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PubMed1997

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement.

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.

Amygdala↗
PubMed1995

Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter.

1. The NMDA-type glutamate receptor antagonist, dizocilpine (MK-801) can protect against neurotoxicity associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its principal metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). It has been suggested that these neurotoxic effects may be mediated by release of excitatory amino acids, but possible alternative mechanisms have been little investigated. 2. MPTP and MPP+ (0.1-1000 microM) were tested in superfused rat striatal synaptosomes preloaded with [3H]-dopamine. Both MPTP (10 microM and higher) and MPP+ (1 microM and higher) evoked an immediate and concentration-dependent release of [3H]-dopamine. The maximal effect exceeded that achievable with nicotine. For subsequent experiments, submaximal concentrations of MPTP (50 microM) and MPP+ (10 microM) were tested. 3. MK-801 (0.1-100 microM) inhibited responses to MPTP (50 microM) and MPP+ (10 microM) in a concentration-dependent manner. However, further tests of NMDA-type glutamate receptor involvement proved negative. Responses to MPTP or MPP+ were unaffected by the omission of Mg2+ or Ca2+ and were not reduced by the NMDA receptor antagonists, AP-7 (200 microM) and kynurenic acid (300 microM). In this assay, N-methyl-D-aspartate (even in the absence of Mg2+ and with added glycine and strychnine) did not evoked [3H]-dopamine release. 4. In crude membrane preparations of rat cerebral cortex, MPTP and MPP+ inhibited high-affinity [3H]-nicotine binding to nicotinic cholinoceptors (IC50 1.8 microM and 26 microM, respectively). 5. [3H]-dopamine release evoked by nicotine (1 microM) was blocked by the nicotinic antagonists,mecamylamine and chlorisondamine, and by MK-801 (all at 100 micro M); K+-evoked release was not affected. Release evoked by MPTP and MPP+ was significantly attenuated by MK-801 but not by mecamylamine or chlorisondamine.6. At a high concentration (1O I1M), the selective dopamine uptake inhibitor, nomifensine, completely blocked [3HJ-dopamine release evoked by amphetamine 0.3 microM and MPP+ 10 flM, attenuated responses to MPTP 50 AM and did not affect responses to 12 mM K+. MK-801 100 microM evinced a similar profile but was less effective.7. MK-801 inhibited [3H]-dopamine uptake in striatal synaptosomes with an IC5o of 115 M.8. It is concluded that high concentrations of MK-801 inhibit the acute dopamine release evoked by MPTP and MPP+ in synaptosomes. This antagonism may occur, at least in part, through inhibition of the cell membrane dopamine transporter. MPTP and MPP+ also appear to interact with brain nicotinic cholinoceptors but the functional consequences of this interaction are not yet clear.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Pharmacological analysis of dopamine stimulation of [35S]-GTP gamma S binding via human D2short and D2long dopamine receptors expressed in recombinant cells.

1. The activation of G-proteins by agonist-occupied D2 or D3 dopamine receptors in membranes from recombinant cells expressing the cloned receptors has been analysed by a [35S]-guanosine 5'-[gamma-thio] triphosphate ([35S]-GTP gamma S) binding assay. 2. The rate of [35S]-GTP gamma S binding was increased by dopamine in a dose-dependent manner in membranes from CHO cells stably expressing either the D2short or D2long dopamine receptor. 3. The dopamine-induced stimulation of [35S]-GTP gamma S binding could be inhibited by a range of antagonists. Affinities for antagonists derived from the inhibition of the dopamine stimulation of [35S]-GTP gamma S binding correlated very well with affinities derived from radioligand binding studies. 4. When the maximum [35S]-GTP gamma S binding responses stimulated by dopamine acting at different receptor subtypes were compared, there was a tendency for the stimulation via the D2short receptor to be greater than via the D2long receptor and for the stimulation via the D3 dopamine receptor to be less than for either D2 receptor. These differences in maximal response were also seen when the inhibitory effects of dopamine on adenylyl cyclase via the three receptor subtypes were compared. 5. The stimulation of [35S]-GTP gamma S binding by dopamine in membranes from recombinant cells therefore provides an excellent system for studying the molecular nature of agonism and the receptor/G-protein interactions for these receptors.

Adenylyl Cyclases↗
PubMed2002

The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors.

The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D(2,3) agonist N-[(3)H]propylnorapomorphine ([(3)H]NPA), than on the binding of the D(2,3) antagonist [(11)C]raclopride in living brain. The binding potential (p(B(0))), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [(11)C]raclopride (p(B(0))(RAC)(C)) = 8.5, and for [(3)H]NPA(p(B(0))(NPA)) = 5.3. Relative to these baseline values after dopamine depletion, saline-treatment decreased the p(B) of [(3)H]NPA by one-half, while the p(B) of [(11)C]raclopride declined by only one-third. Amphetamine decreased the p(B) of [(3)H]NPA to a greater extent than that of [(11)C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [(3)H]NPA than for [(11)C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.

Aminoquinolines↗
PubMed1997

Dopamine oxidation generates an oxidative stress mediated by dopamine semiquinone and unrelated to reactive oxygen species.

Dopamine (100 microM, 10-30 min) inhibits/inactivates the MgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffin granule ghosts. The dopamine dependent inhibition was enhanced by adding soluble dopamine beta-monooxygenase (DBM, 0.2 U/ml) and completely prevented by ascorbate (1 mM), dithiothreitol (2 mM) and approximately 80% by the DBM inhibitor fusaric acid (10 microM). This indicates that the inhibition is caused by the dopamine semiquinone free radical generated during DBM-dependent dopamine oxidation. Catalase, superoxide dismutase or both did not prevent the inhibition, and DBM-catalysed dopamine oxidation did not change the basal level of lipid peroxidation, excluding the involvement of reactive oxygen species as being responsible for the inhibition. N-ethylmaleimide-sensitive ATPase activity (i.e. the proton translocating ATPase) in the vesicle membranes was inhibited during dopamine incubation, indicating that the toxic metabolite (dopamine semiquinone) inhibits proton pumping by inhibiting the endogenous vacuolar H(+)-ATPase. As this proton pump represents the driving force for the vesicular uptake and storage of catecholamines, the dopamine dependent inhibition, if taking place in vivo, may inhibit dopamine uptake in storage vesicles in sympathetic neurons, e.g. as observed in the myopathic hamster heart.

Animals↗
PubMed1987

Effects of oral and intravenous administrations of dopamine and L-dopa on plasma levels of two isomers of dopamine sulfate in man.

The levels of two isomers of dopamine sulfate, dopamine-3-O-sulfate (DA3S) and dopamine-4-O-sulfate (DA4S), in human plasma were measured by HPLC-fluorometry. The basal plasma levels of DA3S and DA4S in the early morning were 13.8 +/- 1.9 and 3.2 +/- 0.5 pmoles/ml, respectively (means +/- S.E.M.). Oral administrations of dopamine (50 mg/body) and 1-dihydroxyphenylalanine (L-DOPA, 250 mg/body) increased the plasma levels of these dopamine sulfates almost 100-fold to 1807 +/- 266 and 1674 +/- 195 pmoles/ml of DA3S, and 466 +/- 83 and 321 +/- 76 pmoles/ml of DA4S. Intravenous dopamine infusion (5 micrograms/kg/min for 30 min) markedly increased the plasma free dopamine concentration, as expected, but increased the levels of DA3S and DA4S only slightly to 110 +/- 32 and 25 +/- 9 pmoles/ml, respectively. In contrast, intravenous L-DOPA (25 mg/body) resulted in a slight increase of free dopamine followed by marked increases of DA3S and DA4S to 691 +/- 219 and 139 +/- 40 pmoles/ml, respectively. These data indicate that O-sulfation of dopamine, especially 3-O-sulfation, is the main pathway for metabolism of intravenously and orally administered L-DOPA and orally ingested dopamine. This sulfation is suggested to occur in the gut wall.

Administration, Oral↗
PubMed2006

Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice.

Sensorimotor gating is a phenomenon that is linked with dopamine neurotransmission in limbic and cortical areas, and disruption of sensorimotor gating has been consistently demonstrated in schizophrenia patients. The nuclear receptor Nurr1 is essential for development of dopamine neurons and, using Nurr1-null heterozygous mice, has been found to be important for normal dopamine neurotransmission as null heterozygous mice have reduced limbic and cortical dopamine levels and elevated open-field locomotor activity. The current investigation compared sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, in Nurr1 wild-type and null heterozygous mice. When mice were weaned between 19 and 21 days of age either into isolation or groups of three to five and tested 12 weeks later, prepulse inhibition was elevated in group-raised null heterozygous mice and significantly disrupted in isolated null heterozygous mice as compared with isolation-raised wild-type mice and group-raised null heterozygous mice. Isolation had no effect on prepulse inhibition in wild-type mice. Isolation reduced tissue dopamine levels and elevated dopamine turnover in the nucleus accumbens and striatum in both wild-type and null heterozygous mice. In the prefrontal cortex, isolation reduced dopamine and 3,4-dihydroxyphenylacetic acid levels in null heterozygous as compared with isolation-raised wild-type mice, whereas no differences were observed between group-raised wild-type and null heterozygous mice. Neither the null heterozygous genotype nor isolation had any effect on basal or stress-induced corticosterone levels. These data suggest that the Nurr1 null heterozygous genotype predisposes these mice to isolation-induced disruption of prepulse inhibition that may be related to the interactions between intrinsic deficiencies in dopamine neurotransmission as a result of the null heterozygous genotype and isolation-induced changes in dopamine neurotransmission. Post-weaning isolation of Nurr1 null heterozygous mice provides a model to explore the interactions of genetic predisposition and environment/neurodevelopment on dopamine function that has important relevance to neuropsychiatric disorders.

Animals↗
PubMed1997

Dopamine release and uptake rates both decrease in the partially denervated striatum in proportion to the loss of dopamine terminals.

The present study tested the hypothesis that normal concentrations of extracellular dopamine are preserved in the partially denervated striatum without active compensatory changes in dopamine uptake or release. One to four weeks after adult rats were unilaterally lesioned with 6-hydroxydopamine, fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes was used to monitor extracellular dopamine levels in vivo, under urethane anesthesia. Simultaneous voltammetric recordings were collected in the lesioned and contralateral control striata. Extracellular dopamine was elicited by bilateral electrical stimulation of the medial forebrain bundle. A 20 Hz stimulation evoked similar concentrations of extracellular dopamine in both lesioned and control striata, although tissue dopamine was decreased 30-70% in lesioned striata, as determined subsequently by HPLC-EC. However, kinetic analysis of the voltammetric recordings revealed that the concentration of dopamine released per stimulus pulse and Vmax for dopamine uptake decreased in proportion to the magnitude of the lesion. These data support the hypothesis that normal extracellular dopamine levels can be generated in the partially lesioned striatum in the absence of active neuronal compensation. These results also suggest that passive mechanisms involved in the regulation of extracellular dopamine play an important role in maintaining function during the preclinical or presymptomatic phase of Parkinson's disease.

Animals↗
PubMed1978

Urinary dopamine in man and rat: effects of inorganic salts on dopamine excretion.

1. Plasma and urine free dopamine (3,4-dihydroxyphenethylamine) were measured in six normal male volunteer subjects and the urinary clearance of dopamine was calculated for each subject. 2. The excretion rates for free dopamine in man were greater than could be explained by simple renal clearance. It was concluded that free dopamine must, therefore, be formed in the kidney. 3. Changes in urinary dopamine excretion were studied in four groups of rats initially maintained on low sodium diet and then given equimolar dietary supplements of NaCl, NaHCO3, KCl or NH4Cl, to study the specificity of the previously observed increase in dopamine excretion after increased dietary NaCl. 4. The mean dopamine excretion increased significantly in rats given NaCl, KCl and NH4Cl, whereas dopamine excretion decreased in those given NaHCO3. 5. The failure of dopamine excretion to rise in response to loading with NaHCO3 was unexpected, and argues against a simple effect of volume expansion by the sodium ion. The increase in dopamine excretion with KCl and NH4Cl showed that this response was not specific to the sodium ion.

Adult↗
PubMed1995

Biochemistry of somatodendritic dopamine release in substantia nigra: an in vivo comparison with striatal dopamine release.

The somatodendritic release of dopamine in substantia nigra previously has been suggested to be nonvesicular in nature and thus to differ from the classical, exocytotic release of dopamine described for the dopaminergic nerve terminal in striatum. We have compared the effects of reserpine, a compound that disrupts vesicular sequestration of monoamines, on the storage and release of dopamine in substantia nigra and striatum of rats. Reserpine administration (5 mg/kg, i.p.) significantly decreased the tissue level of dopamine in substantia nigra pars reticulata, substantia nigra pars compacta, and striatum. In these brain areas, reserpine-induced reductions in tissue dopamine level occurred within 2 h and persisted at 24 h postdrug. In vivo measurements using microdialysis revealed that reserpine administration rapidly decreased the extracellular dopamine concentration to nondetectable levels in substantia nigra as well as in striatum. In both structures, it was observed that reserpine treatment significantly attenuated the release of dopamine evoked by a high dose of amphetamine (10 mg/kg, i.p.) given 2 h later. In contrast, dopamine efflux in response to a low dose of amphetamine (2 mg/kg, i.p.) was not altered by reserpine pretreatment either in substantia nigra or in striatum. The present data suggest the existence, both at the somatodendritic and at the nerve terminal level, of a vesicular pool of dopamine that is the primary site of transmitter storage and that can be displaced by high but not low doses of amphetamine. The physiological release of dopamine in substantia nigra and in striatum is dependent on the integrity of this vesicular store.

Amphetamine↗
PubMed2001

Protection of intracellular dopamine cytotoxicity by dopamine disposition and metabolism factors.

Dopamine has been hypothesized as a contributing factor for the selective degeneration of dopaminergic neurons in Parkinson's disease. However, the cytotoxic mechanisms of dopamine and its metabolites remain poorly understood. Using a stable aromatic amino acid decarboxylase (AADC) expressing a fibroblast cell line, we previously demonstrated a novel, non-oxidative cytotoxicity of intracellular dopamine. In this study, we further investigate the roles of dopamine metabolism and disposition proteins against intracellular dopamine cytotoxicity by co-expressing these factors in AADC-expressing cells. Our results indicate that overexpression of the vesicular monoamine transporter and monoamine oxidase A-induced protection against intracellular dopamine toxicity, and conversely that pharmacological inhibition of these pathways potentiated L-DOPA toxicity in catecholaminergic PC12 cells. Macrophage migration inhibitory factor and glutathione S-transferase (GST), factors that have recently been shown to be involved in dopamine metabolism, also exhibited a strong protective role against intracellular dopamine cytotoxicity. Our results support a potential role for non-oxidative cytoplasmic dopamine toxicity, and imply that disruption in dopamine disposition and/or metabolism could underlie the progressive degeneration of dopaminergic neurons in Parkinson's disease.

Animals↗
PubMed1984

Monitoring the stimulated release of dopamine with in vivo voltammetry. II: Clearance of released dopamine from extracellular fluid.

Microvoltammetric electrodes implanted in the caudate nucleus of the anesthetized rat have been used to monitor dopamine released following electrical stimulation of the medial forebrain bundle. These electrodes are fabricated from unmodified carbon fibers and have been used with normal pulse voltammetry. Dopamine appears in the vicinity of the electrode when the stimulation is initiated, and disappears almost immediately when the stimulation is terminated. The data suggest that the effective diffusion distance is less than 100 micron. Postmortem analysis using liquid chromatography with electrochemical detection shows that dopamine released in this manner is metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC); however, neither substance is observed electrochemically in the extracellular fluid within seconds after the stimulation. In addition, inhibitors of neuronal uptake of dopamine, amphetamine (1.8 or 15 mg X kg-1) or benztropine (25 mg X kg-1), or of dopamine metabolism, pargyline (150 mg X kg-1) or tropolone (100 mg X kg-1), do not significantly affect the rate at which dopamine disappears from extracellular fluid, although they can affect the amount released. These results suggest that dopamine cannot freely diffuse in the extracellular fluid because an extraneuronal uptake mechanism exists that clears dopamine from extracellular fluid into an extraneuronal pool where metabolism to 3,4-dihydroxyphenylacetic acid occurs. Dopamine can be observed during electrical stimulation of the ascending fibers because neuronal and extraneuronal uptake systems are unable to remove dopamine on these short time scales.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Stress-induced dopamine release in the neostriatum: evaluation of the role of action potentials in nigrostriatal dopamine neurons or local initiation by endogenous excitatory amino acids.

It has been hypothesized that excitatory amino acids can initiate dopamine release in neostriatum. We examined whether the increase in extracellular dopamine in neostriatum produced by acute stress reflects presynaptic initiation of dopamine release by endogenous excitatory amino acids. Thirty minutes of intermittent tail-shock stress significantly elevated extracellular concentrations of dopamine, glutamate, aspartate, and gamma-aminobutyric acid in neostriatum of freely moving rats as measured with in vivo microdialysis. Local infusion of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate or the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione via the dialysis probe did not attenuate the stress-induced increase in extracellular dopamine. In fact, the increase was prolonged in rats treated with specific excitatory amino acid receptor antagonists. Infusion of tetrodotoxin into medial forebrain bundle increased extracellular glutamate and aspartate in neostriatum yet reduced basal dopamine in extracellular fluid to below the limit of detection of the assay and eliminated the stress-induced increase in extracellular dopamine. These findings fail to support the hypothesis that the stress-induced increase in extracellular dopamine in neostriatum is initiated locally by excitatory amino acids. Rather, the effects of stress on extracellular dopamine seem to be determined by impulse propagation in dopamine neurons.

2-Amino-5-phosphonovalerate↗
PubMed1979

Subcellular localization of dopamine in the anterior pituitary gland of the rat: apparent association of dopamine with prolactin secretory granules.

The subcellular compartmentalization of endogenous dopamine in the anterior pituitary gland of the rat was investigated using continuous sucrose density gradient centrifugation. When anterior pituitary homogenates were layered on continuous sucrose density gradients (1.0--2.0 M) and centrifuged for 60 min at 40,000 X g, dopamine recovered from the gradients was associated with two sets of subcellular particles. The particles in one set were recovered near the top of the gradient, whereas those in the other set were recovered near the bottom of the gradient in the region where particles containing PRL were also found. In fact, these dense dopamine-containing particles could not be separated from those particles which contained PRL. These findings were suggestive that dopamine and PRL were present in the same particle, viz. the PRL secretory granule. This interpretation was further strengthened when it was established that the PRL-containing granules were separable on the gradient from granules which contained GH, LH, FSH, ACTH, and TSH. When [3H]dopamine was added to the solution in which the anterior lobes were homogenized, no radio-activity was found to be associated with the dense dopamine-containing particles. Also, the addition of a large excess of nonradiolabeled dopamine at the time of homogenization did not influence the amount of dopamine associated with the dense particles. Thus, the apparent association of dopamine with PRL secretory granules was not an artifact of the homogenization process per se. Therefore, it is concluded that an association exists between intracellular dopamine and the PRL secretory granule.

Adrenocorticotropic Hormone↗
PubMed1992

Partial dopamine depletion of the prefrontal cortex leads to enhanced mesolimbic dopamine release elicited by repeated exposure to naturally reinforcing stimuli.

High-speed chronoamperometry was used to monitor the extracellular concentration of dopamine within the nucleus accumbens, a terminal field of the mesolimbic dopamine system, in freely behaving rats exposed daily, on 6 consecutive days, to one of two naturally reinforcing stimuli; a highly palatable food or sex-related olfactory cues. The animals either were intact or had previously received microinjections of 6-hydroxydopamine into prefrontal cortex to lesion dopamine terminals. Food reliably elicited increases in dopamine levels within the nucleus accumbens, and if prefrontal cortical dopamine had been depleted, the response to food increased with repeated testing. Animals exposed to the sexually relevant olfactory stimulus showed progressively enhanced dopamine release with repeated testing, and this enhancement was potentiated by prefrontal cortical dopamine depletion. These results indicate that repeated exposure to naturally reinforcing events can lead to a hyperresponsiveness of the mesolimbic dopamine system upon future activation, and suggest that the dopamine projection to prefrontal cortex exerts an indirect, inhibitory influence on mesolimbic dopamine neurotransmission.

Animals↗
PubMed1976

Dopamine synthesis in rat brain striatal synaptosomes. II. Dibutyryl cyclic adenosine 3':5'-monophosphoric acid and 6-methyltetrahydropterine-induced synthesis increases without an increase in endogenous dopamine release.

The effects of N6, O2'-dibutyryl cyclic adenosine 3':5'-monophosphoric acid (dibutyryl cyclic AMP), DL-6-methyl-5, 6, 7, 8-tetrahydropterine (6-MPH4) and tyramine on dopamine synthesis and endogenous dopamine release in rat brain striatal synaptosomes have been examined. Dibutyryl cyclic AMP (1 mM) produced a 100% increase in dopamine synthesis but had no effect on endogenous dopamine release. Veratridine (75 muM) did not further stimulate dibutyryl cyclic AMP-treated tissue. 6-MPH4 (0.1 mM) also stimulated synthesis without stimulating dopamine release. The stimulation produced by 6-MPH4 was additive to the stimulations produced by either dibutyryl cyclic AMP or veratridine. Tyramine (10(-4) M) inhibited synthesis, while increasing dopamine release. These data suggest that 1) dopamine-releasing agents may have differential effects upon dopamine synthesis, depending on their mechanism of release, 2) dopamine synthesis can be stimulated independently of endogenous dopamine release and 3) the pteridine cofactor necessary for tyrosine hydroxylation is not normally present at saturating levels.

Animals↗
PubMed1993

Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals.

Repeated administration of cocaine to rodents produces a progressive augmentation in motor activity known as behavioral sensitization. By using microdialysis in the ventral striatum, some studies have found that the development of behavioral sensitization is associated with a similar augmentation in dopamine release, while others have not. It was postulated that differences in doses and withdrawal periods may account for the discrepancies between studies. Rats were behaviorally sensitized to daily peripheral injections using two cocaine treatment regimens (15 mg/kg, i.p. x 5 d or 30 mg/kg, i.p. x 5 d). Using in vivo microdialysis in the ventral striatum, the effect of acute cocaine (15 mg/kg, i.p.) on extracellular dopamine content and motor behavior was examined at various times after discontinuing daily treatments. Twenty-four hours after discontinuing the low dose of daily cocaine, the increase in motor activity and extracellular dopamine elicited by an acute cocaine challenge was significantly elevated. In contrast, following the higher daily treatment regimen there was a significant augmentation in motor activity, but the increase in extracellular dopamine produced by cocaine was significantly reduced. When rats were challenged 10-14 d after discontinuing either dosage regimen of daily cocaine, the increase in both motor activity and extracellular dopamine was augmented. In general, the increase in extracellular dopamine by an acute cocaine challenge increased over time when rats were challenged between 1 and 22 d after discontinuing daily cocaine. Basal concentrations of extracellular dopamine were determined by measuring the in vivo flux of dopamine across the dialysis membrane, and there was no significant difference at 24 hr or 2 weeks following the last daily injection of saline or cocaine. It is concluded that behavioral sensitization to cocaine is generally associated with an augmentation in extracellular dopamine in the ventral striatum, but that high doses of daily cocaine produce apparent tolerance to the augmentation in extracellular dopamine during the early withdrawal period.

Animals↗
PubMed1998

Plasma dopamine concentration and effects of low dopamine doses on urinary output after major vascular surgery.

To evaluate plasma dopamine concentration and the effects of low doses infusion on urinary output after abdominal vascular surgery in patients with renal function impairment we performed a prospective clinical study. Twenty hemodynamically stable patients (mean age 66.6 years), with serum creatinine concentration < 2 mg %, who undergoing general anesthesia for major vascular surgery participated. A low dose of dopamine (3 micrograms/kg/min) was administrated to patients with postoperative protracted urinary output < 0.5 ml/kg/hr for at least eight hours. Plasmatic determinations were taken at T0 (no dopamine administration), when urinary output began to increase, or if not, after two hours (T1), at eight (T2), and 24 (T3) hours after the beginning of infusion. After 24 hours the dopamine infusion was stopped and the patient's plasmatic level was measured four hours later (T4). Dopamine plasma concentrations were measured using high-performance liquid chromatography. Plasma dopamine concentration increased in all patients and reached a steady state at T2 (T2 = 76.41 +/- 16.84 ng/ml). Dopamine induced a concentration-dependent increase in urinary output (T0 = 0.45 +/- 0.14; T1 = 1.49 +/- 1.11; T2 = 2.34 +/- 1.44; T3 = 1.57 +/- 0.57; T4 = 0.85 +/- 0.7 ml/kg/hr). Three patients did not have an enhanced urinary output after dopamine infusion; they did have a prolonged clamping time and operation time (162 +/- 24 and 570 +/ 30 min, respectively). We conclude that low dose dopamine induces a dose-dependent increase of urinary output. This phenomenon also has been found in patients when their plasma concentration had not yet reached the steady-state. Lack of responsiveness to dopamine suggests a renal function impairment probably due to the prolonged aortic clamping time.

Acute Kidney Injury↗