Dihydroxyphenylacetic Acid Levels Research Articles

Neurochemical Effects of Methylphenidate and Modafinil in Ameliorating Stress-Induced Cognitive Deficits.

Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory and attention. Stimulant effects can be visualized in terms of increased cognitive abilities through enhancement of dopamine (DA) release. This study examined cognitive responses and brain DA and 5-hydroxytryptamine (5HT) levels after prolonged methylphenidate (MPH) and modafinil administration, to demonstrate their effect on stress-induced cognitive deficits in rats. Effects on cognition were evaluated by passive avoidance and water maze tests. Furthermore brain levels of DA, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5HT and 5-hydroxyindoleacetic acid (5HIAA) were analyzed by high-performance liquid chromatography coupled with electrochemical detection. We found that both MPH and modafinil improved cognition in both restrained and unrestrained rats, as examined through water maze and passive avoidance tests. Furthermore, these substance were associated with increased brain DA and 5-HT levels. Notabily, we observed decrease in DOPAC and HVA levels, while 5-HIAA levels exhibited a slight increase. The prevention of stress-induced cognitive deficits by MPH and modafinil could be elucidated through the interaction between 5HT and DA in regulating cognitive function.

Analysis of Targeted Therapy of Parkinson’s Disease with Coloaded Nanoparticles

The key to the treatment of Parkinson’s disease (PD) is delivering an effective amount of drugs into the brain to work, and supplementing the missing dopamine (Dop) in the brain is still the most effective treatment currently. In this research, borneol (Bor) was utilized to promote the drug to enter the brain through the nasal cavity, and lactoferrin (Lf) was utilized as the targeting molecule to modify the nanoparticles (NPs) so that they entered the brain and focused on the lesion site of PD to achieve targeting. They were then evaluated in vivo and in vitro, thus providing the basis for the development of the Lac-Bor/Dop NPs in PD therapy. In the experiment, the particle size of Lac-Bor/Dop NPs prepared by the optimal prescription process was 163.7±15.6 nm, the Dop drug loading was (7.86±1.68) %, and the Zeta potential was (−21.36±3.34) mV. The in vitro release confirmed that the Lac-Bor/Dop NPs had good sustained release characteristics in PBS medium. The cytotoxicity and uptake experiments confirmed that the cytotoxicity of Dop encapsulated in NPs was markedly inferior to that of free Dop (P <0.05). For SH-SY5Y cells and 16HBE cells, Bor and Lf co-modified NPs can promote cell uptake. In vivo animal imaging counts confirmed that the coloaded NPs were capable of synergistic nasal drug delivery to the brain for better brain targeting. Furthermore, a PD model induced by dopaminergic neuron injury induced by unilateral striatal injection of 6-OHDA was constructed in rats and assigned into various groups to demonstrate the therapeutic effect of NPs on PD rats. The results revealed that relative to other groups, the contralateral rotations of rats in the Lac-Bor/Dop NP group were decreased drastically after 20 days of administration (P <0.01), and the levels of Dop and dihydroxyphenylacetic acid (DOPAC) in the injured striatum were increased markedly (P <0.01), demonstrating that the delivery system could achieve excellent PD therapy effects after nasal administration.

ЭФФЕКТЫ ВОЗДЕЙСТВИЯ ХРОНИЧЕСКОЙ АЛКОГОЛИЗАЦИИ И ГИПОДИНАМИИ НА ПОКАЗАТЕЛИ ДОФАМИНЕРГИЧЕСКОЙ СИСТЕМЫ НЕКОТОРЫХ ОТДЕЛОВ ГОЛОВНОГО МОЗГА КРЫС

Purpose of work. To determine the nature of changes in the content of dopamine and its metabolites in the cerebral cortex, hypothalamus and cerebellum of rats with chronic alcohol intoxication (CAI) against the background of physical inactivity (PI). Material and methods. The experiments were carried out on outbred white male rats weighing 180-220 g. Modeling of PI was carried out by placing rats in individual cages-pencil cases, limiting their mobility, for periods of 14 and 28 days. To simulate CAI, the animals were provided with an ethanol solution as the only source of fluid for 14 and 28 days. Determination of the content of the components of the dopaminergic system (tyrosine, 3,4-dioxyphenylalanine, dopamine, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and norepinephrine) was carried out using ion-pair high-performance liquid chromatography. Results. PI for 14 days is accompanied by signs of activation of the dopaminergic system in the hypothalamus and cerebral cortex of rats. With CAI for a period of 28 days, there are signs of a decrease in the activity of the dopaminergic system in the cerebral cortex. The combined effect of PI and CAI for 14 and 28 days leads to an increase in dopamine turnover in the cerebral cortex of rats. Conclusions. With the combined effect of CAI and PI, the most pronounced changes are observed in the cerebral cortex and are accompanied on the 14th day by an increase in the levels of HVA and DOPAC, and on the 28th day by an increase in the concentration of HVA.

Barbigerone Potentially Alleviates Rotenone-Activated Parkinson's Disease in a Rodent Model by Reducing Oxidative Stress and Neuroinflammatory Cytokines.

Parkinson's disease (PD) is a common age-related and slowly progressive neurodegenerative disease that affects approximately 1% of the elderly population. In recent years, phytocomponents have aroused considerable interest in the research for PD treatment as they provide a plethora of active compounds including antioxidant and anti-inflammatory compounds. Herein, we aimed to investigate the anti-Parkinson's effect of barbigerone, a natural pyranoisoflavone possessing antioxidant activity in a rotenone-induced rat model of PD. To evaluate antioxidant activity, a 0.5 mg/kg dose of rotenone was injected subcutaneously into rats. Barbigerone (10 and 20 mg/kg) was administered to rats for 28 days 1 h prior to rotenone. All behavioral parameters were assessed before sacrificing the rats. On the 29th day, all of the rats were humanely killed and assessed for biochemical changes in antioxidant enzymes (superoxide dismutase, glutathione, malondialdehyde, and catalase), neurotransmitter levels (dopamine, 5-hydroxyindoleacetic acid, serotonin, dihydroxyphenylacetic acid, and homovanillic acid levels), and neuroinflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor-α, nuclear factor kappa B, and IL-6]. The data presented in this study has shown that barbigerone attenuated rotenone-induced motor deficits including the rotarod test, catalepsy, akinesia, and open-field test. Additionally, barbigerone has shown improvements in the biochemical and neuroinflammatory parameters in the rotenone-induced rat model of PD. The results demonstrated that barbigerone exhibits antioxidant and anti-inflammatory actions via reducing oxidative stress and inflammatory cytokines. Altogether, these findings suggest that barbigerone could potentially be utilized as a therapeutic agent against PD.

MiR-30c-5p/ATG5 Axis Regulates the Progression of Parkinson's Disease.

Serum miR-30c-5p correlates with Parkinson’s disease (PD), yet its role has not been illustrated. This research analyzed the function of miR-30c-5p in PD. The behavioral evaluation was performed on MPTP-treated PD mice transfected with miR-30c-5p agomiR, antagomiR, siATG5, or 3-MA (an autophagy inhibitor). Oxidative stress-related factors, miR-30c-5p, and apoptosis- and autophagy-associated proteins in brain tissues or cells were determined by molecular experiments. Tyrosine hydroxylase (TH) and dopamine metabolic markers were detected using immunofluorescence and Diode Array Detector (DAD), respectively. Effects of miR-30c-5p and its target gene Autophagy-related gene (ATG) 5 protein (ATG5) on MPP+-treated SH-SY5Y cells were determined through a series of molecular experiments. MiR-30c-5p was upregulated but ATG5 was downregulated in PD mice. MiR-30c-5p antagomiR attenuated the decrease of ATG5 in PD mice. MiR-30c-5p antagomiR partly alleviated the behavioral symptoms and inhibited the increases of malondialdehyde (MDA), catalase (CAT), and SOD in PD mice. The levels of Bcl-2, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), TH, and LC3 II were downregulated in PD mice, while Bax, cleaved caspase-3, P62, and LC3 I were upregulated. However, miR-30c-5p antagomiR partly reversed the levels of these factors in PD mice. 3-MA could block the effects of miR-30c-5p antagomiR on PD mice. MiR-30c-5p antagomiR attenuated apoptosis and induced autophagy in brain tissues of MPTP-treated mice by targeting ATG5. In vitro assay results also showed that silence of ATG5 reduced the protective effect of miR-30c-5p downregulation on the cells. MiR-30c-5p regulates the progression of Parkinson’s disease through attenuating ATG5-inhibited apoptosis and -induced autophagy.

Effects of biperiden (cholinergic muscarinic m1/m4 receptor antagonist) on ethanol conditioned place preference in mice

BackgroundPrevious studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AimsWe examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. MethodsThirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. ResultsBiperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. ConclusionsOur results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.

Metal brain bioaccumulation and neurobehavioral effects on the wild rodent Liomys irroratus inhabiting mine tailing areas.

Ecotoxicological studies are necessary in order to evaluate the effects of environmental exposure of chemicals on wild animals and their ecological consequences. Particularly, neurobehavioral effects of heavy metal elements on wild rodents have been scarcely investigated. In the present study, we analyzed the effect of metal bioaccumulation (Pb, As, Mg, Ni, and Zn) in the brain and in the liver on exploratory activity, learning, memory, and on some dopaminergic markers in the wild rodent Liomys irroratus living inside mine tailings, at Huautla, Morelos, Mexico. We found higher Pb concentration but lower Zn in striatum, nucleus accumbens, midbrain, and hippocampus in exposed animals in comparison to rodents from the reference site. Exposed rodents exhibited anxious behavior evaluated in the open field, while no alterations in learning were found. However, they displayed slight changes in the memory test in comparison to reference group. The neurochemical evaluation showed higher levels of dopamine and 5-hydroxyindolacetic acid in midbrain, while lower levels of metabolites dihydroxyphenyl acetic acid and homovanillic acid in striatum of exposed rodents. In addition, mRNA expression levels of dopaminergic D2 receptors in nucleus accumbens were lower in animals from the mining zone than in animals from the reference zone. This is the first study that shows that chronic environmental exposure to metals results in behavioral and neurochemical alterations in the wild rodent L. irroratus, a fact that may comprise the survival of the individuals resulting in long-term effects at the population level. Finally, we suggest the use of L. irroratus as a sentinel species for environmental biomonitoring of mining sites.

Lactoferrin Coupled Lower Generation PAMAM Dendrimers for Brain Targeted Delivery of Memantine in Aluminum-Chloride-Induced Alzheimer's Disease in Mice.

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf).Releaseprofile of MEMfrom MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague-Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy ratsdid not result in any significant changes. The in vivo study in an AlCl3-induced Alzheimer's (AD) mice model showed a significant improvement in behavioral responses. Optical density, which reflects the acetylcholinesterase (AChE) activity, was highest in the AL group 0.16 ± 0.01 (higher than the CON group, 0.09 ± 0.02; p < 0.05). No significant suppression of AChE activity was recorded in all the other treated groups. Similarly, the DOPAmine and 3,4 dihydroxyphenylacetic acid (DOPAC) levels were unaffected by the developed formulations. The study reported improved brain bioavailability of MEM in AlCl3-induced Alzheimer's mice leading to improved memory, with the resultant mechanism behind in a descriptive manner. This study is among the preliminary studies reporting the memory improvement aspect ofPAMAM-Lf conjugates for MEM in AlCl3-AD induced mice. The formulation developed was beneficial in AD-induced mice and had a significant impact on the memory aspects.

Role of glucocorticoids on noradrenergic and dopaminergic neurotransmission within the basolateral amygdala and dentate gyrus during morphine withdrawal place aversion.

Aversive memories related to drug withdrawal can generate a motivational state leading to compulsive drug taking. However, the mechanisms underlying the generation of these withdrawal memories remain unclear. Limbic structures, such as the basolateral amygdala (BLA) and the dentate gyrus (DG) of the hippocampus, play a crucial role in the negative affective component of morphine withdrawal. Given the prominent role of glucocorticoids (GCs), noradrenaline (NA), and dopamine (DA) in memory-related processes, in the present study, we employed the conditioned place aversion (CPA) paradigm to uncover the role of GCs on NA and DA neurotransmission within the BLA and NA neurotransmission within the DG during opiate-withdrawal conditioning (memory formation consolidation), and after reexposure to the conditioned environment (memory retrieval). We observed that adrenalectomy impaired naloxone-induced CPA. Memory retrieval was associated with an increase in dihydroxyphenylacetic acid (DOPAC) levels in the BLA in morphine-addicted animals in a GC-independent manner. Importantly, NA turnover was related with the expression of withdrawal physical signs during the conditioning phase and with locomotor activity during the test phase. On the other hand, reduced DA concentration in the BLA was correlated with the CPA score. Our results indicate that while noradrenergic system is more associated with the somatic consequences of withdrawal, dopaminergic neurotransmission modulates the affective state. Nevertheless, it seems necessary that both systems work together with GCs to enable aversive-memory formation and recall.

Plasma catecholamine levels in the early stages of treatment-naïve Parkinson’s disease

Rationale: Parkinson's disease (PD) is a neurodegenerative disorder with predominant involvement of catecholamine-producing neurons of the central and peripheral nervous system. Taking into account the relative availability and low costs of plasma catecholamine measurements, it is worthwhile to study these parameters as biomarkers of the early stages of PD.Aim: To determinate whether plasma levels of dopamine (DA), norepinephrine (NE), L-3,4-dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) in patients with early stages of PD are related with akinetic-rigid and tremor-dominant variants and to compare the results to healthy volunteers.Materials and methods: This was an observational cross-sectional cohort study performed from 2012 to 2015. The main study group included unselected outpatients who attended the Republican Consultative and Diagnostic Center of Movement Disorders and Botulinotherapy (Kazan, Russia) with newly diagnosed early PD (Hoehn and Yahr stages I and II, 1967), of various ages and both genders, who had not been given any specific antiparkinsonian treatment. The control group included healthy volunteers with no clinical signs of PD (they could have other chronic diseases of the non-extrapyramidal origin). Plasma catecholamine levels were measured by gas liquid chromatography.Results: One hundred and thirty (130) treatment-naïve patients with newly diagnosed PD (mean age 59.34 ± 8.42 years, male gender 45.38%) were enrolled into the main study group. The control group included 56 healthy volunteers matched for age and gender. The distribution of various PD forms and stages was as follows: PD tremor-dominant variant 56.9%, PD akinetic-rigid variant 43.1%; PD stage I 76.9%, PD stage II 23.1%. Irrespective of the variant and stage, the PD patients demonstrated decreased NE levels, compared to the controls (95% confidence intervals 124–216 and 248–428 pg/mL, respectively, р &lt; 0.026). DOPA plasma level was reduced only in the patients with akinetic-rigid PD variant (р = 0.017), while DOPAC level in the patients with PD stage II (р = 0.008). The average DA:NE:DOPA:DOPAC ratio was 1:32:105:64 in the control group, 1:62:238:88 in the patients with PD tremor-dominant variant (the difference is significant for NE and DOPA, р &lt; 0.05), and 1:29:96:32 in those with PD akinetic-rigid variant (p &gt; 0.05). In the healthy controls the changes in DOPA levels account for 84% of the DA and NE variability; no correlation between DOPAC and other catecholamines was found. On the contrary, in the PD patients regardless of the stage and the disease variant, DOPAC levels directly correlated with DA (p &lt; 0.04). The PD tremor-dominant variant patients demonstrated a direct correlation between plasma NE and DOPA levels (p &lt; 0.05).Conclusion: The results obtained on absolute and relative parameters catecholamine turnover in the patients with early PD stages support the hypothesis on different pathophysiology of the tremor-dominant and akinetic-rigid variants of PD.

L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat

We previously found that L-tyrosine (L-TYR) but not D-TYR administered by reverse dialysis elevated catecholamine synthesis in vivo in medial prefrontal cortex (MPFC) and striatum of the rat (Brodnik et al., 2012). We now report L-TYR effects on extracellular levels of catecholamines and their metabolites. In MPFC, reverse dialysis of L-TYR elevated in vivo levels of dihydroxyphenylacetic acid (DOPAC) (L-TYR 250–1000 μM), homovanillic acid (HVA) (L-TYR 1000 μM) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (L-TYR 500–1000 μM). In striatum L-TYR 250 μM elevated DOPAC. We also examined L-TYR effects on extracellular dopamine (DA) and norepinephrine (NE) levels during two 30 min pulses (P2 and P1) of K+ (37.5 mM) separated by t = 2.0 h. L-TYR significantly elevated the ratio P2/P1 for DA (L-TYR 125 μM) and NE (L-TYR 125–250 μM) in MPFC but lowered P2/P1 for DA (L-TYR 250 μM) in striatum. Finally, we measured DA levels in brain slices using ex-vivo voltammetry. Perfusion with L-TYR (12.5–50 μM) dose-dependently elevated stimulated DA levels in striatum. In all the above studies, D-TYR had no effect. We conclude that acute increases within the physiological range of L-TYR levels can increase catecholamine metabolism and efflux in MPFC and striatum. Chronically, such repeated increases in L-TYR availability could induce adaptive changes in catecholamine transmission while amplifying the metabolic cost of catecholamine synthesis and degradation. This has implications for neuropsychiatric conditions in which neurotoxicity and/or disordered L-TYR transport have been implicated.

Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: effect of l-DOPA treatment and changes in levodopa-induced dyskinesia.

Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n=8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n=6), or not receiving l-DOPA (PD-N, n=7) as well as non-PD controls (n=16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2h after oral intake of l-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l-DOPA (ii) higher dopamine (DA) levels in PD-LID as compared to controls (iii) higher DA/l-DOPA and lower DOPAC/DA ratio's in PD-LID as compared to PD-L and (iv) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of l-DOPA-treated PD patients may help identify patients at risk of developing LID.

Time course study of microglial and behavioral alterations induced by 6-hydroxydopamine in rats

Understanding the mechanisms responsible for nonmotor manifestations of Parkinson's disease (PD) is crucial in the search for new therapeutic approaches. The aim of the present study was to evaluate the time course of behavioral, neurochemical, and microglial responses after a retrograde partial lesion of the nigrostriatal pathway induced by bilateral injection of 6-hydroxydopamine (6-OHDA). The results showed that 6-OHDA was able to produce both anhedonic and anxiety behaviors; however, an increase of microglial density in some brain areas (substantia nigra, hippocampus and striatum) and deficits in locomotor activity was observed only one week after the lesion. Striatal levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were reduced by approximately 60% at all times tested. Conversely, increased levels of serotonin (5-HT) and its metabolite were also noted in the striatum only at the first week. These data extend our previous findings and suggest that the retrograde and partial damage of dopaminergic neurons in the substantia nigra can induce effects resembling premotor symptoms of PD, two and three weeks after injury.

Sex differences in monoamines following amphetamine and social reward in adolescent rats.

Interaction with social peers may increase rates of drug self-administration, but a recent study from our laboratory showed that social interaction may serve as a type of alternative reward that competes with drug taking in adolescent male rats. Based on those previous results, the current study examined sex differences in preference for social interaction compared with amphetamine (AMPH) in adolescent rats using the conditioned place preference (CPP) paradigm. Similar to previous results with males, females showed AMPH CPP regardless of whether they were individual- or pair-housed. In contrast to males, however, females failed to show social CPP, and they did not prefer a peer-associated compartment over an AMPH-associated compartment in a free-choice test. In separate experiments, dopamine (DA) and serotonin (5-HT) metabolite levels were measured in adolescent males and females that were exposed acutely to peer interaction, no peer interaction, AMPH, or saline. In amygdala, levels of the DA metabolite dihydroxyphenylacetic acid (DOPAC) were altered more in response to peer interaction in males than females; in contrast, there was a greater amygdala DOPAC response to AMPH in females. Furthermore, there were greater changes in the 5-HT metabolite hydroxyindoleacetic acid (5-HIAA) in females than in males following social interaction. These results indicate that the ability of peer interactions to reduce drug reward is greater in adolescent males than females, perhaps due to a greater ability of social cues to activate limbic reward mechanisms in males or a greater ability of AMPH cues to activate limbic reward mechanisms in females.

Dopamine Responsiveness in the Nucl. Accumbens Shell and Parameters of the Heroin-Influenced Conditioned Place Preference in Rats

Previous evidence demonstrated that drug-induced extracellular dopamine (DA) concentrations in the nucl. accumbens shell (AcbSh) might underlie different vulnerabilities to heroin addiction in inbred mice strains. We investigated a potential role of the responsiveness of the DA system in the AcbSh with respect to the vulnerability to heroin-influenced conditioned place preference (CPP) in rats. Animals were randomly assigned to the heroin and saline (control) groups. Heroin-group rats were then reclassified into two groups according to the degree of heroin-induced CPP, high preference (HP) and low-preference (LP) ones. The levels of extracellular DA and dihydroxyphenyl acetic acid (DOPAC) were estimated dynamically by in vivo microdialysis. Compared with the saline group, extracellular DA and DOPAC concentrations in the heroin-treated groups were significantly higher 30 min after the last injection, but the DA level decreased sharply in these groups on days 1 and 3 and became lower than that of the saline group. Compared with LP-group rats, HP-rats displayed a higher heroin-induced increase in the DA concentration 30 min after the last heroin injection and higher DOPAC and DOPAC/DA ratios 14 days after such injection. These results suggest that differences in the DA system responsiveness in the AcbSh may determine individual differences in vulnerability to heroin addiction.

Comparative studies on behavioral neurochemical effects of N,α-diethylphenethylamine and methamphetamine in rats

One objective was to compare the psychostimulating effects of N,α-diethylphenethylamine (NADEP) with those of methamphetamine (METH) in experiments on behavioral activities of rats. Another objective was to compare concentrations of neurotransmitters dopamine (DA), serotonin (5-HT), and their metabolites such as dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in brain tissues (striatum and frontal cortex) carried out after administration of NADEP and METH in rats. The animals were treated with NADEP and METH for 6 consecutive days (5 mg/kg per day, respectively), and the scores of stereotypy were measured on the first, second, fourth, and sixth day. The increase of the stereotypy score was observed in the NADEP-treated group, but it was less than that after treatment with METH. NADEP administration (5 and 10 mg/kg) resulted in a significant increase of DA and 5-HT and a decrease of DOPAC and HVA in the striatum tissues, which were collected 1 h after administration, but the changes of the compounds were less than those after treatment with METH (5 mg/kg). Unlike the METH-treated group, the changed DA, 5-HT, DOPAC, and HVA levels of the NADEP- treated group (5 and 10 mg/kg) were soon recovered within 6 h after administration. Both NADEP and METH had no significant effect on the 5-HIAA concentrations of the brain tissues. These results suggest that NADEP has significant psychostimulatory effects, though the effects were less than those of METH. Thus, NADEP should be carefully monitored to avoid abuse as a psychoactive drug.

A potential target for the treatment of Parkinson's disease: effect of lateral habenula lesions.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is caused predominantly by the degeneration of the nigrostriatal dopaminergic pathway. Lateral habenula (LHb) has efferent projections that terminate in the substantia nigra pars compacta (SNpc) and electrical stimulation of the LHb effectively suppresses the activity of dopamine-containing neurons in the SNpc. This study was aimed to investigate whether LHb lesions can ameliorate the syndromes of PD via affecting the activities of SNpc neurons in 6-hydroxydopamine (6-OHDA)-induced PD model rats. Concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, which is the area projected by the SNpc dopaminergic neurons were assayed by high-performance liquid chromatography (HPLC) coupled with fluorescence detection. The immunohistochemical method was applied to detect the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra. The results showed that LHb lesions induced a significant reduction in apomorphine-induced rotational behavior. The DA, DOPAC and HVA levels in the striatum of PD model rats were increased by the LHb lesions. Therefore, we speculate that the LHb lesions induced a significant amelioration in motor disorders via increasing the DA levels in the striatum, which may lead to a potential therapeutic strategy for the treatment of PD.

Effects of ultrafine diesel exhaust particles on oxidative stress generation and dopamine metabolism in PC-12 cells

A major constituent of urban air pollution is diesel exhaust, a complex mixture of gases, chemicals, and particles. Recent evidence suggests that exposure to air pollution can increase the risk of a fatal stroke, cause cerebrovascular damage, and induce neuroinflammation and oxidative stress that may trigger neurodegenerative diseases, such as Parkinson's disease. The specific aim of this study was to determine whether ultrafine diesel exhaust particles (DEPs), the particle component of exhaust from diesel engines, can induce oxidative stress and effect dopamine metabolism in PC-12 cells. After 24h exposure to DEPs of 200nm or smaller, cell viability, ROS and nitric oxide (NO2) generation, and levels of dopamine (DA) and its metabolites, (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)), were evaluated. Results indicated cell viability was not significantly changed by DEP exposure. However, ROS showed dramatic dose-dependent changes after DEP exposure (2.4 fold increase compared to control at 200μg/mL). NO2 levels were also dose-dependently increased after DEP exposure. Although not in a dose-dependent manner, upon DEP exposure, intracellular DA levels were increased while DOPAC and HVA levels decreased when compared to control. Results suggest that ultrafine DEPs lead to dopamine accumulation in the cytoplasm of PC-12 cells, possibly contributing to ROS formation. Further studies are warranted to elucidate this mechanism.

Zhichan decoction induces differentiation of dopaminergic neurons in Parkinson's disease rats after neural stem cell transplantation.

The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson's disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite (dihydroxyphenylacetic acid and homovanillic acid) content in the midbrain of Parkinson's disease rats was increased after neural stem cell transplantation + Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation + Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson's disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons.

Influences of Intrauterine Ethanol on the Maturation of the Monoaminergic Systems in the Developing Rat Brain

The aim of the present work was to conduct a simultaneous study of the levels of the major transmitters of the brain monoaminergic system, their metabolites, catechol-O-methyltransferase (COMT) activity, and the state of different dopamine receptor subtypes (D1 ,D 2L ,D 2S ,D 4, and D5) in the developing brains of the offspring of maternal rats alcoholized during pregnancy and lactation. Alcoholization of rats during pregnancy decreased the activities of the brain monoaminergic systems, which was manifest as decreases in the noradrenaline and dopamine (DA) levels in alcoholized fetuses, along with decreases in mRNA for the catecholamine-metabolizing enzyme COMT in forebrain structures on day 17 but not on day 13 of prenatal development. There were parallel increases in the contents of mRNA for the long and short splice variants of the type D2 dopamine receptor. During the postnatal period (days 4, 10, and 17), there was a further reduction in the activity of the DA system, and particularly reductions in the dihydroxyphenylacetic acid (DHPAA) level and the DHPAA/DA ratio in rat pups whose mothers had consumed alcohol during pregnancy but transferred to water after birth of their offspring. The activity of the serotonin system during the postnatal period of development in alcoholized rat pups was also decreased, which was apparent at the earliest stages of postnatal development (day 4 of life). Measures of serotonin metabolism then normalized. Thus, the activity of the serotonin system showed greater changes at the early periods of postnatal development (day 4), while suppression of the activity of the DA system was more marked at later stages (day 10 of life).