Dopamine And 3,4-dihydroxyphenylacetic Acid Research Articles

Effect of chronic amphetamine administration on central dopaminergic mechanisms in the vervet.

A biochemical study of central dopaminergic mechanisms was carried out in brain tissue from vervet monkeys who had been subjected to chronic amphetamine administration. The brain concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were markedly reduced. Significant reductions were also observed in the activities of dopa-decarboxylase (DDC) and tyrosine hydroxylase (TH). A kinetic study of TH revealed a 60% reduction in maximum reaction velocity, consistent with destruction of DA neurones. However, homovanillic acid (HVA) concentrations were only moderately reduced, suggesting a nearly normal production of DA. Hence despite the large depletions in DA concentrations, high affinity binding of 3H-spiperone binding to striatal DA receptors was no different from controls. The results are discussed in relation to the amphetamine psychosis in humans.

Differential effects of IV and IP muscimol on central dopamine metabolism.

The effect of IV and IP muscimol on the concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in both the nigrostriatal and mesolimbic dopaminergic pathways has been studied. IV muscimol (2 mg/kg), produced significant decreases in the concentration of DA in both DA systems, while the concentration of DOPAC remained unaltered. However, IP muscimol (5 and 10 mg/kg) caused significant increases in the concentrations of DA or DOPAC in all brain regions examined. Our results suggest differential actions of muscimol on DA metabolism dependent upon the route of administration.

Genotypic influences on striatal dopaminergic regulation in mice

Genotypic influences on dopaminergic-induced behaviors and striatal dopaminergic receptors were evaluated in CBA/J, C57BL/6J and BALB/cJ male mice. CBA/J mice were less behaviorally sensitive to apomorphine (stereotypic behavior) but more sensitive to haloperidol (catalepsy) than C57BL/6J and BALB/cJ mice. Striatal dopaminergic receptors, assayed by binding of [3H]spiroperidol (antagonist) and [3H]ADTN (agonist), were 50% fewer in CBA/J compared to BALB/cJ mice; C57BL/6J mice had low to intermediate numbers of receptors. Striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were similar in all strains. However, a 20% higher DOPAC/dopamine ratio in CBA/J mice suggests greater dopamine turnover. Median eminence dopamine was similar in all strains, but norepinephrine was 30% higher in BALB/cJ mice. CBA/J mice failed to show antagonist-induced supersensitivity-type responses to chronic haloperidol treatment: enhanced stereotypic response to apomorphine and a 30% increase of dopaminergic receptors occurred in C57BL/6J and BALB/cJ mice, but not in CBA/J mice. These data suggest that CBA/J mice either cannot respond to chronic haloperidol treatment or have an elevated threshold for induction of supersensitivity response. Chronic treatment with the dopamine agonist bromocriptine (7d) depressed apomorphine-induced stereotypic behavior in C57BL/6J mice and eliminated stereotypy in BALB/cJ mice, but caused no change in stereotypic behavior in CBA/J mice. Dopaminergic receptors were 15% lower after bromocriptine treatment in all strains. These results suggest that some striatal dopaminergic functions are impaired in CBA/J mice relative to BALB/cJ and C57BL/6J mice. The impaired haloperidol-induced supersensitivity responses in the CBA/J mouse may be a useful model for analyzing similar impairments of supersensitivity responses in old rodents.

Evaluation of the effect of drugs on dopamine metabolism in the rat superior cervical ganglion by HPLC with electrochemical detection

Drugs known to affect central dopamine turnover, were investigated for their effects on dopamine metabolism in the rat superior cervical ganglion (SCG). A highly sensitive method (fmol range) for the determination of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) based on isolation on Sephadex columns in combination with high performance liquid chromatography (HPLC) with electrochemical detection, has been developed. The rate of formation of dopamine as well as of DOPAC was determined by monoamine oxidase inhibition. The calculated rate of formation for dopamine was: 250 pmol/ganglion/h, and for DOPAC: 289 pmol/ganglion/h. (+)-Amphetamine, apomorphine as well as haloperidol induced a decrease in DOPAC concentration in the SCG. The effect of haloperidol lasted for at least 8 h. The DOPAC concentrations indicated that chloral hydrate anesthesia markedly inhibited the activity of dopaminergic neurons in the SCG. These observations strongly suggest that the interaction between postsynaptic receptor blockade and the release of dopamine differs in the SCG and in central dopamine receptors.

Dopamine metabolism, spiperone binding and adenylate cyclase activity in the adult rat hippocampus after ingrowth of dopaminergic neurones from embryonic implants

The growth of dopamine (DA) neurones of rat embryonic mesencephalic brain tissue implanted close to the anterior part of the hippocampus of adult rats was studied by measuring the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the host hippocampus. The hippocampal levels of DA and DOPAC reached maximal values 6 months after transplantation. The neuroleptic drug haloperidol evoked an increase in the levels of DOPAC. No evidence was found for the induction of DA-sensitive adenylate cyclase activity or of binding sites of [3H]spiperone. These results indicate that there is a substantial ingrowth of transplanted DA neurones into the host hippocampus, but no evidence was found for the development of functional contacts between the embryonic DA neurons and the host tissue.

A radioenzymatic method to measure picogram amounts of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in small samples of brain tissue.

A radioenzymatic method for simultaneous determination of dopamine and DOPAC in small brain areas is described. By using this assay, 250 pg of dopamine and 150 pg of DOPAC can be estimated. The present method has been applied to compare the effect of different psychotropic drugs on the dopamine and DOPAC levels in the caudate nucleus, substantia nigra and medial basal hypothalamus.

Pharmacological evidence for dopaminergic pallido-striatal interaction

In rats the contents in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) of neostriatum (nucleus caudatoputamen, NCP) and paleostriatum (globus pallidus, GP) were measured after transection of the capsula interna (CI) or after injection of 6-hydroxydopamine (6-OHDA; 20 μg/2 μl) into the GP of one side. The circling behaviour of the lesioned animals following apomorphine was also studied. 6-OHDA as well as transection decreased the contents in DA and DOPAC in NCP and GP significantly. Following both treatments DA levels in neostriatum were lowest. Nigro-neostriatal pathway lesioned animals (transected or injected with 6-OHDA 16 μg/2 μl into substantia nigra, SN) rotated towards the side of lesion after apomorphine (5 mg/kg IP), whereas GP lesioned animals rotated towards the intact side. In animals with both GP and SN lesions at one side turnings of similar intensity towards both sides were seen. In intact rats DA injections (200 μg/2 μl) into SN or NCP exhibited contralateral, injections into GP exhibited ipsilateral rotations. The results strengthen the hypothesis on the participation of GP in the regulation of neostriatal content of DA and shows the interaction of the hypothetical dopaminergic pallido-striatal pathway with nigro-neostriatal pathways.

Metabolic fate of 3,4-dihydroxyphenylpyruvic acid (DHPP) in rats. I. Specific transformation of DHPP to L-3,4-dihydroxyphenylalanine in vitro.

3, 4-Dihydroxyphenylpyruvic acid-2-14C (DHPP-2-14C) was prepared from glycine-2-14C and the specific formation of L-3, 4-dihydroxyphenylalanine (L-DOPA) from DHPP was shown in vitro. The metabolism of L-DOPA-3-14C was also investigated in vitro for comparison. In rat brain and small intestinal homogenates, L-DOPA was formed gradually as the main metabolite from DHPP-2-14C but dopamine and its metabolites were very slight amount. On the contrary, dopamine was detected dominantly from L-DOPA-3-14C in small intestinal homogenates. In the liver and kidney homogenates, DHPP was metabolized extensively and disappeared immediately with concomitant rapid formation of L-DOPA. Dopamine and 3, 4-dihydroxyphenylacetic acid (DOPAC) were detected subsequently as the main metabolite. The same extensive metabolism of L-DOPA-3-14C was also shown in the liver homogenates. Formation of L-DOPA from DHPP was identified by thin-layer chromatography and reverse isotope dilution method. L-Phenylalanine, L-tyrosine, L-tryptophan and L-glutamate were revealed to be effective amino donors to DHPP. The aromatic L-amino acids were particularly effective but D-phenylalanine showed little activity. The liberation of 14CO2 from DHPP-2-14C was also recognized in vitro. The 14CO2 liberating activity from DHPP-2-14C located in 105000 g supernatant soluble fraction in the liver and kidney wherein the activity in the liver was about 4 fold higher than that in the kidney. The activity was inhibited by sodium azide, sodium diethyldithiocarbamate, p-hydroxyphenylpyruvate and phenylpyruvate but not influenced by SKF 525A, carbon monoxide, EDTA, α, α'-dipyridyl and pyruvate. Methylene blue, dichlorphenolindophenol and ascorbate activated about 2-3 fold.