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PubMed2001

A novel mechanism of dopamine neurotoxicity involving the peripheral extracellular and the plasma membrane dopamine transporter.

Chinese hamster ovary cells stably expressing a rat dopamine transporter (designated D8 cells) and neuroblastoma SK-N-SH cells were used as two model systems to study dopamine neurotoxicity. Within 24 h, 1-10 mM dopamine induced D8 cells into apoptosis while 20-200 microM dopamine induced SK-N-SH cells into cell death. The viability of both cell types decreased in a dose-dependent manner. However, the dopamine uptake activity of D8 cells at 10 mM was not significantly higher than the uptake at 100 microM, suggesting that it was not the high concentration of intracellular dopamine that induced D8 cells into apoptosis, but rather dopamine found in the extracellular space. Furthermore, cocaine, an inhibitor of dopamine uptake, could not block cell death induced by dopamine. Forskolin, an agonist of protein kinase A (PKA), stimulated dopamine uptake in D8 cells and blocked apoptosis induced by the drug. These results suggest that the dopamine transporter mediates a dopamine-dependant apoptotic signal transduction pathway that is independent of dopamine uptake into the cell.

Animals↗
PubMed2003

Dopamine D2 receptor modulates sodium handling via local production of dopamine in the kidney.

We have recently demonstrated that a deletion of the dopamine D2 receptor gene caused suppression of urinary sodium excretion and salt-sensitive elevation of blood pressure in mice. In order to understand the mechanisms underlying this impaired sodium excretion, we studied renal dopamine production and dopamine-induced sodium excretion in 20- to 30-week-old male D2-receptor knockout (D2KO) mice and age- and sex-matched wildtype (WT) mice. Renal local dopamine synthesis, examined by 24-h urine free dopamine excretion (UDAV), was significantly (p < 0.05) reduced in D2KO mice compared to that in WT mice (D2KO versus WT: 1.06 +/- 0.2 versus 1.5 +/- 0.3 ng/mg creatinine). Such a difference between D2KO and WT mice was also observed after oral administration of 3,4-dihydroxyphenylalanine (L-DOPA), a precursor of dopamine, at 5 mg/kg per day for 24 h. Furthermore, activity of aromatic 1-amino acid decarboxylase, a dopamine synthetase, was significantly suppressed in D2KO mice. Next, we examined changes in 24-h urine flow (UV) and 24-h sodium excretion (UNaV) during chronic infusion of dopamine at sub-pressor doses (3-4 microg/kg per min, sq.) or a vehicle via an osmotic pump. Urine flow in 24 h and UNaV were significantly (p < 0.05) smaller in D2KO mice infused with vehicle than in WT mice infused with vehicle (UV: 210 +/- 43 versus 650 +/- 163 microl/day; UNaV: 20.6 +/- 13.2 versus 44.4 +/- 21.6 microEq/day). After administration of dopamine, UV and UNaV in D2KO mice were restored to a level similar to that in WT mice. These results indicate that D2-dopamine receptors play a significant role in renal local dopamine synthesis and that a shortage of dopamine was, at least in part, responsible for the suppression of UV and UNaV in D2KO mice. However, we could not conclude from the present study whether renal tubular sodium reabsorption is intact in D2KO mice because the baseline dopamine contents in kidneys of D2KO mice and WT mice may be different.

Administration, Oral↗
PubMed1999

Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine.

Methamphetamine-induced toxicity has been shown to require striatal dopamine and to involve mechanisms associated with oxidative stress. Dopamine is a reactive molecule that can oxidize to form free radicals and reactive quinones. Although this has been suggested to contribute to the mechanism of toxicity, the oxidation of dopamine has never been directly measured after methamphetamine exposure. In this study we sought to determine whether methamphetamine-induced toxicity is associated with the oxidation of dopamine by measuring the binding of dopamine quinones to cysteinyl residues on protein. We observed that administration of neurotoxic doses of methamphetamine to rats resulted in a two- to threefold increase in protein cysteinyl-dopamine in the striatum 2, 4, and 8 hr after treatment. When methamphetamine was administered at an ambient temperature of 5 degreesC, no increase in dopamine oxidation products was observed, and toxicity was prevented. Furthermore, as shown by striatal microdialysis, animals treated with methamphetamine at 5 degreesC showed DA release identical to that of animals treated at room temperature. These data suggest that the toxicity of methamphetamine and the associated increase in dopamine oxidation are not exclusively the result of increases in extracellular dopamine. Because dopamine-induced modifications of protein structure and function may result in cellular toxicity, it is likely that dopamine oxidation contributes to methamphetamine-induced toxicity to dopamine terminals, adding support to the role of dopamine and the evidence of oxidative stress in this lesion model.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Different changes in striatal dopamine metabolism induced by nicotine in mice kept at different ambient temperatures. Evidence for partly separate metabolic routes of dopamine derived from separate compartmentations.

Further information about the nicotine-induced changes in striatal dopamine metabolism in hypothermic mice was searched by measuring the contents of dopamine and its metabolites (3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and homovanillic acid, HVA) after blocking the synthesis of dopamine by alpha-methyl-p-tyrosine (alpha-MT). This method gave a possibility to study the effect of nicotine on the metabolism of dopamine in two pools (the cytoplasmic "newly-synthesized" dopamine and the granular dopamine). 3 mg/kg of (-)nicotine was given s.c. four times, at 110, 80, 50 and 20 min, and alpha-MT (250 mg/kg i.p.) at 60 min before sacrifice. To prevent the peripheral effects of nicotine all mice were given hexamethonium (10 mg/kg i.p.) at 140 min before sacrifice. Hexamethonium did not alter striatal dopamine metabolism. Experiments were performed at 20-22 degrees C at which temperature nicotine induced hypothermia or at 32-34 degrees C. The alpha-MT-induced proportional decrease of 3-MT content was clearly less than that of dopamine content. On the contrary the alpha-MT treatment decreased the DOPAC content proportionally more than the dopamine content. Thus DOPAC could not be solely formed from the same dopamine pool as 3-MT. These results indicate that 3-MT reflects best the metabolism of the granular dopamine and DOPAC that of the "newly-synthesized" dopamine. In hypothermic mice nicotine administration reduced the alpha-MT-induced depletion of the dopamine content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

beta-Endorphin alters dopamine uptake by the dopamine neurons of the hypothalamus and striatum.

Opioid peptides have well-documented modulatory effects on the synaptic transmission of several neurotransmitters. In both hypothalamus and striatum there is dense innervation by the beta-endorphin and/or enkephalin neuronal systems, and physiologically relevant neuroregulatory interactions of these neurons occur with other important neurotransmitter neuronal systems, such as the dopaminergic tuberoinfundibular and nigroneostriatal systems. Previous reports have examined the effects of opioid peptides on release, synthesis and degradation of dopamine in these brain regions. In this report, we describe the effects of the intracerebral administration of beta-endorphin to increase dopamine (re)uptake by dopaminergic nerve terminals of the hypothalamus and striatum. The specific, high affinity uptake of [3H]dopamine by dopaminergic nerve terminals was studied in a synaptosomal preparation by pharmacological exclusion, using desmethylimipramine, of dopamine uptake into other monoaminergic nerve terminals. The augmentation of in vitro dopamine uptake in both hypothalamus and striatum following intracisternal administration of beta-endorphin is specifically mediated by opiate receptors, since it could be prevented by pretreatment with an opiate receptor antagonist, naltrexone. In hypothalamus, the increased dopamine uptake represents a primary effect of beta-endorphin on hypothalamic dopamine neurons and is not secondary to the opioid peptide-induced stimulation of prolactin secretion, since identical effects of beta-endorphin administration are seen in hypophysectomized and intact animals. The effect of beta-endorphin to increase hypothalamic dopamine uptake was not reflected by a change in the affinity constant for dopamine, but involved an increase in maximal initial velocity of uptake. Naltrexone blocked the effect of beta-endorphin to increase the Vmax for [3H]dopamine uptake by hypothalamic dopamine neurons in both intact and hypophysectomized rats. In vitro exposure of hypothalamic and striatal dopaminergic nerve terminals to a wide range of concentrations of beta-endorphin failed to reproduce the in vivo results; some concentrations of beta-endorphin produced small decreases in [3H]dopamine uptake which were not reversed by naloxone. The data of this study provide evidence for a further mechanism by which beta-endorphin may alter dopaminergic neurotransmission, namely by increasing dopamine reuptake into dopaminergic nerve endings.

Absorption↗
PubMed1995

Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: implications for psychopathology.

The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine depletion produced a highly significant increase. The results support a protective role for mesocortical dopamine in helping the organism cope with stressful situations, and extend previous findings suggesting that dopamine activation in the right cortex is preferentially associated with uncontrollable stress. The right cortex is hypothesized to be at the top of a hierarchy in the processing of such stressful inputs, and endogenous dopaminergic modulation facilitates adaptive responses. Subcortical dopamine terminal regions were also examined for dopamine content and turnover. In addition to depleting cortical dopamine, the three lesion groups showed highly specific alterations in the status of subcortical dopamine systems, compared to either restrained or non-restrained shams. Left brain lesions resulted in significant bilateral increases in amygdala dopamine turnover. Right cortical lesions induced significant bilateral reductions of striatal dopamine content. Bilateral lesions increased dopamine content in the left amygdala and decreased dopamine in the right nucleus accumbens. Also in this group, dopamine turnover was increased in the right nucleus accumbens and decreased in the right amygdala. The data suggest that increases in stress vulnerability induced by cortical lesions may be related, in part, to neurochemical alterations in subcortical structures previously shown to modulate gastric stress pathology. The results also indicate that brain organization is inherently asymmetrical with respect to the regulation of responses to stress, which may be of significance for human psychopathology and its exacerbation by stress.

Amygdala↗
PubMed1999

The relationship between ocular melatonin and dopamine rhythms in the pigeon: effects of melatonin inhibition on dopamine release.

Our previous study has shown that the phases of circadian rhythms of ocular melatonin and dopamine are always opposite and intraocular melatonin injection suppresses dopamine release. Therefore, it is possible that dopamine rhythms result from inhibitory action of melatonin. We have examined this possibility in the following experiments. In the first experiment effects of continuous light on melatonin and dopamine release were examined. The data indicated that continuous light exposure resulted in loss of circadian rhythmicity of melatonin and dopamine by suppressing melatonin and enhancing dopamine levels throughout the day. To further examine the effects of light in the second experiment, 2 h light pulse was applied during the night, then temporal changes of melatonin and dopamine release were studied. The light pulse rapidly suppressed melatonin release, whereas it rapidly increased dopamine release. These changes occurred within 30 min in both melatonin and dopamine. However, the recovery after the cessation of the light stimulus was slower in melatonin than dopamine. In the third experiment it was tested if dopamine release was increased by lowering melatonin release with an intraocular injection of the D2 agonist, quinpirol. Although quinpirol strongly inhibited melatonin release independently of the time of injection, dopamine did not always increase by the inhibition of melatonin. These results indicate that ocular dopamine rhythms are not simply produced by melatonin inhibitory action.

Animals↗
PubMed2003

Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine.

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to investigate roles of BDNF and TrkB in the expression of methamphetamine-induced dopamine release in the nucleus accumbens and dopamine-related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, s.c.) produced a substantial increase in the extracellular levels of dopamine and induced a progressive augmentation of dopamine-related behaviors such as rearing and sniffing. In contrast, both the stimulation of dopamine release and induction of dopamine-related behaviors by methamphetamine were significantly suppressed by pretreatment with intra-nucleus accumbens injection of either BDNF (2.0 microl/rat, 1:1000, 1:300 and 1:100) or TrkB (2.0 microl/rat, 1:1000 and 1:100) antibody. Furthermore, the basal level of dopamine in the nucleus accumbens was not affected by treatment with both BDNF and TrkB antibodies. These findings provide further evidence that BDNF/TrkB pathway is implicated in the methamphetamine-induced release of dopamine and the induction of dopamine-related behaviors.

Amphetamine-Related Disorders↗
PubMed1990

Reexamination of dopamine as the prolactin-release inhibiting factor (PIF): supplementary agent may be required for dopamine to function as the physiological PIF.

A large number of studies have been performed concerning dopamine's inhibitory effect on prolactin release, but many of these studies have examined the effect of dopamine dissolved in a solution containing ascorbic acid. Ascorbic acid, routinely used to protect dopamine from oxidation, alone does not stimulate or inhibit prolactin release, but it can potentiate the inhibitory effect of dopamine in a static monolayer culture system by approximately 100 times. We have closely examined the inhibitory effect of dopamine on prolactin release in the absence of ascorbic acid using a perifusion system. Male rat adenohypophyses were dispersed with trypsin and cultured in a Petri dish to form cell clusters. Inhibition of prolactin release by dopamine (1 mumol/L) in the absence of ascorbic acid was sustained for only 63 min during the 2-h perifusion period. Following a 2-h period of incubation of dopamine in the same experimental solution, the dopamine concentration was reduced from 1 to 0.18 mumol/L, yet this "2-h-old dopamine" was still effective in inhibiting prolactin release (approximately 30 min). This result suggests that the lactotrophs may be desensitized by chronic exposure to a high concentration of dopamine in the absence of ascorbic acid. In contrast, when a low concentration of dopamine (3 nmol/L) containing ascorbic acid (0.1 mmol/L) was perifused, inhibition of prolactin release was sustained for the entire 2-h perifusion period. Although there may be a large number of explanations for dopamine's transient inhibitory effect on prolactin release, the present results suggest that dopamine may require supplementary agent(s) to effectively inhibit prolactin release and thus function as the prolactin release inhibitory factor (PIF).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Handling of dopamine and dopamine sulfate by isolated perfused rat kidney.

The possible contribution of circulating dopamine sulfate to urinary free dopamine and the synthesis of norepinephrine by the renal nerves were examined in the isolated perfused rat kidney. Perfusion of the kidney with dopamine sulfate did not yield significant amounts of free dopamine indicating that, unlike L-dopa, dopamine sulfate is not a good source of urinary free dopamine. The excretion of dopamine sulfate was slower than or comparable with that of free dopamine, suggesting that sulfoconjugation is not a mechanism to facilitate the excretion of free dopamine. Unlike free dopamine, dopamine sulfate was not metabolized by renal catechol-O-methyltransferase or monoamine oxidase. Perfusion of L-dopa and free dopamine led to the generation of norepinephrine in the kidney. This synthesis was abolished when the kidney was denervated, suggesting that the renal nerves were the main sites of the norepinephrine synthesis. Both norepinephrine and dopamine were rapidly metabolized by catechol-O-methyltransferase and monoamine oxidase, but renal phenolsulfotransferase appeared to have no action on the catecholamines.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Dopamine stimulation of active Na and Cl absorption in rabbit ileum: interaction with alpha 2-adrenergic and specific dopamine receptors.

The effects of dopamine on active intestinal ion transport have been evaluated. An epithelial sheet preparation of rabbit ileum was used in vitro with the Ussing chamber-voltage clamp technique. Dopamine, in the presence of 1 mM ascorbic acid, added to the serosal bathing solution caused a dose-dependent decrease in short-circuit current, with a half-maximal effect at 1.2 muM and maximal effect of -50 muA/cm(2) at 50 muM; dopamine decreased the potential difference, and increased the conductance and net Na and net Cl absorption. There was no effect on the residual ion flux. Dopamine did not alter the change in short-circuit current caused by mucosal glucose (10 mM) or serosal theophylline (10 mM). Mucosal dopamine had no effect. The effect of dopamine on short-circuit current was inhibited by the dopamine antagonists haloperidol and domperidone and the alpha(2)-adrenergic antagonist yohimbine; there was no effect of the alpha(1)-antagonist prazosin and the beta-antagonist propranolol. In addition, the alpha(2)-adrenergic agonist clonidine, but not the alpha(1)-agonist methoxamine caused a dose-dependent decrease in short-circuit current. The ileal effects of dopamine did not occur via conversion into norepinephrine or release of norepinephrine from the peripheral nerves since "peripheral sympathectomy" with 6-hydroxydopamine did not alter the dopamine-induced change in ileal short-circuit current. The dopamine effects were not associated with a change in basal ileal cyclic AMP content but were associated with a decrease in total ileal calcium content as measured by atomic absorption spectrometry and as estimated by (45)Ca(++) uptake. The decrease in calcium content could be attributed to a dopamine-induced decrease in (45)Ca(++) influx from the serosal surface. Because of the presence of dopamine in ileal mucosa and these effects on ileal electrolyte transport, it is possible that dopamine may be involved in the physiologic regulation of active intestinal electrolyte absorption.

Animals↗
PubMed1994

Pharmacokinetic and pharmacodynamic studies of L-dopa in rats. II. Effect of L-dopa on dopamine and dopamine metabolite concentration in rat striatum.

The purpose of this investigation was to quantitatively describe the time courses of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations in the striatum after L-dopa injection using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was determined before and after the rapid i.v. injection of 10, 50 and 100 mg/kg using the same animals as in the previous report. The endogenous dopamine, DOPAC and HVA concentrations in the striatum before L-dopa administration were 5.9 +/- 0.7 micrograms, 3.6 +/- 0.4 micrograms and 1.0 +/- 0.2 micrograms/g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9 +/- 0.5 micrograms/g) occurring at 3 min; then it returned to the pre-medication level until 2 h at 100 mg/kg dosing. The time course of dopamine concentration in the striatum was analyzed on a constructed dopamine metabolism model which has a zero-order production rate for the production of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which was estimated in the previous report, and the other from dopamine to dopamine metabolites (DOPAC and HVA). However, the time course of dopamine concentration in the striatum could not be described by this model.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Decreased striatal dopamine efflux after intrastriatal application of benzazepine-class D1 agonists is not mediated via dopamine receptors.

Previous pharmacological studies have reported that striatal dopamine efflux is negatively modulated not only by presynaptic D2 dopamine autoreceptors but also by striatal D1 dopamine receptors. The present experiments employed in vivo microdialysis to further examine the ability of widely used benzazepine-class D1 agonists to modulate striatal dopamine efflux. In the present study, both the partial D1 agonist (+/-)-SKF 38393 (10 microM) and the full D1 agonist (+/-)-SKF 82958 (10 and 100 microM) significantly reduced striatal dopamine efflux during intrastriatal application. Intrastriatal application of the less active enantiomer, S(-)-SKF 38393 (10 microM) did not decrease striatal dopamine suggesting a selective receptor-mediated mode of action of (+/-)-SKF 38393. Additional experiments were conducted with the full D1 agonist (+/-)-SKF 82958 in order to characterize the receptor(s) mediating the observed decrease in dopamine efflux. Neither local application of the D1 antagonist R(+)-SCH 23390 (100 microM) nor local application of the selective D2 antagonist raclopride (5 microM) blocked the ability of (+/-)-SKF 82958 (10 microM) to decrease striatal dopamine efflux. However, intrastriatal application of the less selective D2 antagonist haloperidol (1 microM) did prevent the decrease in striatal dopamine efflux observed during intrastriatal (+/-)-SKF 82958 application. The present data suggest that the ability of intrastriatally applied benzazepine-class D1 agonists to decrease striatal dopamine efflux is receptor-mediated, but this action apparently is not mediated at D1 or D2 receptors. There is therefore no indication for an intrastriatal population of D1 receptors capable of modulating dopamine efflux.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Novel in vivo electrophysiological assay for the effects of cocaine and putative "cocaine antagonists" on dopamine transporter activity of substantia nigra and ventral tegmental area dopamine neurons.

The aim of these studies was to establish a rapid in vivo assay for evaluating potential "cocaine antagonists," i.e., drugs postulated to block cocaine binding to the dopamine transporter (DAT) without corresponding blockade of dopamine reuptake. The assay is based on the ability of dopamine, and drugs that elevate synaptic dopamine levels, to inhibit the extracellular single unit activities of midbrain dopamine neurons in chloral hydrate-anesthetized rats. As expected, cocaine itself (0.06-16 mg/kg, i.v.) caused a dose-dependent inhibition of firing of both substantia nigra and ventral tegmental area (VTA) dopamine neurons, but had a significantly higher potency on VTA than nigral dopamine cells (ED(50)'s 1.2 and 8.8 mg/kg, respectively). VTA cells were also inhibited to a greater extent (to 4.7 +/- 4.5% vs. 41.3 +/- 6.3% of baseline rates at 16 mg/kg, respectively). We next evaluated GBR12909, a piperazine analog promoted as a "cocaine antagonist" because of its ability to bind with high affinity to the DAT, while only modestly elevating extracellular dopamine levels. The agonist- and antagonist-like properties of GBR12909 were evaluated on only VTA dopamine cells since these neurons were more fully inhibited by cocaine and have been implicated in its rewarding effects. Given alone, GBR12909 exhibited modest "cocaine-like" activity insofar as it partially inhibited VTA dopamine neurons (to 59.0 +/- 4.6% of baseline at 8 mg/kg). However, consistent with an antagonist profile, pretreatment with a low (0.5 mg/kg) dose of GBR12909, which depressed firing only slightly, resulted in a >2-fold rightward shift in the dose-response curve to cocaine (ED(50) 2.6 mg/kg). We conclude that electrophysiological testing of putative "anti-cocaine" drugs for their abilities to inhibit the firing of VTA dopamine neurons, and to block their inhibitory responses to cocaine, may provide a rapid in vivo screen for compounds expected to behave as functional cocaine antagonists in the dopamine reward system.

Action Potentials↗
PubMed1996

Dopamine affects the in vitro basal secretion of rat placenta opioids in an opioid and dopamine receptor type-specific manner.

Opioid peptides and their receptors are present in the placenta of many species. Dopamine plays an important role in the regulation of opioid release in the nervous system and it may play a similar role in placenta since dopamine receptors are also present in this tissue. The aim of the present work was to examine the effect of dopamine on the basal release of rat placental opioids. The effect of several dopamine receptor agonists and antagonists was tested on the release of immunoreactive beta-endorphin and immunoreactive dynorphin from perfused rat placenta fragments. We found that dopamine and apomorphine stimulated the secretion of immunoreactive beta-endorphin in a dose-dependent manner. The selective D1 dopamine receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride or SKF-38393 reproduced the effect of dopamine while the selective D1 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl 1,2,3,4,5-tetrahydro-1 H-benzazepine hydrochloride or SCH-23390, prevented the dopamine- and SKF-38393-induced increase of immunoreactive beta-endorphin secretion. The selective and potent D2 dopamine receptor agonist (+/-)-2-(N-phenylethyl-N-propyl) amino-5-hydroxytetralin hydrochloride or PPHT had no effect on immunoreactive beta-endorphin. Finally, none of the agonists tested had any effect on the in vitro secretion of placental immunoreactive dynorphin. Our results suggest that dopamine affects the basal release of placental opioids in an opioid and dopamine receptor-specific manner, its effect being different from the effect it exerts on beta-endorphin in the rat neurointermediate pituitary lobe.

Animals↗
PubMed1998

Biotransformation of L-DOPA to dopamine in the substantia nigra of freely moving rats: effect of dopamine receptor agonists and antagonists.

We investigated the effects of continuous intranigral perfusion of dopamine D1 and D2 receptor agonists and antagonists on the biotransformation of locally applied L-DOPA to dopamine in the substantia nigra of freely moving rats by means of in vivo microdialysis. The "dual-probe" mode was used to monitor simultaneously changes in extracellular dopamine levels in the substantia nigra and the ipsilateral striatum. Intranigral perfusion of 10 microM L-DOPA for 20 min induced a significant 180-fold increase in extracellular nigral dopamine level. No effect of the intranigral L-DOPA administration was observed on dopamine levels in the ipsilateral striatum, suggesting a tight control of extracellular dopamine in the striatum after enhanced nigral dopamine levels. Continuous nigral infusion with the D1 receptor agonist CY 208243 (10 microM) and with the D2 receptor agonist quinpirole at 10 microM (a nonselective concentration) attenuated the L-DOPA-induced increase in dopamine in the substantia nigra by 85 and 75%, respectively. However, perfusion of the substantia nigra with a lower concentration of quinpirole (1 microM) and the D1 antagonist SCH 23390 (10 microM) did not affect the nigral L-DOPA biotransformation. The D2 antagonist (-)-sulpiride (10 microM) also attenuated the L-DOPA-induced dopamine release in the substantia nigra to approximately 10% of that of the control experiments. We confirm that there is an important biotransformation of L-DOPA to dopamine in the substantia nigra. The high concentrations of dopamine formed after L-DOPA administration may be the cause of dyskinesias or further oxidative stress in Parkinson's disease. Simultaneous administration of D1 receptor agonists with L-DOPA attenuates the biotransformation of L-DOPA to dopamine in the substantia nigra. The observed effects could occur via changes in nigral GABA release that in turn influence the firing rate of the nigral dopaminergic neurons.

Animals↗
PubMed2002

Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines.

Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET. We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.

Animals↗
PubMed2005

Asymmetrical changes of dopamine receptors in the striatum after unilateral dopamine depletion.

Dopamine plays an important role in modulating synaptic transmission in the striatum and has great influence on the function of the basal ganglia. Degeneration of dopamine neurons in the substantia nigra (SN) is the major cause of many neurological disorders, and the reduction of dopamine innervation results in alterations of dopamine receptors in the striatum. It has been shown that the nigrostriatal dopamine system has functional and neurochemical asymmetry. To investigate the lateralization of dopamine receptors in the striatum after dopamine denervation, the present study used quantitative autoradiography to compare the changes in dopamine receptor binding in the left and right striatum in rats after unilateral dopamine depletion. In comparison to control levels, dopamine D1)-like receptor binding, labeled with [3H]-SCH23390, in the dorsal striatum was reduced 2 weeks after unilateral lesions of the SN with 6-hydroxydopamine. D1-like receptor binding was decreased in the ipsilateral striatum following unilateral lesions of either the left or right SN. The left and right striatum responded similarly to unilateral SN lesions, as there were no significant differences in the percent decrease in D1-like binding in the two striata. In contrast, D2-like receptor binding, labeled with [3H]-spiroperidol, was significantly increased in the dorsal striatum following an ipsilateral SN lesion. Furthermore, the up-regulation of D2-like receptors in the right striatum was significantly greater than that in the left striatum after an ipsilateral lesion. The asymmetrical up-regulation of striatal D2 receptors after extensive dopamine depletion might contribute to the lateralization of the nigrostriatal system observed in some pathological conditions.

Animals↗