Monitoring the Stimulated Release of Dopamine with In Vivo Voltammetry. I: Characterization of the Response Observed in the Caudate Nucleus of the Rat

Microvoltammetric electrodes were employed in the brain of an anesthetized rat to monitor chemical substances in extracellular fluid following electrical stimulation of the medial forebrain bundle. An increase in concentration of an easily oxidized substance is observed in the caudate nucleus and in the nucleus accumbens. A large amount of evidence suggests that the substance that is observed following stimulation is dopamine. (1) The location of the stimulating electrode must be in known dopaminergic tracts to induce release. (2) Release is most easily observed in brain regions that contain significant numbers of dopamine-containing neurons. (3) Two voltammetric electrodes with very different electrochemical responses provide voltammograms of the released species that are unique for catechols in one case and catecholamines in another case. (4) The amount of 3,4-dihydroxyphenylacetic acid found in striatal tissue by postmortem analysis correlates with the calculated amount of dopamine released. (5) Inhibition of tyrosine hydroxylase, and thus dopamine synthesis, decreases the observed release while inhibition of monoamine oxidase, and thus formation of dopamine metabolites, does not. (6) The dependence of release on stimulation parameters agrees with results obtained with perfusion techniques. Thus, a new method has been developed to characterize endogenous dopamine release in the rat brain and can be used on a time scale of seconds.     

Metabolism of norepinephrine during nerve stimulation in dog trachea

We determined the relative importance of neuronal and extraneuronal uptake in the metabolism of norepinephrine (NE) released during electrical stimulation (ES) of isolated canine tracheal smooth muscle (TSM). Strips of TSM were labeled with L-[3H]NE (2 X 10(-7) M) and mounted for superfusion. Superfusate was collected continuously before, during, and after ES (15 V, 0.5 ms, 5 Hz). Measurements were made of [3H]NE and its metabolites in superfusate and in tissue. Neuronal uptake followed by metabolism was estimated by measuring the amount of 3,4-dihydroxyphenylglycol (DOPEG). Extraneuronal uptake was estimated by measuring O-methylated metabolites (OMM). ES caused large increases in the efflux of NE, DOPEG, and OMM from TSM. However, the overflow of OMM was six times greater than that of DOPEG. Cocaine (10(-5) M) abolished the increased efflux of DOPEG during ES and enhanced the overflow of NE and OMM. We conclude that extraneuronal uptake constitutes the primary metabolic pathway for NE released from adrenergic nerves innervating TSM.     

Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum.

Fluoxetine injected i.p. into rats at a dose of 10 mg/kg rapidly increased serotonin concentration in microdialysis fluid from the striatum by at least 4-fold, an increase that was maintained throughout the 3 hr observation period. Dopamine concentration in the microdialysis fluid did not change. The concentration of the two dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, was not changed in the microdialysis fluid, whereas the concentration of the serotonin metabolite, 5-hydroxyindoleacetic acid, was significantly decreased after fluoxetine injection. The increased extracellular concentration of serotonin no doubt resulted from inhibition of the serotonin uptake carrier by fluoxetine, and the lack of change in dopamine is evidence for the specificity of action of this uptake inhibitor.     

l-3,4-Dihydroxyphenylalanine-Induced Dopamine Release in the Striatum of Intact and 6-Hydroxydopamine-Treated Rats: Differential Effects of Monoamine Oxidase A and B Inhibitors

Abstract: Administration of l -DOPA (50 mg/kg) elicits a significant increase in extracellular dopamine in striata of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine but not in striata of intact rats. To assess the role of dopaminergic nerve terminals in determining the effects of exogenous l -DOPA on extracellular dopamine levels in striatum, we examined the relative contributions of monoamine oxidase A and monoamine oxidase B to the catabolism of dopamine synthesized from exogenous l -DOPA. Extracellular concentrations of dopamine and its catabolite, 3,4-dihydroxyphenylacetic acid, were monitored with in vivo dialysis in striata of intact rats and of rats with unilateral 6-hydroxydopamine lesions of striatal dopamine. Clorgyline (2 mg/kg), an inhibitor of monoamine oxidase A, significantly increased dopamine and decreased 3,4-dihydroxyphenylacetic acid in intact but not in dopamine-depleted striata. Inhibition of monoamine oxidase B with either l -deprenyl (1 mg/kg) or Ro 19-6327 (1 mg/kg) did not significantly affect dopamine or 3,4-dihydroxyphenylacetic acid in striata of intact or dopamine-depleted rats. In intact rats, administration of clorgyline in conjunction with l -DOPA produced a >20-fold increase in dopamine and prevented the l -DOPA-induced increase in 3,4-dihydroxyphenylacetic acid. Although both l -deprenyl and Ro 19-6327 administered in combination with l -DOPA elicited a small but significant increase in dopamine, levels of 3,4-dihydroxyphenylacetic acid were not affected. In rats pretreated with 6-hydroxydopamine, clorgyline had no significant effect on the increases in dopamine and 3,4-dihydroxyphenylacetic acid elicited by l -DOPA. Furthermore, neither l -deprenyl nor Ro 19-6327 affected l -DOPA-induced increases in dopamine and 3,4-dihydroxyphenylacetic acid in dopamine-depleted striata. The present findings indicate that deamination by monoamine oxidase A is the primary mechanism for catabolism of striatal dopamine, both under basal conditions and after administration of exogenous l -DOPA. Loss of dopaminergic terminals eliminates this action of monoamine oxidase A but does not enhance deamination by monoamine oxidase B. These data support a model in which exogenous l -DOPA elicits enhanced extracellular accumulation of dopamine in the dopamine-depleted striatum because some transmitter synthesis occurs at nondopaminergic sites and the dopamine terminals that normally take up and catabolize this pool of transmitter are absent.     

Clearance of Exogenous Dopamine in Rat Dorsal Striatum and Nucleus Accumbens: Role of Metabolism and Effects of Locally Applied Uptake Inhibitors

In vivo electrochemistry was used to investigate the mechanisms contributing to the clearance of locally applied dopamine in the dorsal striatum and nucleus accumbens of urethane-anesthetized rats. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated carbon fiber electrodes. When a finite amount of dopamine was pressure-ejected at 5-min intervals from a micropipette adjacent to the electrode, transient and reproducible dopamine signals were detected. Substitution of L-a-methyldopamine, a substrate for the dopamine transporter but not for monoamine oxidase, for dopamine in the micropipette did not substantially alter the time course of the resulting signals. This indicates that metabolism of locally applied dopamine to 3,4-dihydroxyphenylacetic acid is not responsible for the decline in the dopamine signal. Similarly, changing the applied oxidation potential from ±0.45 to ±0.80 V, which allows for detection of 3-methoxytyramine formed from dopamine via catechol-O-methyltransferase, had little effect on signal amplitude or time course. In contrast, lesioning the dopamine terminals with 6-hydroxydopamine, or locally applying the dopamine uptake inhibitors cocaine or nomifensine before pressure ejection of dopamine, significantly increased the amplitude and time course of the dopamine signals in both regions. The effects of cocaine and nomifensine were greater in the nucleus accumbens than in the dorsal striatum. Local application of lidocaine and procaine had no effect on the dopamine signals. Initial attempts at modeling resulted in curves that were in qualitative agreement with our experimental findings. Taken together, these data indicate that (1) uptake of dopamine by the neuronal dopamine transporter, rather than metabolism or diffusion, is the major mechanism for clearing locally applied dopamine from the extracellular milieu of the dorsal striatum and nucleus accumbens, and (2) the nucleus accumbens is more sensitive to the effects of inhibitors of dopamine uptake than is the dorsal striatum.     

Effect of Sulpiride on the Amphetamine-Induced Changes in Extracellular Dopamine,DOPAC, and Hydroxyl Radical Generation in the Rat Striatum

The neurotoxic effects of psychostimulants are mediated by several mechanisms, which together lead to neuronal damage. These mechanisms include an increase in the extracellular content of dopamine, stimulation of dopamine oxidation, accumulation of extracellular glutamate, and an increase in body temperature. In the present study, the dopamine receptor antagonist sulpiride proved able to prevent the delayed loss of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and depressed the gradual generation of hydroxyl radicals induced in the rat striatum by D-amphetamine. However, sulpiride at a dose of 75 mg/kg × 2, coadministered with D-amphetamine (7.5 mg/kg × 4), potentiated the increase in extracellular dopamine and initially slightly enhanced D-amphetamine-induced stereotypy. The gradual increase in hydroxyl radical generation predicts the depletion of dopamine and DOPAC in the rat striatum after D-amphetamine administration, but the increase in extracellular dopamine is not a pivotal factor in the enhanced production of hydroxyl radicals.     

Effects of D-2 Antagonists on Frequency-Dependent Stimulated Dopamine Overflow in Nucleus Accumbens and Caudate-Putamen

Stimulated dopamine overflow has been measured with in vivo voltammetry in the caudate-putamen and nucleus accumbens. Overflow was induced by electrical stimulation of the medial forebrain bundle with 120 1-ms, 300-microA, biphasic pulses at frequencies between 10 and 60 Hz. Overflow was measured with a Nafion-coated, carbon-fiber electrode used with fast-scan voltammetry (300 V s-1). Quantification and identification of dopamine concentrations down to 100 nM in vivo is possible with this technique. The overflow curves were fit to a kinetic model that describes the measured response as a function of uptake (characterized by a Vmax and Km) and release (characterized by the concentration of dopamine released per stimulus pulse). Overflow curves in both regions could be described with similar kinetic parameters except for the Vmax, which in the nucleus accumbens was only 60% of that measured in the caudate-putamen. Uptake inhibition by nomifensine (20 mg kg-1) caused an apparent 15-fold change in the value of Km in the nucleus accumbens, similar to results previously reported in the caudate-putamen. In contrast, metoclopramide (10 mg kg-1) and sulpiride (100 mg kg-1) altered the apparent amount of dopamine released per stimulus pulse without a change in the uptake kinetics.     

Real-Time Measurement of Electrically Evoked Extracellular Dopamine in the Striatum of Freely Moving Rats

Abstract: The real-time measurement of electrically evoked dopamine was established in brain extracellular fluid of freely moving rats. Dopamine was monitored by fast-scan cyclic voltammetry at carbon fiber microelectrodes lowered into the striatum by means of a detachable micromanipulator. A stimulating electrode, previously implanted in the substantia nigra, was used to evoke striatal dopamine efflux. Evoked extracellular dopamine was both current and frequency dependent. When low current intensities (±125 µA) and frequencies (10–20 Hz) were applied, detectable levels of dopamine were elicited without a perceptible behavioral response. Reproducible concentrations of extracellular dopamine could be evoked in the same rat for at least 2 months. These concentrations, moreover, were significantly higher in freely moving rats compared with rats anesthetized with Equithesin. Analysis of measured curves for dopamine uptake and release rates revealed that anesthesia inhibits release but does not affect uptake. It is concluded that (a) fast-scan cyclic voltammetry at carbon fiber microelectrodes is a viable technique for the measurement of electrically evoked dopamine in brain extracellular fluid of freely moving rats, (b) it is possible to determine in situ rate constants for dopamine release and uptake from these temporally and spatially resolved measurements of levels of dopamine, and (c) transient changes in extracellular dopamine levels elicited by electrical stimulation are affected by anesthesia.     

Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum

The objective of this study was to examine whether the limited diffusion distance of dopamine in rat striatum produces spatial heterogeneity in the extracellular dopamine concentration on a dimensional scale of a few micrometers. Such heterogeneity would be significant because it would imply that the concentration of dopamine at a given receptor depends on the receptor's ultrastructural location. Spatially resolved measurements of extracellular dopamine were performed in the striatum of chloral hydrate-anesthetized rats with carbon fiber microdisk electrodes. Dopamine was monitored during electrical stimulation of the nigrostriatal pathway before and after administration of drugs that selectively affect the kinetics of evoked dopamine release and dopamine uptake. The effects of nomifensine (20 mg/kg), L-DOPA (250 mg/kg), and alpha-methyl-p-tyrosine (250 mg/kg) on the amplitude of the stimulation responses were examined. The outcome of these experiments was compared with predictions derived from a mathematical model that combines diffusion with the kinetics of release and uptake. The results demonstrate that the extracellular dopamine concentration is spatially heterogeneous on a micrometer scale and that changing the kinetics of dopamine release and uptake has different effects on this spatial distribution. The impact of these results on brain neurochemistry is considered.     

Extensive conjugation of dopamine (3,4-dihydroxyphenethylamine) metabolites in cultured human skin fibroblasts and rat hepatoma cells.

[G-3H]Dopamine (3,4-dihydroxyphenethylamine) metabolism in human skin fibroblasts and rat hepatoma cells in culture was determined by high-pressure liquid-chromatographic analysis of both cell extract and uptake medium. Conjugated metabolites were selectively hydrolysed by incubation with arylsulphatase or beta-glucuronidase before analysis. The principal metabolites of dopamine in fibroblast cells are 3-methoxytyramine 4-O-sulphate and 3-methoxytyramine. No significant differences, either in the amounts of these metabolites or in the amount of dopamine metabolism, were observed in fibroblasts from both normal and homocystinuric individuals. In rat hepatoma cells, the major metabolite of dopamine was 3-methoxytyramine 4- or 3-O-glucuronide; lower concentrations of dopamine 4- or 3-O-glucuronide, 4-hydroxy-3-methoxyphenylacetic acid, 3,4-dihydroxyphenylacetic acid and two unidentified glucuronide conjugates were also observed. Significant differences in the relative concentrations of these metabolites in cell and uptake medium were observed in both cell systems.     

Uptake of Dopamine Released by Impulse Flow in the Rat Mesolimbic and Striatal Systems In Vivo

Abstract: The release of dopamine in the striatum, nucleus accumbens, and olfactory tubercle of anesthetized rats was evoked by electrical stimulation of the mesolimbic dopaminergic pathway (four pulses at 15 Hz or four pulses at 200 Hz). Carbon fiber electrodes were implanted in these regions to monitor evoked dopamine overflow by continuous amperometry. The kinetics of dopamine elimination were estimated by measuring the time to 50% decay of the dopamine oxidation current after stimulation ceased. This time ranged from 64 ms in the striatum to 113 ms in the nucleus accumbens. Inhibition of dopamine uptake by nomifensine (2–20 mg/kg), GBR 12909 (20 mg/kg), cocaine (20 mg/kg), mazindol (10 mg/kg), or bupropion (25 mg/kg) enhanced this decay time by up to +602%. Uptake inhibition also produced an increase in the maximal amplitude of dopamine overflow evoked by four pulses at 15 Hz. This latter effect was larger in the striatum (+420%) than in mesolimbic areas (+140%). These results show in vivo that these uptake inhibitors actually slow the clearance of dopamine released by action potentials and suggest that dopaminergic transmission is both prolonged and potentiated strongly by these drugs, in particular in the striatum.     

Dopamine and hepatic oxygen supply-demand relationship

The present study examined the effect of small, vasodilating doses of dopamine on the hepatic oxygen supply--uptake ratio. Thirteen miniature pigs weighing 18-27 kg were studied under sodium pentobarbital anesthesia. Hepatic arterial and portal blood flows were measured. Oxygen content in arterial, portal, and hepatic venous blood was determined. Dopamine was infused in doses of 5, 10, and 15 micrograms.kg-1.min-1. Dopamine infusion was associated with a dose-related increase in hepatic oxygen uptake and a dose-independent increase in hepatic oxygen delivery with a maximal increase (30%) in the hepatic oxygen delivery at 10 micrograms.kg-1.min-1. The hepatic oxygen delivery--uptake ratio remained unchanged during dopamine infusion in doses of 5 and 10 micrograms.kg-1.min-1 and significantly decreased during the dose of 15 micrograms.kg-1.min-1. The study demonstrated that an increase in cardiac output and hepatic oxygen delivery during dopamine administration was not associated with an improvement in hepatic oxygen supply--demand relationship since hepatic oxygen uptake also increased.     

Extracellular Striatal Concentrations of Endogenous 3,4-Dihydroxyphenylalanine in the Absence of a Decarboxylase Inhibitor: A Dynamic Index of Dopamine Synthesis In Vivo

Abstract: Basal levels of endogenous 3,4-dihydroxyphenylalanine (DOPA) were detected by HPLC coupled with coulometric detection in dialysates from freely moving rats implanted 48–72 h earlier with transversal dialysis fibers in the dorsal caudate. Because decarboxylase inhibitor is absent in the Ringer's solution, this method allows monitoring of basal output of dopamine (DA) and 3,4-dihydroxyphenylacetic acid, as well as DOPA. Extracellular DOPA concentrations were reduced by the tyrosine hydroxylase inhibitor α-methylparatyrosine (200 mg/kg, i.p.) and by the dopaminergic agonist apomorphine (0.25 mg/kg, s.c.). The dopaminergic antagonist haloperidol (0.2 mg/kg, s.c.) stimulated DOPA output by about 60% over basal values. γ-Butyrolactone, at doses of 700 mg/kg, i.p., which are known to block dopaminergic neuronal firing and which reduce DA release, stimulated DOPA output maximally by 130% over basal values. Tetrodotoxin, which blocks DA release by blocking voltage-dependent Na⁺ channels, increased DOPA output maximally by 100% over basal values. The results indicate that basal DOPA can be detected and monitored in the extracellular fluid of the caudate of freely moving rats by transcerebral dialysis and can be taken as a dynamic index of DA synthesis in pharmacological conditions.     

Coupled Effects of Mass Transfer and Uptake Kinetics on In Vivo Microdialysis of Dopamine

Abstract: Voltammetric microelectrodes and microdialysis probes were used simultaneously to monitor extracellular dopamine in rat striatum during electrical stimulation of the medial forebrain bundle. Microelectrodes were placed far away (1 mm) from, immediately adjacent to, and at the outlet of microdialysis probes. In drug-naive rats, electrical stimulation (45 Hz, 25 s) evoked a robust response at microelectrodes far away from the probes, but there was no response at microelectrodes adjacent to and at the outlet of the probes. After nomifensine administration (20 mg/kg i.p.), stimulation evoked robust responses at all three microelectrode placements. These results demonstrate first that evoked release in tissue adjacent to microdialysis probes is suppressed in comparison with evoked release in tissue far away from the probes and second that equilibration of the dopamine concentration in the extracellular fluid adjacent to and far away from the probes is prevented by the high-affinity dopamine transporter. Hence, models of microdialysis, which assume the properties of tissue to be spatially uniform, require modification to account for the distance that separates viable sites of evoked dopamine release from the probe. We introduce new mass transfer resistance parameters that qualitatively explain the observed effects of uptake inhibition on stimulation responses recorded with microdialysis and voltammetry.     

Amphetamine and Other Weak Bases Act to Promote Reverse Transport of Dopamine in Ventral Midbrain Neurons

Abstract: Amphetamine-like psychostimulants are thought to produce rewarding effects by increasing dopamine levels at mesolimbic synapses. Paradoxically, dopamine uptake blockers, which generally increase extracellular dopamine, inhibit amphetamine-induced dopamine overflow. This effect could be due to either inhibition of amphetamine uptake or inhibition of dopamine efflux through the transporter (reverse transport). We used weak bases and dopamine uptake blockers in ventral midbrain neuron cultures to separate the effects on blockade of amphetamine uptake from reverse transport of dopamine. Amphetamine, ammonium chloride, tributylamine, and monensin, at concentrations that produce similar reductions in acidic pH gradients, increased dopamine release. This effect was inhibited by uptake blockers. Although in the case of amphetamine the inhibition of release could have been due to blockade of amphetamine uptake, inhibition also occurred with weak bases that are not transporter substrates. This suggests that reduction of vesicular pH gradients increases cytoplasmic dopamine which in turn promotes reverse transport. Consistent with this model, extracellular 3,4-dihydroxyphenylacetic acid was increased by ammonium chloride and monensin, as would be expected with elevated cytoplasmic dopamine levels. These findings extend the weak base mechanism of amphetamine action, in which amphetamine reduces vesicular pH gradients resulting in increased cytoplasmic dopamine that promotes reverse transport.     

Effects of Graded Levels of Tissue Oxygen Pressure on Dopamine Metabolism in the Striatum of Newborn Piglets

Abstract: The effect of graded levels of tissue hypoxia on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid has been monitored in vivo by microdialysis. Reproducible levels of decreased oxygen in the brain were obtained by increasing the rate of ventilation from the control value of 25/min to as high as 95/min. With increasing ventilatory rate, the oxygen pressure in the cortex decreased from ∼40 torr to 16 torr. As the oxygen pressure decreased stepwise from 40 to 27, 22, and 16 torr, the dopamine levels in the extracellular medium rose by 70, 90, and 150%, respectively, returning to baseline within a few minutes of return to control ventilation rates. Levels of the catabolic products 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid decreased with decreasing tissue oxygen. Unlike the dopamine levels, these catabolite levels continued to decrease through 30 min of recovery (to 50% of control), returning to baseline only after recovery periods of 1–2 h. These data suggest that hypoxia induces long-term alterations in the neurotransmitter turnover. The marked effects of mild tissue hypoxia (decrease of oxygen from 40 torr to 26 torr) on both the extracellular dopamine concentration and dopamine metabolism indicate that the metabolic consequences of decreased tissue oxygen pressure extend to higher values than generally appreciated.     

Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment

Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.     

d-Fenfluramine Increases Striatal Extracellular Dopamine In Vivo Independently of Serotonergic Terminals or Dopamine Uptake Sites

Abstract: The effect of various doses of the serotonin (5-HT) release-inducing agent d -fenfluramine ( d -fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d -fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 µ M ). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 µ M d -fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 µ M d -fenf was slightly but significantly reduced by the local application of 25 µ M citalopgram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 µ M ) did not modify significantly the effect of d -fenf. The rise of DA outflow induced by 25 µ M d -fenf was strongly reduced in the presence of 1 µ M tetrodotoxin (TTX) or by the removal of Ca²⁺ from the perfusion medium. The results obtained show that d -fenf increases the striatal extracellular DA concentration by a Ca²⁺-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.     

Effects of Apomorphine on In Vivo Release of Dopamine and Its Metabolites in the Prefrontal Cortex and the Striatum, Studied by a Microdialysis Method

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.     

Regional changes in catecholamine content of the pregnant uterus

High-pressure liquid chromatography with electrochemical detection was used to identify and measure catecholamines in rat, rabbit, sheep, guinea-pig and human uteri and follow changes with pregnancy. Noradrenaline was consistently the major catecholamine and pregnancy caused a regionally specific fall in its concentration which, in rat, rabbit and guinea-pig, was associated with a decline in total content. Adrenaline was undetectable (less than 10 pmol/g myometrium) in all species and at all gestational ages studied. Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected at high concentrations in guinea-pig and particularly sheep uterus. In guinea-pig uterus the dopamine/DOPAC ratio fell dramatically with pregnancy, suggesting that increased quantities of dopamine were released and catabolized. The dopamine/noradrenaline ratios suggested that dopamine is stored with noradrenaline in adrenergic neurones in guinea-pig myometrium and within an additional neuronal or cellular store(s) in sheep uterus.