to the brain. The present study evaluated the interference of BIA 3-202 upon levels of l-3,4-dihydroxyphenylalanine ( l-DOPA) and metabolites in plasma (3- O-methyl- l-DOPA) and brain [3- O-methyl- l-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with l-DOPA (20 mg/kg) plus benserazide (30 mg/kg). At different time points (1, 3 and 6 h) after the administration of BIA 3-202 (0, 3, 10 and 30 mg/kg) or l-DOPA plus benserazide, rats were sacrificed and the right striatum was quickly dissected out and stored for the assay of l-DOPA, 3- O-methyl- l-DOPA, dopamine and amine metabolites. Levels of l-DOPA, 3- O-methyl- l-DOPA, dopamine, DOPAC and HVA in the striatum in l-DOPA plus benserazide-treated rats were higher than in vehicle-treated rats. However, this increase in striatal l-DOPA, dopamine, DOPAC and HVA was, in a dose- and time-dependent manner, even higher ( P<0.05) in rats given BIA 3-202 (3, 10 and 30 mg/kg). This effect was accompanied by a marked decrease in 3- O-methyl- l-DOPA levels in the striatum of l-DOPA plus benserazide-treated rats. Increases in levels of l-DOPA and decreases in 3- O-methyl- l-DOPA levels in plasma also accompanied the administration of BIA 3-202. BIA 3-202 did not significantly affect levels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concluded that administration of BIA 3-202 enhances the availability of l-DOPA to the brain by reducing its O-methylation in the periphery, which may prove beneficial in parkinsonian patients treated with l-DOPA plus an aromatic amino acid decarboxylase inhibitor.

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.

The potent, selective mGlu2/3 receptor agonist LY379268 increases extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid in the medial prefrontal cortex of the freely moving rat.

Previous work has shown that the potent, selective metabotropic glutamate mGlu2/3 receptor agonist LY379268 acts like the atypical antipsychotic clozapine in behavioral assays. To investigate further the potential antipsychotic actions of this agent, we examined the effects of LY379268 using microdialysis in awake, freely moving rats, on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) in rat medial prefrontal cortex. Systemic LY379268 increased extracellular levels of dopamine, DOPAC, HVA, and 5-HIAA in a dose-dependent, somewhat delayed manner. LY379268 (3 mg/kg s.c. ) increased levels of dopamine, DOPAC, HVA, and 5-HIAA to 168, 170, 169, and 151% of basal, respectively. Clozapine (10 mg/kg) also increased dopamine, DOPAC, and HVA levels, with increases of 255, 262, and 173%, respectively, but was without effect on extracellular 5-HIAA levels by 3 mg/kg LY379268 were reversed by the selective mGlu2/3 receptor antagonist LY341495 (1 mg/kg). Furthermore, LY379268 (3 mg/kg)-evoked increases in DOPAC and HVA were partially blocked and the increase in 5-HIAA was completely blocked by local application of 3 microM tetrodotoxin. Therefore, we have demonstrated that mGlu2/3 receptor agonists activate dopaminergic and serotonergic brain pathways previously associated with the action of atypical antipsychotics such as clozapine and other psychiatric agents.

In vivo effects of the putative cognitive enhancer KA-672.HCl in comparison with 8-hydroxy-2-(DI- N-propylamino) tetralin and haloperidol on dopamine, 3,4-dihydroxypheny-lacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions

1. 1. KA-672.HC1 (7-methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-dimethyl-2 H-1-benzopyran-2-one hydrochloride), designed as a cognitive enhancer, has been investigated through behavioural and binding studies. However, little is known about its biochemical effects on the dopaminergic and serotoninergic system in vivo. 2. 2. In the present study the authors investigated the effects of KA-672.HCl (0. l mg/kg and 1 mg/kg) 8-hydroxy-2-(di- N-propylamino) tetralin (8-OH-DPAT) (1 mg/kg), haloperidol (0.1 mg/kg) and a mixture of haloperidol and 8-OH-DPAT on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, in striatum and cerebral cortex of rats. 3. 3. Male Wistar rats received an intraperitoneal injection of the drugs or vehicle 1 hour before striatal and cortical brain tissues were dissected out for neurochemical analysis. 4. 4. KA-672.HC1, 8-OH-DPAT and haloperidol significantly reduced striatal DA levels, whereas only KA-672.HC1 significantly reduced cortical DA levels. 8-OH-DPAT and haloperidol induced a significant increase in cortical DOPAC levels but only haloperidol significantly elevated the striatal DOPAC content. In contrast, only the higher dose of KA-672.HCl elevated striatal DOPAC levels. Furthermore, KA-672.HCl significantly reduced striatal 5-HT levels and slightly elevated striatal 5-HIAA concentrations. 8-OH-DPAT significantly decreased striatal 5-HIAA levels. All substances were able to enhance the cortical and striatal DA turnover. 5. 5. The cortical and striatal 5-HT turnover was significantly decreased following 8-OH-DPAT treatment and significantly increased in the striatum after haloperidol and KA-672.HCl treatment. 6. 6. The data suggest that KA-672.HCl possesses D 2 antagonistic as well as 5-HT 1A agonistic properties. However, additional mechanisms of actions by interaction with other neurotransmitter systems Such as acetylcholine, excitatory or inhibitory amino acids need to be determined.