DA) And Its Metabolites 3,4-dihydroxyphenylacetic Acid Research Articles

Retinal dopamine and its metabolite contents in zitter rats and spontaneously epileptic rats.

In order to investigate the relationship between visual dysfunction and retinal DA metabolism in zitter rats and spontaneously epileptic rats (SER), we measured the amounts of retinal dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillate (HVA). DA, DOPAC and HVA contents were markedly decreased in zitter rats as compared with the controls, Kyo:Wistar or Sprague-Dawley rats. In contrast, in SER, retinal DA and its metabolite contents were not significantly different from those of Kyo:Wistar rats. SER showed higher levels of DA and its metabolites in comparison with Sprague-Dawley rats. Thus, it is suggested that the debilitation of retinal DA synthesis is at least partly related to the visual dysfunction observed in zitter rats, but not that of SER.

Transient improvement of amphetamine-induced rotational behavior by PC12 cell grafts: studies with microdialysis

The effects of striatal transplantation of PC12 cells on amphetamine-induced rotational behavior and monoamine levels were examined in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions in the nigrostriatal pathway. A total of 9 × 104 or 9 × 105 cells of PC12 was implanted into 3 sites in the striatum and changes in amphetamine (3 mg/kg, i.p.)-induced rotational behavior were observed for 8 weeks. Two weeks after transplantation, a significant reduction in rotation was observed. However, this improvement disappeared after 3 weeks. Three of 7 rats implanted with 9 × 104 cells and 6 of 7 rats with 9 × 105 cells died between 3 and 4 weeks after transplantation. In 6-OHDA-injected control rats, the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in brain dialysates were profoundly reduced to between 0 and 11% of normal rats, while the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level remained unchanged. These reductions in DA and its metabolites did not recover at 2 or 8 weeks after the transplantation of 9 × 104 PC12 cells. 5-HIAA was reduced at 2 weeks and recovered to nearly control levels at 8 weeks. Histologically, PC12 cells proliferated to form a large tumor mass at 2 weeks. There were almost no processes growing from the aggregated PC12 cells into the host tissue. These results indicate that PC12 grafts do not release detectable quantities of DA into the deafferented striatum, and suggest that the transient improvements in rotational behavior may be due to a non-specific suppression in neuronal function induced by the growing tumor mass.

Effects of taurine, homotaurine and GABA on hypothalamic and striatal dopamine metabolism.

To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of gamma-aminobutyric acid (GABA) and homotaurine (a GABAA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 mumol/rat, and rat were sacrificed 15 and 60 min later, respectively. Homotaurine (by 11%) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 mumol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 mumol the amino acids decreased striatal 3-MT by about 40%. At 36 mumol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 mumol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 mumol but not at 36 mumol slightly (20%) increased DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of genotype in brain dopamine metabolism and dopamine-dependent behavior of mice

In mice of eight inbred strains—BALB/c, AKR/J, DBA/2, CBA, C57B1/6, DD, CC57Br, and C3H/He—brain dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in striatum and nucleus accumbens with tuberculum olfactorium, the structures of two main dopaminergic systems—nigrostriatal and mesolimbic—were determined. In both dopaminergic regions, no strain effect on either dopamine or DOPAC levels was found, while for HVA content a highly significant hereditary determination was shown. Influences of selective D 1 and D 2 dopamine receptor agonists—SK&F 38393 and quinpirole, respectively—as well as that of a mixed D 1 D 2 agonist, apomorphine, on general locomotor activity and stereotypic climbing were studied. By that, marked genotypic differences in dopamine-dependent behavior and dopamine receptor sensitivity were observed. Although both SK&F 38393 (5 mg/kg) and apomorphine (0.25 mg/kg) decreased locomotion, the effect being genotype dependent, in all strains of mice quinpirole (2.5 mg/kg) proved more potent in locomotor inhibition. SK&F 38393 (10 mg/kg) induced climbing, but 2.5 mg/kg apomorphine in most strains was much more effective. At the same time, quinpirole (up to 8 mg/kg) failed to induce this behavior. This suggests the crucial role of D 1 receptors in the generation of climbing, attracting, at the same time, attention to the importance of D 1 D 2 interaction. The observed drastic interstrain differences in dopamine receptor sensitivity demonstrate the essential role of genotype in the effects of dopaminergic drugs.

Changes in brain monoamine metabolism in rats with acute ischemic hepatic failure under artificial cardiopulmonary management.

A study was conducted to investigate changes in monoamine metabolism in the brain of rats with acute ischemic hepatic failure (AHF) induced by two-stage hepatic devascularization. Strict artificial cardiopulmonary management was used to exclude possible confounding effects of hypotension, hypothermia and hypoxemia that often appear in AHF. Rats were put in an incubator at 34 degrees C before the ligation of the hepatic artery (second stage operation), tracheotomized and ventilated artificially throughout the remaining experimental periods. No significant difference was observed in physiological parameters, including body temperature, pulse rate and systolic arterial blood pressure or PaO2 between AHF and sham operated rats. Brain levels of norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), and serotonin (5-hydroxytryptamine, 5HT) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by HPLC-voltametry. AHF rats showed significantly higher MHPG, DOPAC, 5HIAA and lower NE levels in the brain compared to controls. In addition, a significant negative correlation between NE and tyrosine (Tyr), a significant positive correlation between MHPG and Tyr or phenylalanine (Phe), and a significant positive correlation between DOPAC and Tyr or Phe were observed. In conclusion, the changes in monoamine metabolism in the brain of AHF rats are clearly induced specifically by hepatic failure itself, possibly through an altered metabolism of amino acids.

Effects of Intranigral Substance P and Neurokinin A Injections on Extracellular Dopamine Levels Measured with Microdialysis in the Striatum and Frontoparietal Cortex of Rats

Extracellular levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum and frontoparietal (sensorimotor) cortex in halothane-anesthetized rats were analyzed simultaneously using in vivo microdialysis. Basal DA levels, measured from the microdialysis perfusate, were 6.4 +/- 0.8 nM (n = 15) in the striatum and 0.9 +/- 0.1 nM (n = 15) in the frontoparietal cortex. Subcutaneous injections of d-amphetamine (2 mg/kg) increased DA levels 10-fold in the striatum and fivefold in the cortex. Injections of substance P (0.07 nmol/0.2 microliters) into the substantia nigra pars reticulata (SNR) increased DA and DOPAC levels approximately 30% in the ipsilateral striatum and approximately 50% in the ipsilateral frontoparietal cortex. Injections of neurokinin A (0.09 nmol/0.2 microliter) into the SNR increased DA and DOPAC levels approximately 30% in the ipsilateral striatum but did not significantly affect DA levels in the ipsilateral frontoparietal cortex, although DOPAC levels were increased by approximately 50%. It is suggested that striatal and cortical DA release is regulated differently by nigral substance P and neurokinin A terminals.

Effects of cocaine and footshock stress on extracellular dopamine levels in the ventral striatum

Behavioral and neurochemical cross-sensitization between cocaine and stress was examined. The effects of stress and cocaine on extracellular levels of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis in the rostral ventral striatum, including the nucleus accumbens. Pretreatment with a daily 20 min footshock stress (0.45 mA/200 ms/s) for 5 days enhanced the cocaine-induced increase in extracellular dopamine levels in shock compared to sham shock-pretreated rats. The motor stimulant response to acute cocaine was also augmented in shock-pretreated rats. There was a slight but significant decrease in the levels of DOPAC and HVA in both groups following cocaine but no differences between shock and sham shock animals. In contrast, in the converse experiment, pretreatment with daily cocaine (15 mg/kg, i.p.) for 5 days did not significantly alter the stress-induced levels of extracellular dopamine compared to controls. The levels of DOPAC and HVA were not different between cocaine- and saline-pretreated groups although there was a trend towards enhanced metabolite levels in cocaine-pretreated animals. These data in part support a role for enhanced dopamine neurotransmission in mediating behavioral cross-sensitization between psychostimulants and stress.

Effects of Ethanol and Low-Carbohydrate Diet on Contents of Noradrenalin, Dopamine, Serotonin and their Metabolites in Rat Brain.

Effects of ethanol consumption and intake of low-carbohydrate (low-CHO) diet on noradrenaline (NA), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5HT) and its metabolite, 5-hydroxyindoleacetic acid (5HIAA) contents in six brain regions of rats were investigated. 1) Change of DA neuron Ethanol-containing control diet (hypercaloric ethanol diet) did not affect DA content in any area of brain, but decreased HVA in cortex and hypothalamus and increased DOPAC and HVA in midbrain. Low-CHO diet increased DA content in striatum, DOPAC and HVA in midbrain, but decreased DOPAC in hippocampus and hypothalamus, and HVA in cortex, pons and medulla, hippocampus and hypothalamus. Ethanol-containing low-CHO diet (isocaloric ethanol diet) increased DA level in striatum, DOPAC and HVA in midbrain, but decreased HVA in cortex, hippocampus, striatum and hypothalamus. These results suggest that i) hypercaloric ethanol diet has an opposite effect to carbohydrate on DA metabolism: hypercaloric ethanol diet and lowered carbohydrate intake per se enhance DA metabolism in midbrain, whereas inhibit it in cortex and hypothalamus, ii) lowered carbohydrate intake also declines DA metabolism in pons and medulla and hippocampus, whereas enhances DA synthesis in striatum, iii) the combined effect of ethanol and carbohydrate intake on DA metabolism is inhibited each other in the rats of isocaloric ethanol diet feeding, and this diet decreased DA metabolism in striatum. 2) Change of 5HT neuron Hypercaloric ethanol diet did not affect the contents of 5HT and 5HIAA in any region of brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Enantiomeric differences in the effects of 3,4-methylenedioxymethamphetamine on extracellular monoamines and metabolites in the striatum of freely-moving rats: An in vivo microdialysis study

The effects of (+) and (−) 3,4-methylenedioxymethamphetamine (MDMA) and racemic p-chloroamphetamine (PCA) on extracellular dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as the metabolite of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), were determined in dialysates of the striatum conscious rats by using intracerebral dialysis and high performance liquid chromatography with electrochemical detection (HPLC-EC). The (+) and (−)MDMA isomers (5, 10 mg/kg, s.c.) and PCA (2.5, 5 mg/kg, s.c.) caused a rapid increase of extracellular levels of dopamine and decreased extracellular levels of DOPAC and HVA immediately after administration in dialysates of striatum. The order of potency for this effect was PCA>(+)MDMA>(−)MDMA. The levels of 5-HIAA also decreased after the administration of drugs, but the effect had a slower time course than DOPAC and HVA and did not exhibit an enantiomeric difference. The data indicate that, although these drugs are thought to affect the 5-HT neuronal system preferentially, they also affect dopamine systems and by a mechanism in which the (+) isomer was more potent than the (−).

In vivo striatal dopamine release by TRH analog YM-14673 is blocked by M1 muscarinic receptor antagonist

A dialysis loop cannula was implanted into rat striatum under anesthetized conditions, and after 3 days surgical recovery the area was perfused with Ringer's solution, under freely moving conditions. Dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite, 5-hydroxyindoleacetic acid (5HIAA), recovered in the dialysate were measured by high-performance liquid chromatography with electrochemical detection. Thyrotropin-releasing hormone (TRH) and its analog YM-14673 were systemically administered. TRH (10 and 20 mg/kg) and YM-14673 (1 mg/kg) increased in vivo striatal DA, DOPAC, HVA and 5HIAA release. Treatment with YM-14673 increased DA, DOPAC, HVA and 5HIAA release to 145, 150, 155 and 125%, respectively, of basal levels. The effects of YM-14673 on DA release and metabolism were completely blocked by an M1 muscarinic receptor antagonist, pirenzepine (10(?5) M), perfused into the striatum through the dialysis membrane, and by pretreatment of an excitotoxin, kainic acid (2.5 ?g/2 ?l), microinjected directly into the striatum. In comparison with the case of DA, the effect of YM-14673 on the 5HIAA level was only slightly suppressed by pirenzepine and kainic acid. These results suggest that in vivo striatal DA release by TRH may be dependent upon the activation of cholinergic neurons.

Differences in dopamine release and metabolism in rat striatal subregions following acute clozapine using in vivo microdialysis.

This study examined and compared the effects of acute clozapine administration over a range of doses on the release of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in dorsolateral and fundus striata. Basal extracellular DA levels were significantly higher in the dorsolateral striatum. However, DOPAC levels were similar in both regions. Acute treatment with clozapine (40 mg/kg) was associated with an increase in extracellular dopamine in the dorsolateral striatum but not in the fundus. In contrast, an increase in extracellular DOPAC was seen in both regions following all doses of the drug; however, clozapine was more potent in the dorsolateral striatum than in the fundus. These results illustrate the functional heterogeneity of the striatum and in addition, indicate a possible dissociation between the effect of acute clozapine on DA release and DA metabolism.

Distribution of dopamine D1 and D2 receptors in rabbit cortical areas, hippocampus, and neostriatum in relation to dopamine contents

The densities of dopamine D1 and D2 receptors were measured by using [3H]SCH23390 and [3H]raclopride, respectively, in the rabbit cingulate, visual, sensorimotor, and entorhinal-piriform cortical areas; the dorsal and ventral hippocampus; and the putamen as well as the medial and lateral caudate. Endogenous dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), and 3-methoxytyramine (3-MT) were assayed by HPLC with electrochemical detection. The distributions of [3H]SCH23390 and [3H]raclopride binding were heterogenous with the greatest densities in the neostriatum. The concentrations of DA and its metabolites were also highest in this structure. Regions with low DA content, i.e., cortex and hippocampus, had lower densities of [3H]SCH23390 and [3H]raclopride binding. Furthermore, these sites were differentially localized within the various regions and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors are discussed in relation to the dopaminergic innervation and the turnover estimated by the ratios between endogenous DA and its metabolites.

Basal and amphetamine-induced asymmetries in striatal dopamine release and metabolism: bilateral in vivo microdialysis in normal rats

In vivo microdialysis was used to monitor bilaterally the release of dopamine and its metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the striata of both anesthetized and awake, freely moving female rats. Under baseline conditions, an asymmetry in dopamine release was reciprocally related to an asymmetry in DOPAC. Baseline dopamine and DOPAC asymmetries were predictive of the preferred direction of amphetamine-induced rotation: the striatum having higher dopamine and lower DOPAC was contralateral to the preferred direction of rotation. Amphetamine ( d-amphetamine sulfate, 1.25 mg/kg) enhanced dopamine release and decreased DOPAC and HVA; the increase in dopamine was greater in the ipsilateral striatum. Effects in anesthetized and awake rats were similar. Variations in rotation and in the dopamine asymmetry after amphetamine were correlated across time within individual awake rats.

Rapid postmortem increase in extracellular dopamine in the rat brain as assessed by brain microdialysis.

Extracellular dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat nucleus accumbens were determined before and shortly following death using microdialysis. A maximal 400-fold increase in the output of DA was observed within the first 5 min of death. DA output remained elevated over the following hour at a level of approximately 70-fold above pre-death values. In contrast to that of DA, DOPAC and HVA output gradually declined. Before death the extracellular DOPAC/DA ratio was about 250; after death this ratio dropped to 0.44 at 5 min. These observations may have important implications for experiments measuring the output of (endogenous) DA and its metabolites from brain tissue in vitro: autoregulation of, e.g., transmitter release and synthesis in vitro may be seriously disrupted by the observed depletion of transmitter storage granules.

Intracerebrally administered (6r)- l- erythro-tetrahydrobiopterin does not affect extracellular levels of dopamine and serotonin metabolites in rat striatum in vivo during measurement by brain micro-dialysis system

By the use of the brain micro-dialysis technique combined with HPLC, the changes in the extracellular levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and a serotonin(5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were examined in the rat striatum before and after intracerebral injection of a vehicle or (6R)- l-erythro-tetrahydrobiopterin (6R-BH 4), the natural form of the cofactor for the tryrosine hydroxylase and tryptophan hydroxylase. No apparent change after the 6R-BH, treatment was found in the levels of DA, DOPAC, HVA and 5-HIAA in the striatal dialysate. In contrast, the levels of total biopterin in both the operated (dialysis probe-implanted) and unoperated striatum of 6R-BH 4-treated rats increased by 23- and 93-fold, respectively, when compared with those of the control, vehicle-treated rats. The results indicate that increased levels of the tetrahydrobiopterin cofactor may not affect the release of DA and the extracellular level of DA and 5-HT metabolites in the physiologically normal brain.

Effects of endophyte-infected fescue on concentrations of prolactin in blood sera and the anterior pituitary and concentrations of dopamine and dopamine metabolites in brains of steers.

An experiment was conducted to determine if the decrease in circulating concentrations of prolactin in cattle consuming endophyte (Acremonium coenophialum) -infected tall fescue (Festuca arundinacea) was associated with changes in prolactin concentrations in the anterior pituitary and concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) in the stalk median eminence (SME), preoptic area (POA) and hypothalamus (HP). Six crossbred steers that grazed high-endophyte (greater than 90% infected) fescue and four steers that grazed low-endophyte (less than 1% infected) fescue from April to September were slaughtered. Brains and pituitaries were removed and dissected. Extracts from neural tissue were analyzed for DA, DOPAC and HVA using high performance liquid chromatography/electrochemical detection. Pituitary extracts and sera from blood samples taken 5 d prior to slaughter were subjected to prolactin radioimmunoassay. Consumption of high-endophyte fescue was associated with decreased concentrations of prolactin in serum (P less than .01) and in the anterior pituitary (P = .08), decreased (P less than .05) concentrations of DA in the SME and decreased (P less than .01) concentrations of HVA in the POA and HP, but it did not influence levels of DOPAC. These results suggest that endophyte toxins may reduce prolactin synthesis and release and may alter activity of dopaminergic neurons.

Effect of aging on monoamines and their metabolites in the rat brain

Concentrations of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their acid metabolites were assayed in specific brain areas of Wistar rats of various ages. DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were significantly lower in striatum and mesolimbic areas of old (24 mos) rats than young adult (3 mos), but not mature (12 mos) rats. The decrease of homovanillic acid (HVA) was significant in mesolimbic areas but not in striatum. Neither cortical NE nor its metabolite methoxyhydroxyphenylglycol sulphate (MHPG-SO4) were significantly changed by aging. 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the brainstem showed a tendency to a decrease and increase respectively in aged animals compared with young adults, but the differences were not statistically significant. However, the ratio of 5-HIAA to 5-HT concentrations was significantly higher in aged animals. The conclusion can be drawn that, in these brain areas, DA is more vulnerable to aging than NE and 5-HT, the metabolism of the latter being even enhanced.

Altered responsiveness of regional brain dopamine and DOPAC levels to systemic administration of quinpirole, a dopamine D 2 agonist, in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that administration of quinpirole (LY171555), a potent and highly selective dopamine (DA) D 2 receptor agonist, to conscious Sprague-Dawley rats produces increases in arterial pressure through the activation of sympathetic outflow and vasopressinergic activity. To test the hypotheses that quinpirole inhibits in vivo release of DA from central dopaminergic neurons by activation of DA receptors in the central nervous system (CNS) and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we examined the effects of quinpirole on stores of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions of 4-week DOCA/NaCl-hypertensive rats and their normotensive controls. Levels of DA and DOPAC were measured in brain regions by HPLC 15 min after the i.v. administration of quinpirole (1 mg/kg). Quinpirole resulted in a significant increase in DA stores and decrease in DOPAC stores in most brain regions examined in both DOCA/NaCl-hypertensive rats and normotensive controls, presumably by inhibiting DA release through a presynaptic mechanism. In the vehicle-treated groups, DA stores in the anterior hypothalamus and DOPAC stores in the nucleus accumbens were lower in DOCA/NaCl-hypertensive rats than in H 2O controls. Following quinpirole administration, DA stores in the anterior hypothalamus increased significantly in DOCA/NaCl-treated rats but not in H 2O controls and DOPAC stores in the nucleus accumbens decreased significantly in H 2O control rats but not in DOCA/NaCl-treated rats. These observations provide further evidence for the presence of inhibitory DA D 2 receptors which modulate the activity of dopaminergic neurons in the CNS. This regulatory mechanism appears to be altered in the DOCA/NaCl model of hypertension. The increased responsiveness to quinpirole in the anterior hypothalamus and nucleus accumbens of DOCA/NaCl-treated rats could represent upregulation of central DA D 2 receptors as a consequence of reduced central dopaminergic activity, as previously found in this model of hypertension.

Effects of perinatal vitamin B6 deficiency on dopaminergic neurochemistry.

Long-Evans dams were fed either a vitamin B6-deficient or a control diet from day 13-14 of gestation and throughout lactation. A control pair-fed group was also included because of differences in food intake between vitamin B6-deficient and control ad libitum dams. The progeny of vitamin B6-deficient dams had all the classic symptoms of B6 deficiency. These included weight loss, ataxia, tremor, and epileptic seizures. Concentrations of the neurotransmitter dopamine (DA), and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as D-2 dopamine receptor binding, 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activity, and vitamin B6 levels were measured in the corpus striatum of progeny at 7, 14, and 18 days after birth. Striatal DA and HVA levels were significantly decreased in B6-deficient animals when compared to ad libitum or pair-fed controls. Daily injections of vitamin B6 to deprived animals from the 14th to 18th day after birth improved the abnormal movement and normalized the concentration of DA but not of HVA in corpus striatum. Striatal D-2 dopamine receptor binding using [3H]spiperone as ligand was significantly reduced in 18-day-old animals as compared to ad libitum and pair-fed controls. No significant differences were found at 14 days. The administration of vitamin B6 to deprived animals did not raise the level of D-2 receptor binding during the period of observation. Scatchard plots indicated that the differences in binding were due to changes in receptor number and not in KD. Corpus striatum DOPA decarboxylase activity with and without the addition of exogenous pyridoxal phosphate was significantly reduced in 14- and 18-day-old animals when compared to pair-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced response to the inhibitory action of LY171555, a dopamine D 2-agonist, on in vivo striatal dopamine release in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that LY171555 (quinpirole), a specific dopamine (DA) D 2-receptor agonist, has a pressor effect in the conscious rat which is accompanied by increased sympathetic outflow and arginine vasopressin release. To test the hypothesis that LY171555 inhibits in vivo release of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), from central dopaminergic neurons of the conscious, freely moving rat by activation of presynaptic DA receptors in the central nervous system and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we used the in vivo push-pull perfusion method to study the effect of LY171555 on central DA release in normotensive and DOCA/NaCl-hypertensive rats. Levels of the DOPAC and HVA were measured in striatal perfusates by HPLC before and after administration of LY171555 (1 mg/kg, i.v.) of conscious, unrestrained 4-week DOCA/NaCl hypertensive and uninephrectomized H 2O control rats. There were no significant differences in basal striatal HVA (80 ± 12 vs 89 ± 11 pg/min; DOCA/NaCl vs control) or DOPAC levels (37 ± 5 vs 17 pg/min; DOCA/NaCl vs control) during the entire 240-min collection period. LY171555 significantly reduced HVA and DOPAC levels in perfused striatum in both normotensive control and DOCA/NaCl-hypertensive rats. The LY 17555-induced suppression in HVA levels was significantly greater in DOCA/NaCl rats (Δ = 60.7 ± 3.6%) than in H 2O controls (Δ = 49.0 ± 3.5%, P < 0.05). Pretreatment with metoclopramide (10 mg/kg, i.v.), a specific central and peripheral DA D 2-receptor antagonist, completely blocked the suppressive effects of LY171555 on HVA and DOPAC levels. These observations provide direct evidence for the presence of functionally significant presynaptic inhibitory DA D 2-receptors which modulate dopaminergic neuro-transmission in the striatum of conscious, freely moving rats. This regulatory mechanism appears to be altered in the DOCA/NaCl model of hypertension. These results support the concept that DOCA/NaCl-hypertensive rats have altered central dopaminergic activity.