Increased DA Levels Research Articles

Behavioral and neurochemical interactions of the tricyclic antidepressant drug desipramine with L-DOPA in 6-OHDA-lesioned rats. Implications for motor and psychiatric functions in Parkinson’s disease

RationaleThe pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson’s disease under chronic L-DOPA therapy are insufficiently explored.ObjectivesThe aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion.MethodsThe antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method.ResultsDesipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus.ConclusionsThe performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson’s disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.

Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster

BackgroundDopamine (DA) is a neurotransmitter that plays roles in movement, cognition, attention, and reward responses, and deficient DA signaling is associated with the progression of a number of neurological diseases, such as Parkinson’s disease. Due to its critical functions, DA expression levels in the brain are tightly controlled, with one important and rate-limiting step in its biosynthetic pathway being catalyzed by tyrosine hydroxylase (TH), an enzyme that uses iron ion (Fe2+) as a cofactor. A role for metal ions has additionally been associated with the etiology of Parkinson’s disease. However, the way dopamine synthesis is regulated in vivo or whether regulation of metal ion levels is a component of DA synthesis is not fully understood. Here, we analyze the role of Catsup, the Drosophila ortholog of the mammalian zinc transporter SLC39A7 (ZIP7), in regulating dopamine levels.ResultsWe found that Catsup is a functional zinc transporter that regulates intracellular zinc distribution between the ER/Golgi and the cytosol. Loss-of-function of Catsup leads to increased DA levels, and we showed that the increased dopamine production is due to a reduction in zinc levels in the cytosol. Zinc ion (Zn2+) negatively regulates dopamine synthesis through direct inhibition of TH activity, by antagonizing Fe2+ binding to TH, thus rendering the enzyme ineffective or non-functional.ConclusionsOur findings uncovered a previously unknown mechanism underlying the control of cellular dopamine expression, with normal levels of dopamine synthesis being maintained through a balance between Fe2+ and Zn2+ ions. The findings also provide support for metal modulation as a possible therapeutic strategy in the treatment of Parkinson’s disease and other dopamine-related diseases.

Risk-taking, locomotor activity and dopamine levels in the nucleus accumbens and medial prefrontal cortex in male rats treated prenatally with alcohol

BackgroundPrenatal alcohol exposure (PA) restricted to days 8–20 of rat gestation reduces the activity of the dopaminergic neurons (DA) in the ventral tegmental area (VTA). Hyperactivity and impulsivity have been observed under this treatment; however, it is unknown whether DA levels are affected. Decision-making in risk situations, meanwhile, has been associated with impulsive behavior, but because studies of this phenomenon in animal models are limited, we do not yet know whether PA has any effect. The present study investigated the effects of PA on risk-taking behavior and locomotor activity in pre-pubertal male rats. In addition, DA levels in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) in response to methylphenidate (MP) were assessed. MethodsDams were treated with either two daily 3.0-g/kg doses of alcohol or an isocaloric solution, from days 8–20 of gestation. Locomotor activity and risk-taking in pre-pubertal male rats after PA, and DA levels in the NAcc and mPFC after a single dose of MP (5mg/kg), were analyzed. ResultsHyperactivity and increased risk-taking behavior were observed in the rats treated prenatally with alcohol compared to controls. Methylphenidate increased DA levels in the NAcc regardless of prenatal treatment, but significantly higher DA levels were found in the PA group regardless of postnatal treatment with saline or MP. ConclusionThe presence of hyperactivity and increased risk-taking behavior after prenatal alcohol treatment is supported. Results suggest that higher DA levels in the rats with PA could be due to a down-regulation of postsynaptic receptors, the desensitization of presynaptic receptors, or a compensatory over-activity of DA neurons in the VTA.

Putative role of monoamines in the antidepressant-like mechanism induced by striatal MT2 blockade

It has been observed that the secretion pattern of melatonin is modified in Parkinson's disease (PD). Hence, it is hypothesized that dysregulations of melatonin MT2 receptors may be involved in the installation of depression in PD patients. Together with recent evidence based on the use of the intranigral rotenone model of PD, have led to the hypothesis that modulating the striatal MT2 receptor could provide a more comprehensive understanding of the antidepressant properties triggered. To further investigate this issue, male Wistar rats were infused with intranigral rotenone (12μg/μL) and seven days later subjected to a rapid eye movement sleep deprivation (REMSD) for 24h. After, we injected within the striatum the MT2 selective agonist, 8-M-PDOT (10μg/μL), the MT2 selective antagonist, 4-P-PDOT (5μg/μL) or vehicle. Subsequently, they were tested in the forced swimming test and were allowed to perform the sleep rebound (REB). Then, the rats were re-tested, and the striatum, hippocampus and substantia nigra pars compacta (SNpc) were collected for neurochemical purposes. Results indicated substantial antidepressant effects promoted by the blockade of striatal MT2 receptors that were potentiated by REMSD. MT2 activation increased DA levels in the striatum and hippocampus, while MT2 blockade increase DA in the SNpc. 4-P-PDOT treatment of the rotenone REMSD group generated a decrement in 5-HT levels within the striatum, hippocampus and SNpc. However, increased 5-HT turnover was observed among these structures. Therefore, we demonstrated the neurochemical antidepressant effect induced by striatal MT2 blockage associated with REMSD in the rotenone model of PD.

Effects of developmental methylphenidate (MPH) treatment on monoamine neurochemistry of male and female rats

Attention Deficit Hyperactivity Disorder (ADHD) is estimated to affect 4–5% of the adult human population (Kessler et al., 2006; Willcutt, 2012). Often prescribed to attenuate ADHD symptoms (Nair and Moss, 2009), methylphenidate hydrochloride (MPH) can have substantial positive effects. However, there is a paucity of literature regarding its use during pregnancy. Thus, adult women with ADHD face a difficult decision when contemplating pregnancy. In this study, pregnant Sprague–Dawley rats were orally treated a total of 0 (water), 6 (low), 18 (medium), or 42 (high) mgMPH/kgbodyweight/day (divided into three doses) on gestational days 6–21 (i.e., the low dose received 2mgMPH/kgbodyweight3×/day). Offspring were orally treated with the same daily dose as their dam (divided into two doses) on postnatal days (PNDs) 1–21. One offspring/sex/litter was sacrificed at PND 22 or PND 104 (n=6–7/age/sex/treatment group) and the striatum was quickly dissected and frozen. High Performance Liquid Chromatography (HPLC) coupled to a Photo Diode Array detector (PDA) was used to analyze monoamine content in the striatum of one side while a sandwich ELISA was used to analyze tyrosine hydroxylase (TH) from the other side. Age significantly affected monoamine and metabolite content as well as turnover ratios (i.e., DA, DOPAC, HVA, DOPAC/DA, HVA/DA, 5-HT and 5-HIAA); however, there were no significant effects of sex. Adult rats of the low MPH group had higher DA levels than control adults (p<0.05). At both ages, subjects of the low MPH group had higher TH levels than controls (p<0.05), although neither effect (i.e., higher DA or TH levels) exhibited an apparent dose–response. PND 22 subjects of the high MPH treatment group had higher ratios of HVA/DA and DOPAC/DA than same-age control subjects (p<0.05). The increased TH levels of the low MPH group may be related to the increased DA levels of adult rats. While developmental MPH treatment appears to have some effects on monoamine system development, further studies are required to determine if these alterations manifest as functional changes in behavior.

Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain

Bisphenol A (BPA), an endocrine-disrupting chemical, is widely present in the environment. It has been reported that perinatal exposure to low doses of BPA that are less than the tolerable daily intake level (50μg/kg/day) affects anxiety-like behavior and dopamine levels in the brain. Although the dopaminergic system in the brain is considered to be related to anxiety, no study has reported the effects of low-dose BPA exposure on the dopaminergic system in the brain and on anxiety-like behavior using the same methods of BPA exposure. To investigate the relationship between alterations in anxiety-like behavior and changes in the dopaminergic system in the brain induced by BPA, we examined the effects of BPA on anxiety-like behavior using an open field test in juvenile and adult mice and measured DA and DOPAC levels and the DOPAC/DA ratio in the dorsal hippocampus (HIP), amygdala (AMY), and medulla oblongata (MED) using high-performance liquid chromatography (HPLC) in adult mice. In males, BPA decreased the time spent in the center area of the open field in both juveniles and adults. In addition, BPA increased DA levels in the dorsal HIP and MED and decreased the DOPAC/DA ratio in the dorsal HIP, AMY, and MED in adults. The activity of monoamine oxidase (MAO)-B, the enzyme that metabolizes DA into DOPAC, was reduced in the MED. In females, those changes were not observed. These results suggest that an increase in anxiety-like behavior induced by perinatal exposure to BPA may be related to decreases in DA metabolites in the brain, and there are sex differences in those BPA effects.

Induction of conditioned place preference and dopamine release by salsolinol in posterior VTA of rats: Involvement of μ-opioid receptors

Salsolinol (Sal), locally administered into the posterior VTA (pVTA) of rats, produces psychomotor responses and reinforcing effects, probably, through the activation of μ-opioid receptors (MORs). The neurochemical correlates of these phenomena are, however, practically unknown. In this paper, we explore the neurochemical events and the mechanisms involved in these behaviors. To do that, we test the ability of Sal, directly microinjected into the pVTA, to induce conditioned place preference (CPP) and to increase dopamine levels in the nucleus accumbens shell. Bilateral injections of 30pmol of Sal induced a strong CPP (rats spent around 70% of the total test time), a result that could be explained by the fact that Sal microinjected into the pVTA increased DA levels in the ipsilateral accumbens up to 141% of baseline. The local pretreatment with β-FNA, an antagonist of MORs, prevented this increase, supporting our hypothesis on the involvement of MORs in the Sal-derived effects.

Modification of inherent and drug-induced dopaminergic activity after exposure to benzo(α)pyrene

The aim of this study was to investigate the effect of benzo(α)pyrene (B(α)P), a representative polycyclic aromatic hydrocarbon (PAH), on dopaminergic activity in brain. (B(α)P) altered dopaminergic activity in discrete regions of the rat brain, including the hippocampus, hypothalamus, caudate putamen and nucleus accumbens. Specifically, B(α)P increased DA levels in the hippocampus and DA turnover in the caudate putamen. In addition, B(α)P suppressed DA levels in the caudate putamen and DA turnover in the nucleus accumbens. B(α)P also altered the effect of several dopaminergic agents, L-DOPA, sulpiride and bromocriptine, on DA activity. In particular, B(α)P enhanced the L-DOPA-induced increase in the DA turnover ratio in the caudate putamen and increased DA levels in the nucleus accumbens. B(α)P also reversed the sulpiride-induced increase of DA turnover in the nucleus accumbens and the bromocriptine-induced increase of DA turnover in the hippocampus. In addition, DA turnover was increased by B(α)P in the nucleus accumbens and caudate putamen and DA levels were suppressed in the nucleus accumbens of bromocriptine treated rats, though the drug alone had no effect. These changes indicate that exposure to B(α)P and related compounds may affect dopaminergic function in discrete brain regions that are implicated in cognitive functions, psychosis, depression and Parkinson's disease, and may possibly interfere with their pharmacological intervention.

Dopamine activity in the occipital and temporal cortices of rats: Dissociating effects of sensory but not pharmacological stimulation

Little is known about the functional role of DA in other cortical areas than in the prefrontal cortex. Here we demonstrate that visual stimulation increases DA activity as measured by in vivo microdialysis in the occipital, but not in the temporal cortex of freely moving rats. Auditory stimulation neither acutely affected DA in the occipital nor in the temporal cortex. A pharmacological challenge with cocaine (0, 5, 10, 20 mg/kg; i.p.) increased DA levels in both areas dose-dependently. These data suggest that DA might play a role in visual processing selectively in the occipital cortex. Furthermore, the results indicate that DA in both regions may contribute to cocaine's behavioral effects.

L-threo 3,4-dihydroxyphenylserine treatment during mouse perinatal and rat postnatal development does not alter the impact of dietary copper deficiency

Dietary copper (Cu) deficiency was induced perinatally in Swiss Albino mice and postnatally in male Holtzman rats to investigate the effect of L-threo 3,4-dihydroxyphenylserine (DOPS) on pup survival and catecholamine levels in a 2×2 factorial design. Mouse dams were placed on one of four treatments 14 days after mating and rats at postnatal day 19 (P19). Treatments were Cu-adequate (Cu+) and Cu-deficient (Cu−) diets with or without DOPS (1mg/ml) in the drinking water. Mouse pups were killed at P14 and rats at P49. Mortality in Cu− pups was 46% and not significantly improved by DOPS, 39%. A repeat study with mice adding ascorbic acid in the water with DOPS showed no improvement. Compared to Cu+ animals, Cu− animals were smaller, anemic and had a 92% reduction in liver Cu. DOPS treatment made no improvement to and in some cases exacerbated the Cu deficiency. Catecholamine levels measured in heart and brain by LCEC showed decreased NE levels and increased DA levels in Cu− animals compared to controls. DOPS treatment did not alter this pattern. Although DOPS was present in treated animal's tissues, survival in mice and catecholamine levels in mice and rats were not altered by the 1mg/ml dose of DOPS.

Neurochemical and Behavioural Effects of Chronic Aldicarb Administration in Rats

Abstract: Changes in neurochemical parameters, behavioural and memory performances due to aldicarb (a carbamate pesticide) treatment was investigated after chronic oral administration in rats. Rats received water, or aldicarb 1 ppb (=0.12 g/kg/day), aldicarb 10 ppb (=1.2 g/kg/day) and aldicarb 100 ppb (=12 g/kg/day) for 4 months. The locomotor and explorative activities were reduced, and aldicarb significantly decreased brain AChE activity while an increase was found in the passive avoidance and water‐maze performance. In the striatum, aldicarb 10 ppb and 100 ppb, significantly reduced DOPA but not DOPAC concentrations, while the 10 ppb and 100 ppb doses significant increased DA levels. Aldicarb did not affect DA, DOPA and DOPAC levels in the accumbens. The neuropharmacologic effects of chronic dosing with aldicarb, AChE inhibition and dopaminergic modulation could be useful for treatment of memory deficits related to CNS disorders.)

Neurochemical and behavioural effects of chronic aldicarb administration in rats.

Changes in neurochemical parameters, behavioural and memory performances due to aldicarb (a carbamate pesticide) treatment was investigated after chronic oral administration in rats. Rats received water, or aldicarb 1 ppb (= 0.12 g/kg/day), aldicarb 10 ppb (= 1.2 g/kg/day) and aldicarb 100 ppb (= 12 g/kg/day) for 4 months. The locomotor and explorative activities were reduced, and aldicarb significantly decreased brain AChE activity while an increase was found in the passive avoidance and water-maze performance. In the striatum, aldicarb 10 ppb and 100 ppb, significantly reduced DOPA but not DOPAC concentrations, while the 10 ppb and 100 ppb doses significant increased DA levels. Aldicarb did not affect DA, DOPA and DOPAC levels in the accumbens. The neuropharmacologic effects of chronic dosing with aldicarb, AChE inhibition and dopaminergic modulation could be useful for treatment of memory deficits related to CNS disorders.

Effects of amperozide on psychostimulant-induced hyperlocomotion and dopamine release in the nucleus accumbens

- N-Ethyl-4-[4′,4′-bis( p-fluorophenyl)-butyl]-1-piperazine carboxamide [amperozied (APZ) is a novel atypical neuroleptic that appears to selectively act on the limbic system. The present study investigated behavioral and biochemical effects of APZ on either d-amphetamine (AMPH)- or cocaine (COC)-treated rats. Behavior was assessed by locomotor activity measurements. Compared to saline controls, APZ (5 and 10 mg/kg, SC) decreased spontaneous locomotion. AMPH (1.0 mg/kg, SC)- or COC (10 mg/kg, IP)-induced hyperlocomotion was markedly reduced by APZ administered 20 min earlier. Biochemical data were obtained by in vivo microdialysis in freely moving animals. APZ dose dependently increased interstitial concentrations of dopamine (DA, +25%) and its metabolite, homovanillic acid (HVA, +20%), in the nucleus accumbens (NAC). While either AMPH or COC alone increased DA levels (450 and 270%, respectively), pretreatment with APZ had no effect on these increases. In contrast, APZ pretreatment dose dependently attenuated the reduction of DA metabolites induced by both AMPH and COC. Thus, APZ blocked hyperlocomotion induced by psychostimulants without producing correlative changes in DA concentrations in the NAC.

Regional studies of brain biogenic amines in castrated muricidal and non-muricidal wistar rats

Castrated Wistar rats were isolated for 8 months and their muricidal behavior was investigated. Significantly fewer (35%) of such rats became muricidal (CM) compared to controls. The steady-state levels of 5-HT, 5-HIAA, DA, DOPAC, and NE, as well as the changes in synthesis or utilization rats of 5-HT and DA, were analyzed in 15 brain areas derived from CM rats and non-muricidal (CNM) control subjects. In CM rats, higher 5-HT levels were recorded in 5 areas considered to be involved in muricidal behavior: raphe, amygdala, olfactory tubercles, olfactory bulbs, and striatum. The alterations of serotonergic neurotransmission in castrated muricidal rats differ strikingly from those observed in non-castrated muricidal rats. An increase of 5-HT level and in the 5-HT synthesis index as well as a lower 5-HT utilization index were recorded in the raphe of CM rats. Our data suggest that the decrease of 5-HT levels generally said to be the main alteration in the muricidal rat's brain has to be reconsidered. Increased DA levels were observed in CM rats: raphe (50%), amygdala, olfactory tubercles, striatum, and septum (40%), while DA was decreased in cortical areas. There were slight increases of DA synthesis indices in the septum, olfactory tubercles and striatum with a decreased utilization index in the olfactory tubercles. Few alterations in NE levels were observed in CM rats: a decrease in the olfactory tubercles, superior colliculus, and striatum and an increase in temporal cortex. The monoaminergic alterations correlate with the modulation of muricidal behavior. Some areas (the olfactory tubercles, raphe, striatum, and temporal cortex) seem to be particularly involved. © 1992 Wiley-Liss, Inc.

Effects of amantadine on dopaminergic neurons in discrete regions of the rat brain.

The effect of a dopamine agonist, amantadine, on dopaminergic neurons was investigated in rat brains. Amantadine (40 mg/kg, i.p.) tended to increase DA (16%) and DOPAC (24%) levels. Further, amantadine (40 mg/kg, i.p.) significantly increased HVA levels in frontal cortex (44% above baseline after 40 mg/kg, i.p.) but not in corpus striatum and nucleus accumbens. Amantadine significantly increased DA levels at doses of 10, 20 and 40 mg/kg, i.p., in corpus striatum. On the other hand, amantadine decreased the L-DOPA accumulation by 30% in frontal cortex. This decreasing effect of amantadine may be attributable to a negative feedback mechanism by DA autoregulation. Our findings, therefore, suggest that amantadine may accelerate dopaminergic neurotransmission by increasing DA release from the frontal cortex and may possibly improve senile dementia.

Is dopamine a neurohormone of the adrenal medulla? Studies with morphine stimulation.

Dopamine (da) concentrations in rat adrenals, plasma and brain were variably elevated 1 h after a large parenteral dose of morphine. In adrenals, unlabelled DA increased 2-fold and labelled DA, synthesized from 3H-tyrosine, increased more than 4-fold. The increases could be prevented by inhibition of DA-synthesizing enzymes and spinal cord transection, respectively. Labelled DA in plasma increased 2.7-fold after morphine in intact rats but did not increase in those with spinal cord transection. It is concluded that: (1) morphine stimulates the adrenal by increasing nerve impulse flow, (2) increased nerve impulse flow increases DA synthesis and levels, and (3) the increased DA levels result in increased release of DA into the bloodstream.