Striatal Homovanillic Acid Levels Research Articles

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.

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain

The effects of two amphetamine-like designer drugs, 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), on dopaminergic and serotonergic systems in the rat brain were investigated and compared to those of methamphetamine (METH). Like METH, single or multiple 10 mg/kg doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid, in several serotonergic nerve terminal regions. In all regions examined, the reduction in 5-HT content corresponded to the depression of TPH activity. Unlike multiple METH administrations, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. At this time, striatal levels of homovanillic acid were significantly elevated suggesting that both drugs influence dopamine turnover. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.

D- and L-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than 1-fenfluramin in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of 1-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration 1-fenfluramine 5–20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO 4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO 4 levels. Neither 1- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg 1-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively. The effect of d-fenfluramine on brain 5-HT seems to be important for its anorectic activity while the functional outcome of the interaction of l-fenfluramine with catecholamines remains to be clarified.

Effects of 250 mg% ethanol on monoamine and amino acid release from rat striatal slices

A single IP injection of 2.5 g ethanol/kg body weight into the rat increased the striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) one hour later to 133 and 141% of control values, respectively. Blood alcohol concentrations at this time were approximately 250 mg%. The increased striatal tissue levels of DOPAC and HVA found after IP administration did not appear to be due to a direct effect of ethanol on the efflux of these two metabolites or on the release of dopamine (DA) since in vitro studies with striatal slices demonstrated that 250 mg% ethanol had no effect on the endogenous release of DOPAC, HVA, or DA. However, ethanol did enhance the K +-stimulated, Ca 2+-dependent release of glutamate and aspartate from striatal slices to 168 and 214% of control values, respectively. The release of glutamate and aspartate from slices of midbrain (minus colliculi) was also increased by 250 mg% ethanol. On the other hand, the release of GABA, NE and 5-HT did not appear to be significantly altered by 250 mg% ethanol. The in vitro findings have led to the hypothesis that the elevated DOPAC and HVA levels observed in the striatum following an acute IP injection of 2.5 g/kg of ethanol are due to increased release of DA produced by the excitatory actions of glutamate (and/or aspartate) on dopaminergic neurons.

Dopaminomimetic action of diphenylhydantoin in rat striatum: effect on homovanillic acid and cyclic AMP levels.

Diphenylhydantoin (DPH) is known to induce reversible paroxysmal dyskinesias and paranoid psychosis in humans, but its interactions with dopamine (DA) metabolism are not clear. Single doses of DPH (60-100 mg kg-1), with serum levels over 10 micrograms ml-1, reduced homovanillic acid (HVA) levels in rat striatum. The DPH-induced HVA decrease was enhanced by supersensitivity of postsynaptic DA receptors following chronic haloperidol (Hal) administration. DPH 60 mg kg-1 given acutely enhanced the HVA decrease induced by apomorphine (Apo) and partially counteracted the HVA increase following acute Hal (0.1-0.5-2 mg kg-1). After chronic DPH treatment, Apo was ineffective in reducing striatal HVA levels. Concomitant chronic treatment with DPH and Hal counteracted the development of supersensitivity of postsynaptic DA receptors to Apo. Single doses of DPH (30-60-100 mg kg-1) increased cyclic AMP striatal content; this effect was blocked by Hal. A dopaminomimetic DPH action and a subsensitivity of postsynaptic DA receptors after chronic DPH seem to be suggested. These effects could be related to the dyskinetic and psychotic syndromes produced by the drug.

Long-term effects of a priming dose and short-term infusion of amphetamine on striatal dopamine neurons in rats

A priming dose (15 mg/kg i.p.) of (+)-amphetamine sulfate combined with a 16 h subcutaneous infusion of 1.36 mg of the drug per hour to rats via its release from osmotic minipumps produced marked decreases in striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the synaptosomal uptake of [ 3H]DA which lasted for at least 12 weeks. The decrease in striatal DA persisted through 24 weeks after drug treatment. In contrast, striatal levels of DOPAC, HVA and synaptosomal DA uptake recovered to control levels by 24 weeks after amphetamine treatment.

The release of endogenous dopamine and its metabolites from rat striatum as detected in push-pull perfusates: effects of systematically administered drugs.

The release of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was determined in push-pull perfusates from the striatum of the anaesthetized rat with high pressure liquid chromatography and electrochemical detection. Striking differences were found between the released amounts of DA (less than 7 fmol/min) and those of the metabolites (approx 0.5 pmol/min). It was calculated that 5% of the DA metabolites left the striatum via the push-pull cannula. The effects of systemic application of apomorphine, (+)-amphetamine, haloperidol or haloperidol in combination with amfonelic acid on the release of DA and its metabolites, were investigated. The release rate of DOPAC correlated well with the drug-induced changes of these metabolites in striatal tissue, however, this was not the case for HVA. The increase of striatal levels of DOPAC and HVA induced by the anaesthesia is a serious limitation of the method. To enable reliable estimation of the release of DA, 1 microM (+)-amphetamine had to be added to the perfusion medium (which may have modified the origin of DOPAC and HVA in the perfusates). (+)-Amphetamine (5 mg/kg, intravenous) induced a two- to threefold increase in the release of DA. Systemic administration of apomorphine, haloperidol or haloperidol in combination with amfonelic acid did not change the output of the neurotransmitter in the push-pull cannula. This implies that neuroleptics cause only a small and transient rise in DA release, whereas the pronounced and persisting increase in DOPAC and HVA seen after neuroleptics is the result of enhanced metabolism related to increased synthesis of DA.

The effect of long-term concurrent administration of chlorpromazine and lithium on the striatal and frontal cortical dopamine metabolism in rats.

The effects of lithium and chlorpromazine chronically administered alone and together on the dopamine metabolism in the rat striatum and frontal cortex were investigated by measurement of the levels of dopamine (DA) and its main metabolite, homovanillic acid (HVA). Long-term chlorpromazine administration caused a significant increase in the striatal DA level and a decrease in that of HVA and HVA/DA ratio without any changes in those of the frontal cortex. The prolonged administration of lithium elevated the striatal levels of both HVA and DA, but no change in the frontal cortex was observed. The concurrent administration of chlorpromazine and lithium caused a significant increase in the frontal cortical DA level and a decrease in that of HVA and HVA/DA ratio. The striatal DA and HVA levels increased under the effect of the combined treatment, while the HVA/DA ratio remained unchanged.

Cross-tolerance of dopamine metabolism to baclofen, gamma-butyrolactone and HA-966 in the striatum and olfactory tubercle of the rat.

Abstract Rats received 7 daily injections with baclofen (40 mg/kg), GBL (750 mg/kg) or HA-966 (100 mg/kg). Dopamine (DA) was measured in the striatum and olfactory tubercle (OT) of rats, sacrificed 0.5 h or 1 h after the last injection. Marked tolerance and cross-tolerance for the DA-elevating effect of these drugs was seen in the striatum, but not in OT. When on day 7 a unilateral lesion of the nigrostriatal pathway was made, also some tolerance to the DA increase in the striatum on the lesioned side was seen in HA-966-pretreated rats, but it was small compared to the tolerance after an additional drug administration in non-lesioned animals. A low dose of apomorphine (0.25 mg/kg, i.p.) had no effect on DA, dihydroxyphenylacetic acid DOPAC) or homovanillic acid (HVA) levels in the lesioned striata, whether the rats had been pretreated for 6 days with HA-966 or not. However, this dose of apomorphine had a significantly more lowering effect on striatal DOPAC and HVA levels on the unlesioned side of HA-966 pretreated rats. The results show that tolerance develops to the increase of DA synthesis, which is possibly receptor-mediated. This tolerance develops more readily in the striatum than in the olfactory tubercle.

The effect of phencyclidine on dopamine synthesis and metabolism in rat striatum

Previous behavioral and neurochemical studies indicate that phenyclidine (PCP), a potent psychotomimetic agent, interacts with central dopaminergic systems. We have examined the effects of PCP on the rate of accumulation of 3,4-dihydroxyphenylalanine (DOPA) after the inhibition of L-aromatic amino acid decarboxylase and on the levels of dopamine (DA) metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. PCP, in doses from 2.5 to 50 mg/kg, decreased the rate of striatal DOPA accumulation. PCP did not antagonize the increase in the rate of striatal DOPA formation caused by haloperidol, reserpine or γ-butyrolactone (GBL). When given alone, PCP decreased striatal levels of DOPAC and HVA, while it greatly potentiated the haloperidol-induced rise in striatal levels of these two metabolites. PCP is considerably less effective than d-amphetamine in promoting the release of 3H-DA from preloaded striatal slices in vitro. Our results are consistent with the interpretation that PCP potentiates the synaptic effects of endogenous DA. Its mechanism of action appears to be closely related to that of a category of drugs known as non-amphetamine stimulants, which, among others, includes methylphenidate, amfonelic acid and cocaine.

Effect of diazepam on dopamine and homovanillic acid levels in the corpus striatum of rats pretreated with ?-hydroxybutyric acid

The effects of increasing doses of diazepam on striatal dopamine (DA) and homovanillic acid (HVA) levels were studied in rats pretreated with γ-hydroxybutyric acid (GHB). A dose of 750 mg/kg of GHB causes a rise of both DA and HVA striatal levels in rats. Diazepam, administered to animals pretreated with GHB, induces a further increase of striatal DA and HVA levels.

Specificity of serotoninergic involvement in the decrease of food intake induced by quipazine in the rat

The effect of quipazine on brain monoamines and the significance of this interaction in its anorectic activity was studied in rats. At doses ranging from 2.5 to 10 mg/kg quipazine markedly reduced brain 5-hydroxyindolacetic acid concentrations without significant effects on steady-state levels of serotonin, noradrenaline and dopamine. Striatal levels of homovanillic acid were significantly reduced by 10 mg/kg of quipazine but not modified by a dose of 5 mg/kg. Quipazine counteracted the decrease of brain serotonin induced by fenfluramine but did not significantly modify the effect of 6-hydroxydopamine on brain nonadrenaline and dopamine. The decrease of food intake induced by 5 mg/kg of quipazine was completely prevented by pretreatment with methergoline but was not affected by an intraventricular injection of 6-hydroxydopamine or pretreatment with penfluridol, propranolol or phentolamine. The results indicate that at doses between 2.5 and 5 mg/kg quipazine specifically acts on brain serotonin and this interaction may be important for its anorectic activity.

Tolerance to stereotyped behaviour and to decrease in striatal homovanillic acid levels after repeated treatment with apomorphine dipivaloyl ester

Tolerance to stereotyped behaviour and to decrease in striatal homovanillic acid levels after repeated treatment with apomorphine dipivaloyl ester

Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats.

Animals received either haloperidol (2 mg/kg) or probenecid (200 mg/kg) in conjunction with tyrosine (100 mg/kg) or its diluent. Striatal homovanillic acid levels increased in probenecid-treated animals to the same range whether they were given tyrosine or not. In haloperidol-treated animals the levels of homovanillic acid were significantly elevated in animals receiving tyrosine. Tyrosine and homovanillic acid levels were highly correlated as determined by linear regression analysis.

Increase in striatal acetylcholine by picrotoxin in the rat: Evidence for a gabergic-dopaminergic-cholinergic link

Picrotoxin, 2 mg/kg i.p., a GABA receptor blocking agent, increased rat striatal acetylcholine content by approximately 70% without altering the levels of this amine in the cerebral hemispheres, mesencephalon, diencephalon, hippocampus and cerebellum. Striatal choline levels were concomitantly decreased by about 25%. This dose of picrotoxin also increased striatal homovanillic acid levels by about 30%, an effect which was not antagonized by pretreatment with the dopamine receptor stimulating agent, piribedil. Picrotoxin did not affect striatal choline-O-acetyltransferase or cholinesterase activity after in vitro incubation. The action of picrotoxin on striatal acetylcholine levels was partially antagonized by pimozide and completely blocked by alpha-methyl-para-tyrosine pretreatment while the intraventricular injection of 6-hydroxydopamine was without effect. Convulsions were not prevented by any of these treatments. The results are interpreted as follows: picrotoxin released dopamine through disinhibition of the dopaminergic neurons as a result of blockade of gabergic receptors. The increased dopaminergic activity inhibited cholinergic neurons and lead to an increase in acetylcholine content. The data thus provide evidence for a possible gabergic (inhibitory)—dopaminergic (inhibitory)-cholinergic link terminating in the striatum.

A relation between drug concentrations in brain and striatal homovanillic acid levels in chlorpromazine treated rats

Levels of homovanillic acid in striatum and chlorpromazine in brain and plasma of rats after acute and chronic treatment were determined by mass fragmentography. A significant positive correlation was found between the striatal homovanillic acid level and the chlorpromazine concentration in brain after acute as well as chronic treatment. A significant relation was also obtained between the homovanillic acid level in striatum and the chlorpromazine content of plasma after acute but not chronic treatment. After chronic treatment the drug concentration-effect relationship was significantly displaced to the right which may indicate the development of pharmacodynamic tolerance to the effect of the drug.

Spontaneous and drug-induced changes of cerebral dopamine turnover during postnatal development of rats.

Abstract In the whole brain, the striatum and the brain without the striata of rats, the dopamine (DA) and the noradrenaline (NA) levels progressively increased from day 1 to day 60 after birth. Furthermore, in whole brain a continuous rise of the 3,4-dihydroxyphenylacetic acid (DOPAC) content was observed during the postnatal period. The homovanillic acid (HVA) concentration showed peak values at 12–18 days; thereafter it declined again until adult levels were reached at 30–60 days. The striatal HVA levels at 60 days were higher than those at day 4, whereas in the brain without striata the concentration of the acid was lower at day 60 than at day 4. Probenecid caused the same HVA increment in the brain at all ages. The haloperidol-induced increase of cerebral HVA was smaller in the early (1–12 days) than in the later period (18–60 days) of postnatal development. Apomorphine was progressively more effective in reducing the HVA levels from day 1 to day 60. It is concluded that the turnover of striatal DA is relatively high during the first days of the postnatal period and then progressively decreases until the adult rate is reached at about 60 days. This change may be connected with the maturation of the DA stores, the DA receptors and the feedback mechanism regulating DA synthesis. The decrease of the HVA levels in the extrastriatal brain parts between days 12 and 60 is possibly due to maturation of the noradrenergic system.

Morphine catalepsy in the rat: relation to striatal dopamine metabolism

In rats morphine, like chlopromazine, produced catalepsy and raised striatal homovanillic acid levels. Analysis of interactions between each of these cataleptogenic agents and naloxone, 1-DOPA and apomorphine strongly suggests that morphine influences striatal dopamine (DA) metabolism and produces catalepsy by a mechanism different from that of chlorpromazine.

Striatal homovanillic acid levels in rats after combined treatments with amphetamine and neuroleptics

Dextro-amphetamine, 10 mg/kg, antagonized the rise of striatal homovanillicacid induced by chlorpromazine, 4 mg/kg, and potentiated the rise induced by triperidol, 0.25 mg/kg. Te results suggest that different mechanisms may be involved in the mode of action of these two neuroleptics at the level of brain dopaminergic receptors.