Release Of Endogenous Dopamine Research Articles

The mechanism of amphetamine-induced inhibition of rat substantia nigra compacta neurones investigated with intracellular recording in vitro.

1. The effects of (+)-amphetamine (1-300 microM) applied by superfusion, on substantia nigra zona compacta neurones were studied in slices of the rat mesencephalon with intracellular recording techniques (current and voltage clamp mode). 2. Amphetamine inhibited the action potential discharge, hyperpolarized the cells and increased the membrane conductance. Under voltage clamp it produced an outward current. 3. The amphetamine outward current reversed at potentials negative to -100 mV (2.5 mM extracellular potassium) and was reduced by barium, (1 mM) suggesting an increased potassium conductance. 4. In slices treated with tetrodotoxin and calcium-free solution and added cobalt, amphetamine was still effective. 5. (-)-Sulpiride, (1 microM) a D2 antagonist, blocked the effects of both amphetamine and dopamine. 6. In slices treated for more than 3 h with 30 microM alpha-methyl-DL-tyrosine, an agent known to block the synthesis of dopamine, the action of amphetamine was attenuated, while dopamine was still effective. 7. Responses to applied dopamine were potentiated by cocaine (10 microM) but unaffected by amphetamine (1-3 microM). 8. It is suggested that the inhibition of substantia nigra compacta neurones by amphetamine is mainly due to the release of endogenous dopamine.

Investigations of the roles of dihydropyridine and ?-conotoxin-sensitive calcium channels in mediating depolarisation-evoked endogenous dopamine release from striatal slices

The relative roles of L- and N-type voltage-sensitive calcium channels (VSCC) in mediating endogenous dopamine release have been investigated by examining the effects of the dihydropyridine (DHP) agonist BAY K 8644 and the antagonist PN 200-110, as well as the VSCC-blocking peptide omega-conotoxin GVIA, on depolarisation-evoked dopamine release from superfused rat striatal slices. Dopamine release evoked by electrical field stimulation was virtually unaffected by either of the DHP drugs, but release evoked by raising the K+ concentration to 25 mmol/l was significantly increased by BAY K 8644 and reduced stereospecifically by PN 200-110. Quantitative differences between electrically-evoked and K+-evoked dopamine release with respect to their dependence on extracellular calcium concentration were also observed, with electrically-evoked release requiring higher calcium concentrations. The adenylate cyclase activator forskolin itself increased dopamine release, but did not appear to influence the effectiveness of either DHP drug in altering dopamine release. In contrast to the relatively small effects of the DHP drugs, omega-conotoxin produced a major reduction in electrically-evoked dopamine release as well as a substantial decrease in K+-evoked release. Since omega-conotoxin is thought to block both L- and N-type neuronal VSCC whereas DHP drugs affect only L-type VSCC, these findings suggest that electrically-evoked dopamine release is mediated mainly by calcium influx through N-type VSCC, accounting for the reported lack of effect of many organic calcium antagonists on this process. In contrast, K+-evoked dopamine release appears to involve both L- and N-type VSCC, and can occur at lower extracellular calcium concentrations.

Protein kinase C activation enhances K+-stimulated endogenous dopamine release from rat striatal synaptosomes in the absence of an increase in cytosolic Ca2+.

The possibility that protein kinase C modulates neurotransmitter release in brain was investigated by examining the effects of 12-O-tetradecanoylphorbol 13-acetate (TPA) on Ca2+ transport and endogenous dopamine release from rat striatal synaptosomes. TPA (0.16 and 1.6 microM) significantly increased dopamine release by 24 and 33%, respectively, after a 20-min preincubation with TPA followed by 60 s of depolarization with 30 mM KCl. Depolarization-induced 45Ca2+ uptake, measured simultaneously with dopamine release, was not significantly increased by TPA. Neither 45Ca2+ uptake nor dopamine release was altered under resting conditions. When the time course of K+-stimulated 45Ca2+ uptake and dopamine release was examined, TPA (1.6 microM) enhanced dopamine release after 15, 30, and 60 s, but not 1, 3, or 5 s, of depolarization. A slight increase in 45Ca2+ uptake after 60 s of depolarization was also seen. The addition of 30 mM KCl to synaptosomes which had been preloaded with the Ca2+-sensitive fluorophore fura-2 increased the cytosolic free Ca2+ concentration ([Ca2+]i) from 445 nM to 506 nM after 10 s of depolarization and remained elevated after 60 s. TPA had no effect on [Ca2+]i under depolarizing or resting conditions. Replacing extracellular Ca2+ with 100 microM EGTA reduced K+-stimulated (60 s) endogenous dopamine release by 53% and decreased [Ca2+]i to 120 nM. In Ca2+-free medium, 30 mM KCl did not produce an increase in the [Ca2+]i. TPA (1.6 microM) did not alter the [Ca2+]i under resting or depolarizing conditions, but did increase K+-stimulated dopamine release in Ca2+-free medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatodendritic release of endogenous dopamine: in vivo dialysis in the A10 dopamine region

Using in vivo dialysis in the A10 region of the anesthetized rat, somatodendritic release of endogenous dopamine was demonstrated. Although endogenous dopamine release from the A10 region was enhanced by amphetamine pretreatment in a dose-related manner, the amount of dopamine released was markedly less than the axonal release of dopamine measured simultaneously in the nucleus accumbens.

Amantadine and the End-Stage Dementia of Alzheimerʼs Type

Significant improvement of mental status was noted with amantadine therapy in three patients in whom autopsy subsequently showed Alzheimer's disease. Two patients showed a dramatic improvement during the treatment. Their mute, immobile states were reversed and they were able to speak a few coherent words. Their mental status deteriorated when the drug was withdrawn. Transient clinical improvement was noted when amantadine was reinstituted. In all patients EEG showed typical repetitive periodic sharp waves (PSW) similar to those seen in Creutzfeldt-Jacob disease. Alterations of PSW accompanied the initial clinical improvement. We speculate that amantadine acts as a central stimulant by enhancing the release of central endogenous dopamine and possibly other neurotransmitters.

Reduced light responsiveness of the cone pathway during prolonged darkness does not result from an increase of dopaminergic activity in the fish retina

Dopaminergic activity in the fish retina during prolonged darkness was analyzed by monitoring total dopamine (DA) content, dihydroxyphenylacetic acid (DOPAC) and endogenous release of DA. Whereas DOPAC values drop to a third within the first 90 min of darkness, the releasable pool of DA increases by a third during this period. Endogenous release of DA drops to about 25% within the first 30 min and remains at this low level during continuous darkness. These data demonstrate that the electrophysiologically observed sensitivity reduction of horizontal cells during prolonged darkness is not due to an increase of dopaminergic activity during this period.

Enhanced dopamine synthesis and release in vitro in the median eminence of rat hypothalamus are associated with involution of estradiol-induced pituitary tumors.

Changes in the functions of tuberoinfundibular dopaminergic (TIDA) neurons were investigated during the period when the involution of estradiol-induced PRL-secreting pituitary tumors was occurring. Dopamine synthesis and release in vitro by TIDA neurons were determined by 3,4-dihydroxyphenylalanine (DOPA) accumulation in the median eminence and endogenous dopamine release from the median eminence, respectively. Three weeks after a single injection of 2 mg estradiol valerate into ovariectomized rats, there was a marked increase in the weight of anterior pituitaries and the concentration of serum PRL, but a decrease in K+-induced DOPA accumulation in vitro in the median eminence. Twelve weeks after estradiol treatment, by which time pituitary weights and PRL concentrations declined considerably, K+-induced DOPA accumulation in the median eminence rose 5-fold compared to that in control animals. This change in DOPA accumulation persisted for 24 weeks. Increases were observed at 12 weeks in K+-induced as well as basal and (Bu)2cAMP-induced DOPA accumulation in the median eminence. The increases in basal and (Bu2cAMP-induced DOPA accumulation were not altered by Ca2+ removal from medium. In parallel to the changes in DOPA accumulation, basal and K+-induced release in vitro of dopamine from the median eminence into the medium were decreased 3 weeks after estradiol treatment, but increased at 12 and, in part, 24 weeks. The increases in basal and K+-induced dopamine release were observed even after Ca2+ removal from medium. These results suggest that basal, extracellular Ca2+-dependent, and cAMP-dependent dopamine synthesis as well as basal and depolarization-induced dopamine release in TIDA neurons are stimulated during the period of involution of pituitary tumors associated with estradiol withdrawal.

Neuronal bungarotoxin blocks the nicotinic stimulation of endogenous dopamine release from rat striatum

Nicotinic receptors in the brain are receiving increased attention due in part to the recent cloning of receptor subunits and to postmortem studies revealing alterations in receptor density associated with Alzheimer's disease. The peptide neurotoxin neuronal bungarotoxin (NBT) has been shown to block nicotinic cholinergic responses in autonomic ganglia and in retinal ganglion cells. These findings suggest that NBT may be a useful probe for studying nicotinic receptors in the brain. Therefore, we have investigated the effects of NBT on the nicotine-mediated enhancement of endogenous dopamine release from rat striatal slices. It was found that the transient increase in dopamine release caused by 100 μM nicotine was completely blocked by 100 nM NBT, indicating that NBT is a functional nicotinic antagonist in this system.

Ceruletide suppresses endogenous dopamine release via vagal afferent system, studied by in vivo intracerebral dialysis

Ceruletide, a cholecystokinin-related decapeptide, has been reported to have some therapeutic effects on tardive dyskinesia and other involuntary movement disorders. In order to clarify the effects of ceruletide on dopaminergic activity in the rat striatum, we measured the release of endogenous dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after intraperitoneal administration of ceruletide (2, 20, 200 μg/kg) using in vivo intracerebral dialysis techniques. After administration of ceruletide (200 μg/kg), extracellular DA decreased significantly (P < 0.05) for 0.5–3 h. The maximal reduction of extracellular DA (by 29%) was observed for 2–2.5 h. Extracellular DA was reduced (21%) by 20 but not by 2 μg/kg ceruletide. DOPAC and HVA did not change at any dose of ceruletide. We also demonstrated that bilateral subdiaphragmatic vagotomy blocked this inhibitory effect of ceruletide on DA release. These findings indicate that peripherally administered ceruletide suppresses endogenous DA release via the vagal afferent system.

Pattern of catecholamine release in the nucleus tractus solitarii of the cat.

The release of endogenous dopamine, noradrenaline and adrenaline was studied in the nucleus tractus solitarii (subnucleus medialis) of anaesthetized cats. Two push-pull cannulae were inserted into the right and left nuclei tractus solitarii which were simultaneously superfused with artificial cerebrospinal fluid. The release of the neurotransmitters was determined in the superfusates which were continuously collected in 10 min or 2.5 min time periods for 6 h or 2 h, respectively. Collection of the superfusates in time periods of 10 min showed that the release rates of endogenous dopamine, noradrenaline and adrenaline varied rhythmically according to an ultradian rhythm, the time interval between 2 adjacent phases of high release rate being approximately 1 h. Some of the phases of high release rates of the three endogenous catecholamines timely coincided with each other. Collection of the perfusates in time periods of 2.5 min revealed the existence of additional oscillations with a frequency of about 1 cycle/10 min for dopamine, noradrenaline and adrenaline. The findings suggest that catecholamines are released in the nucleus tractus solitarii according to an ultradian rhythm with low (1 cycle per h) and high (1 cycle per 10 min) frequencies, which might reflect the activity of catecholaminergic neurons in this brain structure.

Stimulation of endogenous dopamine release and metabolism in amphibian retina by light- and K +-evoked depolarization

The release and metabolism of dopamine (DA) in retina was assessed using an in vitro eye cup preparation of the African clawed frog. The concentration of DA in the incubation medium and of 3,4-dihydroxyphenylacetic acid (DOPAC) and DA in retinas was measured by high-performance liquid chromatography with electrochemical detection (HPLC-ED). K +-induced depolarization stimulated DA overflow from the eye cups into the incubation medium and increased tissue DOPAC levels in dark-adapted retinas. Basal and K +-stimulated DA overflow and DOPAC accumulation were Ca 2+-dependent. Exposure of dark-adapted retinas to constant white light for 1 h also increased DA overflow and DOPAC levels, while 1 h of alternating 10 s periods of light and dark had no effect. The results indicate that DA release and metabolism may be stimulated as a function of light-adaptation.

Aging does not alter the voltage-dependent release of endogenous dopamine from mouse striatal synaptosomes

Striatal synaptosomes isolated from 3-, 12-, and 24-month-old C57B1/6J mice were exposed to low (5 mM) and high (30 mM) concentrations of potassium of 1, 3, 5, 15 and 30 s. There were no age-related differences in the total intrasynaptosomal content of dopamine among the three age groups of mice. The basal release of endogenous dopamine from synaptosomes isolated from 24-month-old animals was significantly greater than that from synaptosomes isolated from 3-month-old animals at all time points tested. Similarly the potassium stimulated release of dopamine from 24-month-old animals was also higher than that from the 3-month-old group, but this increase was not statistically significant. The net voltage-dependent release of dopamine (stimulated minus basal) was similar for all groups at all time points measured. The increase in basal dopamine release in the 24-month-old animals may reflect an increased fragility or leakiness of the synaptosomal preparation.

Effect of pretreatment with amphetamine on the interaction between amphetamine and dopamine neurons in the nucleus accumbens

The present study was designed to examine the effect of pretreatment with amphetamine on the ability of amphetamine to release dopamine from slices of the nucleus accumbens and striatum and to stimulate locomotor activity or stereotyped behavior, after direct injection into either the nucleus accumbens or the striatum. Rats were injected twice daily for 5 days with either amphetamine (5 mg/kg, i.p.) or saline. At 33 days after this pretreatment, the release of endogenous dopamine from both regions of the brain in vitro by amphetamine and the changes in behavioral responses to the direct injection of amphetamine into either region were examined. Amphetamine at both 1 and 10 μM stimulated the release of endogenous dopamine from slices prepared from both of the brain areas. The release of dopamine by amphetamine was increased in rats pretreated with amphetamine. Consistent with its ability to stimulate endogenous release of dopamine, amphetamine, when injected into the nucleus accumbens, stimulated locomotor activity, while stereotyped behavior was enhanced when amphetamine was injected into the striatum. However, the locomotor activity and stereotyped behavioral responses to small doses of amphetamine (5, 10 or 25 μg) were not significantly greater in amphetamine-pretreated rats, compared to saline-pretreated animals. A greater stimulation of both responses in amphetamine-pretreated rats was only observed when a large dose (50 μg) of amphetamine was administered into either the nucleus accumbens or striatum. Thus, the enhanced release of dopamine, induced by amphetamine from the nucleus accumbens or striatum of amphetamine-pretreated rats, corresponds with an enhanced hypermotility or stereotyped behavior responses to amphetamine injected into the nucleus accumbens or striatum, respectively, but only when a large dose of amphetamine was administered.

Priming of D1-dopamine receptor responses: long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats

The present study demonstrates that repeated administration of SKF-38393, a D1-dopamine agonist, is necessary for maximal behavioral supersensitivity of D1-dopamine receptor responses in neonatal 6-OHDA-lesioned rats, confirming earlier work. This repeated administration of SKF-38393, which is referred to as priming of D1-dopamine receptor responses, resulted in a progressive increase in locomotor activity, as well as several other behaviors. This priming phenomenon lasted at least 6 months. Repeated administration of the D2-dopamine agonist LY-171555 also increased behavioral responses to the D1-dopamine agonist. However, previous administration of a D2-dopamine agonist was not necessary for priming of D1-dopamine receptor responses, because D1-dopamine receptor priming could be produced in the presence of a D2-dopamine receptor antagonist. Blockade of D1-dopamine receptors with SCH-23390 prior to injection of SKF-38393 prevented the increasing responsiveness following repeated administration of this D1-dopamine agonist. Selective neonatal destruction of dopamine-containing neurons produced the same result as did destruction of catecholamine-containing neurons, indicating that the noradrenergic system is not involved in this phenomenon. Priming of D1-dopamine receptor responses by repeated administration of SKF-38393 was not observed in unlesioned controls or in rats that received catecholamine-depleting lesions as adults. Repeated administration of scopolamine also was able to prime behavioral responses to SKF-38393 in neonatal 6-OHDA-lesioned rats, indicating that endogenous release of dopamine can prime D1-dopamine receptor responses in neonatally lesioned rats. In addition, responses to indirect-acting agonists were enhanced in rats that had been primed with a D1-dopamine agonist when compared wit responses in unprimed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Release pattern of endogenous dopamine in teleost retinae during light adaptation and pharmacological stimulation

The release of endogenous dopamine from teleost retinae was studied using high-performance-liquid-chromatography and electrochemical detection. Dopamine was measured in superfusates of isolated retinae after stimulation with flickering light as well as in the presence of GABA, l-glutamate, kainate or taurine. The effect of the receptor antagonists bicuculline, picrotoxin and kynurenic acid was also tested in retinae kept in the dark. We report a low level, basal release of dopamine in the dark ( 20 pg × 10 min −1/retina ), which is transiently increased by stimulation with flickering light. This light evoked release of dopamine is inhibited by GABA and l-glutamate, whilst antagonists of these retinal transmitters stimulate release in the dark.

The effects of pH on amphetamine-induced dopamine release as measured by [formula omitted] dialysis

The release of endogenous dopamine (DA) from the rat corpus striatum before and after the administration of d-amphetamine sulphate (AMPH) was monitored by in vivo dialysis to compare the effects of perfusion media at pH 6.0 and at pH 7.4. Basal release of DA did not differ significantly at pH 6.0 (61.25 ± 5.34 pg/sample, n = 4) or pH 7.4 (58.02 ± 14.17 pg/sample, n = 4). The basal value of homovanillic acid (HVA) was not significantly reduced at pH 7.4 as compared with pH 6.0; while there was a significant reduction in 3, 4-dihydroxyphenylacetic acid (DOPAC) at pH 7.4 as compared to pH 6.0. Intraperitoneal injection of 2.5 mg/kg AMPH resulted in a 21 fold increase in the concentration of DA appearing in subsequent dialysis samples. This increase in DA release was not significantly affected by the pH. Equally the decrease in DOPAC and HVA content following AMPH were also not altered by the pH. These present results differ from experiments using push-pull cannulae and suggest that responses observed with the two techniques may not be equivalent.

Influence of Infused β-Adrenergic Agonists on Porcine Blood Metabolites and Catecholamines

Anesthetized pigs were infused sequentially with increased concentrations of beta-adrenergic agonists. At selected times during infusion, blood pressure, heart rate and plasma concentrations of free fatty acids (FFA), glycerol, glucose, lactate, norepinephrine, epinephrine and dopamine were measured. Azaperone, a drug used to calm the pigs before anesthesia, caused hypotension and bradycardia but did not affect plasma metabolites. Infusion of norepinephrine, epinephrine, isoproterenol or clenbuterol produced changes in plasma metabolites and plasma catecholamines. These changes during norepinephrine infusion were attributed to the infused agonist, whereas those during epinephrine infusion might have resulted to some extent from release of norepinephrine. Plasma isoproterenol was not quantified because it interfered with the assay of epinephrine and dopamine so that it was not possible to distinguish between infused isoproterenol and release of endogenous epinephrine and dopamine. Infusion of clenbuterol caused a small increase in plasma norepinephrine so that some of the increase in plasma FFA, glycerol and lactate during clenbuterol infusion may result from release of endogenous norepinephrine.

P-399 - K+-stimulated release of endogenous dopamine and GABA from striatal and prefrontal cortex slices of rats repeatedly administered with haloperidol

P-399 - K+-stimulated release of endogenous dopamine and GABA from striatal and prefrontal cortex slices of rats repeatedly administered with haloperidol

Differential sensitivity of synaptosomal calcium entry and endogenous dopamine release to ω-conotoxin

The presynaptic neurotoxin omega-conotoxin (ω-CgTx) was tested for its ability to inhibit voltage-dependent calcium flux and transmitter release in rat brain synaptosomes. Conotoxin (0.001–10 μM) had no effect on calcium uptake or endogenous dopamine release from rat striatal synaptosomes in the absence of potassium depolarization. Fast-phase potassium stimulated calcium influx was only partially (20–30%) inhibited by conotoxin at concentrations between 1 nM and 10 μM. The fast-phase release of endogenous dopamine from the same synaptosomal preparation was inhibited by approximately 25% at 0.01 μM and by 60% at 10 μM. These results suggest that a subgroup of high affinity ω-CgTx-sensitive calcium channels may be involved in regulating the release of endogenous dopamine from brain synaptosomes.

Ethanol enhances the calcium-dependent stimulus-induced release of endogenous dopamine from slices of rat striatum and nucleus accumbens in vitro

When slices of striatum from the rat were preincubated for 40 min in calcium-free medium in vitro, the subsequent release of endogenous dopamine (DA) induced by 40 mM KCl was completely calcium-dependent, showing a maximal response in the presence of 1.5 mM CaCl 2, and a half-maximal response in the presence of 0.5mM CaCl 2. In this calcium-dependent preparation, ethanol, at concentrations of 80–120 mM, significantly increased the KCl-induced release of endogenous DA from the striatum by 19–29%. This effect was not reproducible in calcium-replete incubation medium (2.0 mM CaCl 2), suggesting that the phenomenon was calcium-dependent. Preliminary studies in the nucleus accumbens of the rat showed a similar increase (30%) in the calcium-dependent, KCl-induced release of endogenous DA in the presence of 100 mM ethanol.