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PubMed1995

Dopamine in the lobster Homarus gammarus: II. Dopamine-immunoreactive neurons and development of the nervous system.

Dopamine-immunoreactive neurons were revealed in lobster embryos, larvae, and postlarvae, and staining patterns were compared to neuronal labeling in the juvenile lobster nervous system (Cournil et al. [1994] J. Comp. Neurol. 344:455-469). Dopamine immunoreactivity is first detected by midembryonic life in 35-40 neuronal somata located anteriorly in brain and subesophageal ganglion. When the lobsters assume a benthic life during the first postlarval stage, an average of 58 cell bodies are labeled. The acquisition of dopamine in lobster neurons is a protracted event spanning embryonic, larval, and postlarval life and finally reaching the full complement of roughly 100 neurons in juvenile stages. Some of the dopaminergic neurons previously identified in the mature nervous system, such as the paired Br cells, L cells, and mandibular cells, are labeled in embryos and persist throughout development. In contrast, other neurons stain transiently for dopamine during the developmental period, but, by the adult stage, these neurons are no longer immunoreactive. Such transiently labeled neurons project to the foregut, the thoracic dorsal muscles, the neurohormonal pericardial plexus, and the pericardial pouches. It is proposed that these neurons are alive and functioning in adult lobster but that dopamine levels have been abolished, providing that neurotransmitter status is a dynamic, changing process.

Animals↗

PubMed1998

Mutational and biochemical analysis of dopamine in dystonia: evidence for decreased dopamine D2 receptor inhibition.

The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D2 receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D2 receptor-mediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.

Animals↗

PubMed1989

Dopamine inhibits corticosteroid secretion in frog adrenocortical cells: evidence for the involvement of prostaglandins in the mechanism of action of dopamine.

We have investigated the possible involvement of arachidonic acid metabolites in dopamine-induced inhibition of adrenocortical steroidogenesis. Administration of dopamine (5 x 10(-5) M) for 20 min to perifused frog adrenal slices caused a marked reduction of the release of both prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha, the stable metabolite of prostacyclin (PGI2). Dopamine also induced a significant inhibition of corticosterone and aldosterone secretion. A lag period of 20 min was observed between inhibition of prostanoid and corticosteroid releases. Prolonged dopamine infusion did not prevent the stimulatory effect of PGE1, PGE2 or arachidonic acid on corticosteroid secretion. These observations indicate that activation of dopaminergic receptors in adrenocortical cells is linked to an inhibition of arachidonic acid metabolism. Our data also suggest that the inhibitory effect of dopamine occurs at a step preceding arachidonic acid formation.

Adrenal Cortex↗

PubMed1987

Nigrostriatal dopamine neurons: modulation of impulse-induced activation of tyrosine hydroxylation by dopamine autoreceptors.

The role of dopamine autoreceptors on nerve terminals in controlling the activity of tyrosine hydroxylase in the striatum was examined using a model involving supramaximal electrical stimulation of the nigro-neostriatal fibers and accumulation of 3,4-dihydroxyphenylalanine (DOPA) as a measure of the activity of tyrosine hydroxylase in vivo. In this way effects of drugs on impulse flow in these neurons could be negated and the effects on dopamine autoreceptors evaluated. Electrical stimulation, haloperidol, pimozide and clozapine increased the activity of tyrosine hydroxylase in vivo while trivastal, a dopamine agonist, had no significant effect. Combination of electrical stimulation with haloperidol or pimozide produced an additive effect on the activity of tyrosine hydroxylase, consistent with blockade of autoreceptors on nerve terminals. The combination of stimulation with clozapine (a drug shown to have minimal blocking action on autoreceptors in this model) produced an effect equivalent to stimulation alone, consistent with a lack of effect on autoreceptors. Trivastal reduced the effect of electrical stimulation, indicating a stimulatory action on dopamine autoreceptors on nerve terminals. These data are consistent with the theory of regulation of the activity of tyrosine hydroxylase in dopaminergic nerve terminals of the striatum by means of dopamine autoreceptors.

Animals↗

PubMed1991

Effects of acute and chronic systemic administration of some typical antipsychotic drugs on turnover of dopamine and potassium ion-induced release of dopamine in the striatum of the rat in vivo.

Chronoamperometry was used to measure the dose dependency of antipsychotic drug (spiperone, haloperidol and chlorpromazine)-induced increases in depolarization-stimulated release of dopamine in the striatum of the rat in vivo. The dose-response curves were found to be at least biphasic (small doses increased release and large doses inhibited release) and different in shape from dose-response curves for increases in the turnover of dopamine, suggesting that the two processes may not be related. The threshold dose to induce increased depolarization-stimulated release of dopamine correlated with the values in the literature for doses required to block stereotype induced by apomorphine and amphetamine and doses sufficient to cause a maximal increase in release correlated with the doses required for the induction of catalepsy. In addition, the ratio of the doses required to obtain half-maximal and maximal increases in stimulated release of dopamine, matched values in the literature of the ratio of doses required to ameliorate psychotic symptoms, whereas the doses required to reverse the increase induced by antipsychotic drugs did not. Chronic administration of haloperidol resulted in alterations in the dose-response curves for both the release and turnover of DA. Chronic administration caused a reversal of the effect of acute administration in the small dose range (inhibition as opposed to enhancement of release), a decrease in the maximum magnitude of release of dopamine obtained and an overall shift to the right of the dose-response curve. Chronic administration of haloperidol decreased turnover, relative to animals receiving the drug acutely and no shift in the position of the dose-response curve was observed.

Animals↗

PubMed1988

Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway--II. Differential localization of dopamine and cholecystokinin receptors.

The autoradiographical localization of dopamine D1, D2 and cholecystokinin receptors has been investigated in rat brain 6 months following unilateral infusion of 1-methyl-4-phenyl pyridinium ion (MPP+) (10 micrograms/day for 7 days) into the nigrostriatal dopamine pathway. Treatment with 1-methyl-4-phenyl pyridinium ion produced a marked depletion of dopamine cell bodies in the substantia nigra together with greater than 95% loss of tyrosine hydroxylase immunoreactivity in the striatum. Measurement of specific [3H]spiperone binding to D2 receptors indicated a 38% increase (P less than 0.01) in the maximal binding capacity of [3H]spiperone to striatal membrane homogenates and a 13% increase (P less than 0.05) in specific [3H]spiperone binding to striatal tissue sections, verifying striatal D2 receptor denervation supersensitivity. In contrast, MPP+ lesion of the nigrostriatal tract had no effect on the autoradiographical localization of striatal D1 or cholecystokinin receptors. In addition, there was a 38% loss (P less than 0.05) of D2 receptor binding sites in the substantia nigra pars compacta, whilst D1 receptors remained unchanged. Similar changes in dopamine and cholecystokinin receptor number were found following 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. These results provide further evidence that 1-methyl-4-phenyl pyridinium ion treatment in rats produces extensive destruction of the dopaminergic nigrostriatal tract and supports the differential anatomical localization of striatal and nigral D1, D2 and cholecystokinin receptors.

1-Methyl-4-phenylpyridinium↗

PubMed2006

Brain hemodynamic changes mediated by dopamine receptors: Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling.

The coupling between neurotransmitter-induced changes in neuronal activity and the resultant hemodynamic response is central to the interpretation of neuroimaging techniques. In the present study, MRI experiments showed that dopamine transporter blockers such as cocaine and dopamine releasers such as amphetamine and D1 receptor agonists induced large positive increases in relative cerebral blood volume (rCBV) that were not sensitive to nitric oxide synthase inhibition. However, D1/D5 receptor antagonism with SCH-23390 prevented or blocked the hemodynamic response without any concomitant effect on dopamine release. Dopamine D2/D3 receptor agonists, in contrast, induced negative changes in rCBV in brain regions corresponding largely to those endowed with these receptors. D1 and D5 receptor mRNAs were expressed in microvessels of responsive brain areas, while D2 and D3 receptors were not consistently associated with the microvascular bed. D3 receptors had an astroglial localization. Together, these experiments show that direct effects of dopamine upon the vasculature cannot be ignored in measuring the hemodynamic coupling associated with dopaminergic drugs. These results further suggest that this coupling is partially mediated through D1/D5 receptors on the microvasculature leading to increased rCBV and through astroglial D3 receptors leading to decreased rCBV. These data provide additional support for the role of local post-synaptic events in neurovascular coupling and emphasize that the interpretation of fMRI signals exclusively in terms of neuronal activity may be incomplete.

Animals↗

PubMed2004

Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes.

The functional specificity of dopamine receptor subtypes remains incompletely understood, in part due to the absence of highly selective agonists and antagonists. Phenotypic analysis of dopamine receptor knockout mice has been instrumental in identifying the role of dopamine receptor subtypes in mediating dopamine's effects on motor function, cognition, reward, and emotional behaviors. In this article, we provide an update of recent studies in dopamine receptor knockout mice and discuss the limitations and future promise of this approach.

Animals↗

PubMed1998

Dopamine and the mechanisms of cognition: Part I. A neural network model predicting dopamine effects on selective attention.

BACKGROUND: Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task. METHODS: Task performance is stimulated using principles and mechanisms that capture salient aspects of information processing in neural ensembles. Dopamine effects are simulated as a change in gain of neural assemblies in the area of release. RESULTS: The model leads to different predictions as a function of the hypothesized location of dopamine effects. Motor system effects are simulated as a change in gain over the response layer of the model. This induces speeding of reaction times but an impairment of accuracy. Cognitive attentional effects are simulated as a change in gain over the attention layer. This induces a speeding of reaction times and an improvement of accuracy, especially at very fast reaction times and when processing of the stimulus requires selective attention. CONCLUSIONS: A computer simulation using widely accepted principles of processing in neural ensembles can account for reaction time distributions and time-accuracy curves in a selective attention task. The simulation can be used to generate predictions about the effects of dopamine agonists on performance. An empirical study evaluating these predictions is described in a companion paper.

Attention↗

PubMed1999

A systematic regional study of dopamine and dopamine-derived salsolinol and norsalsolinol levels in human brain areas.

Dopamine and the dopamine-derived tetrahydroisoquinoline alkaloids salsolinol and norsalsolinol were measured by high-performance liquid chromatography with electrochemical detection in 15 regions of the human brain. The regional distribution of dopamine in 32 brains was similar to previous reports with highest concentrations in the basal ganglia, especially in the striatum, followed by the substantia nigra and the hypothalamus. Significant amounts of salsolinol and norsalsolinol were only found in these dopamine-rich areas, whereas in the other regions no alkaloids were detected. These findings suggest that the concentration of the substrate dopamine may determine the alkaloid level during in vivo formation.

Adult↗

PubMed1994

Age-dependent alterations in dopamine content, tyrosine hydroxylase activity, and dopamine uptake in the striatum of the weaver mutant mouse.

Mice of different ages and homozygous or heterozygous for the weaver gene (wv) were used to study the time course for the effect of the weaver gene on several striatal dopaminergic parameters. Dopamine uptake was decreased in the homozygous weaver at all ages examined. The deficit in uptake at the earliest age studied, postnatal day 3, was approximately 50% and increased to greater than 70% at older ages. In control mice, dopamine uptake reached a maximum by postnatal day 22, but in homozygous weaver mice, development of uptake activity was curtailed by postnatal day 7. Dopamine content and tyrosine hydroxylase activity were significantly decreased in the homozygous weaver at all ages studied except postnatal days 7 and 10. The magnitude of the deficit in dopamine content ranged from approximately 40% at postnatal days 3 and 5 to about 70% in adults (6 months to 1 year of age). The magnitude of the deficit in tyrosine hydroxylase activity ranged from 40 to 70%. In general, no major differences between heterozygotes and controls were observed for any of the dopaminergic parameters investigated. The results of the present investigation indicate that neurochemical alterations can be observed in the striata of weaver mice as early as postnatal day 3 and raise the possibility that the striatal dopamine transporter may be an early target of the weaver mutation.

Aging↗

PubMed1979

Haemodynamic effects of dopamine and dopamine combined with nitroglycerin in patients subjected to coronary bypass surgery.

The haemodynamic effects of dopamine and dopamine with nitroglycerin were evaluated in eight patients with coronary heart disease who underwent aortocoronary bypass surgery. The study was performed under anaesthesia and before surgery. Dopamine 8 micrograms kg-1 min-1 alone produced a marked increase of the cardiac index from 2.47 to 3.47 litre min-1 m-2 but only small changes in heart rate (from 65 to 68 beat min-1). This improvement in cardiac performance was accompanied by an increase of the mean pulmonary artery pressure from 10.9 to 21.3 mm Hg and in the left ventricular filling pressure from 6.1 to 13.8 mm Hg with unchanged systemic and pulmonary vascular resistance. Mean arterial pressure increased from 72 to 103 mm Hg. Simultaneous infusion of dopamine (8 micrograms kg-1 min-1) and nitroglycerin (mean dose 0.5 microgram 21.3 to 14.4 mm Hg) and of left ventricular filling pressure (from 13.8 to 7.9 mm Hg). Cardiac index (from 3.47 to 3.34 litre min-1 m-2) and mean arterial pressure (from 103 to 95 mm Hg) were not reduced to the same extent by the addition of nitroglycerin. The combined treatment of dopamine with nitroglycerine seems to be of value in patients with pre-existing high left ventricular filling pressure or with pulmonary hypertension.

Adult↗

PubMed1986

Mobilization of storage pool dopamine and late ipsilateral augmentation of striatal dopamine synthesis in the trained circling rat.

Rats were infused intraventricularly with [3H]tyrosine over a 20-min period during various times while circling. 3,4-Dihydroxyphenylethylamine (dopamine) and dihydroxyphenylacetic acid (DOPAC) levels were measured using HPLC with electrochemical detection and fractions were collected for tritium monitoring. During the first 20 min of circling, the specific activity of dopamine was increased by 290% in striatum contralateral to the circling direction whereas DOPAC specific activity was increased 50% on the same side. This differential change in relative specific activity suggests that unlabeled storage pool dopamine was mobilized to DOPAC during circling. Synthesis of dopamine and DOPAC in contralateral striatum returned to baseline levels as turning slowed (50-70 min). When turning ceased, there was an increase in ipsilateral striatal dopamine synthesis during the 20-min period following circling. We hypothesize that this ipsilateral increase represents either a "stop" signal following circling or a release of inhibition of ipsilateral nigral neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Estimation of free dopamine in the cytoplasm of the giant dopamine cell of Planorbis corneus by voltammetry and capillary electrophoresis.

Voltammetric electrodes having a tip diameter of 2-12 microns and microscale capillary zone electrophoresis have been used for dynamic and static monitoring of dopamine in the somal cytoplasm of the giant dopamine neuron of Planorbis corneus. Intracellular dopamine levels can be altered by extracellular application of dopamine or ethanol. The latter experiment provides a means to estimate total stores of endogenous dopamine, and the evidence presented suggests that at least 98% of these stores are bound and not directly accessible to the cytoplasm.

Animals↗

PubMed1991

Cyclic AMP modulates differentially the release of dopamine induced by hypoxia and other stimuli and increases dopamine synthesis in the rabbit carotid body.

We have investigated the effects of different treatments that increase cyclic AMP levels on the in vitro synthesis and release of catecholamines in the rabbit carotid body. We also measured the rate of 45Ca2+ efflux from previously loaded carotid bodies under different conditions. Forskolin produced a dose-dependent increase in the release of [3H]dopamine elicited by a hypoxic stimulus of medium intensity (PO2 = 33 mm Hg) without altering basal [3H]dopamine release (100% O2-equilibrated medium). At a concentration of 5 x 10(-6) M, forskolin increased the release of [3H]dopamine induced by hypoxic stimuli of different intensities; the increase was maximal (498%) at the lowest intensity of hypoxic stimuli (PO2 = 66 mm Hg), averaged 260% for hypoxic stimuli of intermediate intensity and 2 x 10(-4) M cyanide, and was 150% under anoxia. Dibutyryl cyclic AMP (2 mM) and 3-isobutyl-1-methylxanthine (0.5 mM) mimicked forskolin effects under hypoxic stimulation. Forskolin (5 x 10(-6) M) also increased (180%) the release of [3H]dopamine induced by 20% CO2/pH 6.6, 2.5 x 10(-4) M dinitrophenol, and 3 x 10(-5) M ionomycin. Forskolin and 3-isobutyl-1-methylxanthine were without effect on the release of [3H]dopamine elicited by 30 mM extracellular K+. Forskolin (5 x 10(-6) M) augmented significantly the rate of 45Ca2+ efflux induced by hypoxic stimuli (PO2 of 33 and 66 mm Hg) and 2 x 10(-4) M cyanide and showed a tendency to increase (20%) the 45Ca2+ efflux induced by dinitrophenol and low pH and to decrease (21%) the efflux induced by 30 mM K+ without altering the rate of efflux under basal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1976

The dopamine hypothesis of schizophrenia: focus on the dopamine receptor.

Alleviation of schizophrenic symptoms by phenothiazines and butyrophenones is associated with blockade of dopamine receptors, while exacerbation of symptoms by amphetamines appears to result from enhanced synaptic activity of dopamine and/or norepinephrine. The author suggests that biochemical labeling of the dopamine receptor with 3H-dopamine and 3H-haloperidol may clarify mechanisms of drug effects on the dopamine receptor.

Amphetamine↗

PubMed1976

Dopamine synthesis in rat brain striatal synaptosomes. I. Correlations between veratridine-induced synthesis stimulation and endogenous dopamine release.

The effects of depolarizing concentrations of veratridine were studied to determine the degree to which dopamine synthesis stimulation was correlated with stimulated endogenous dopamine release in rat brain striatal synaptosomes. Incubations included cocaine and pargyline to prevent dopamine reuptake and metabolism, respectively. Veratridine produced a 44% increase in dopamine release in 10 minutes and a similar increase in synthesis rate. Preincubation with tetrodotoxin prevented the increase in both release and synthesis, while incubation in a calcium-free medium antagonized both responses approximately 50%. Addition of 1 mM ethylene glycol bis(beta-aminoethylether)-N, N'-tetraacetic acid to the calcium-free incubation medium further inhibited the release response, but not the synthesis stimulation. These results indicate that, in general, the degree of synthesis stimulation produced by depolarizing agents such as veratridine can be correlated with their stimulation of dopamine release, suggesting either 1)that transmitter release itself is a signal for synthesis stimulation, possibly by removal of feedback inhibition of tyrosine hydroxylase or 2) that depolarizing agents increase synthesis through a secondary metabolic change that is either caused by, or at least accompanied by, transmitter release.

Animals↗

PubMed1997

The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group.

BACKGROUND: Based mainly on the selective antagonism of clozapine at D4 compared with D2 dopamine receptors, hopes have run high that a selective D4 dopamine receptor antagonist might improve the pharmacological treatment of patients with schizophrenia. We report, to our knowledge, the first multicenter study of the antipsychotic potential of a highly specific D4 dopamine receptor antagonist (ie, L-745,870) in patients with acute schizophrenia. METHODS: Thirty-eight acutely psychotic and neuroleptic responsive (by history) newly admitted inpatients with schizophrenia were randomized to 4 weeks of double-blind treatment (2:1) with either L-745,870 (n = 26), 15 mg/d, or placebo (n = 12) after a 3- to 5-day placebo run-in period. RESULTS: Overall, a greater percentage of patients receiving L-745,870 compared with patients receiving placebo discontinued the study for insufficient therapeutic response (32% vs 16%). At the end of 4 weeks by last observation carried forward analysis, the mean change from baseline to week 4 on the total Brief Psychiatric Rating Scale favored placebo (i.e., -8 points [-15% change from baseline] vs -1 point [-2% change from baseline] for placebo vs L-745,870, P = .09). Similar differences in favor of placebo in changes from baseline mean scores were observed for the not carried forward analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on the sum of selected positive symptom items of the Brief Psychiatric Rating Scale, and for the Clinical Global Impression analysis (P = .03, last observation carried forward). A greater percentage of patients receiving L-745,870 had scores indicative of some level of worsening (compared with baseline) on the total Brief Psychiatric Rating Scale and the Clinical Global Impressions' Severity of Illness Scale as well as positive symptoms compared with those receiving placebo. CONCLUSION: The selective D4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpatients with acute schizophrenia.

Acute Disease↗