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At least 685 records · Page 38Linked to original sources

PubMed1991

Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release.

Microdialysis and high-performance liquid chromatography with electrochemical detection were used to determine extracellular levels of dopamine following ventral tegmental morphine injections into chloral hydrate-anesthetized rats. Morphine (13.2 nanomoles in 0.5 microliter of Ringer's solution) caused 50-150% increases in nucleus accumbens dopamine and metabolites; latency for the effect was on the order of 15 min with peak effects occurring in 30-50 min. Contralateral dopamine levels were influenced only minimally. These data suggest opiate receptors in or near the ventral tegmental area as sites of the opioid action that is responsible for opioid activation of the mesolimbic dopamine system.

Animals↗

PubMed1988

Alkylation of striatal dopamine receptors abolishes stereotyped behavior but has no effect on dopamine stimulated adenylate cyclase activity.

The role of dopamine stimulated adenylate cyclase (AC) activity in behaviours elicited by apomorphine stimulation of striatal dopamine receptors was investigated. Rats were treated with the irreversible dopamine receptor alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) alone or after pretreatment with either a D1 or D2 receptor antagonist and subsequently challenged with apomorphine. Animals that received no antagonist pretreatment showed significantly decreased striatal concentrations of D1 and D2 receptors and an abolition of apomorphine induced sniffing behaviour despite showing no change in striatal AC activity. In the groups which received antagonist pretreatment the reduction in the sniffing response paralleled the reduction in D2 receptor concentration whereas the incidence of vacuous oral movements was inversely related. In no case were the behavioural responses associated with changes in AC activity. We conclude that these behavioural effects observed in response to dopamine stimulation by apomorphine may be mediated through another second messenger system.

Adenylyl Cyclases↗

PubMed1989

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.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Association of dopamine D1 and D2 receptors with specific cellular elements in the basal ganglia of the cat: the uneven topography of dopamine receptors in the striatum is determined by intrinsic striatal cells, not nigrostriatal axons.

To ascertain the cellular associations of the D1 and D2 dopamine receptor subtypes in components of the basal ganglia, cats were prepared with unilateral, axon-sparing, ibotenic acid lesions of the striatum (n = 6) or lesions of the nigrostriatal dopamine system by intranigral infusion of 6-hydroxydopamine (n = 8). After 42 days survival, tissue sections from the brains were processed for quantitative, in vitro receptor autoradiography with [3H]SCH23390 (D1 radioligand) or [3H]spiroperidol (D2 radioligand). Lesion-induced changes in basal ganglia nuclei were assessed by comparing them to the corresponding nuclei on the intact side and in naive brains. Ibotenate lesions cause a decline in specific D1 and D2 receptor-binding in the area of the striatal lesion of 94% and 85%, respectively, and completely eliminate the uneven patterns of high- and low-density binding that are characteristic of the cat's caudate nucleus. The globus pallidus, entopeduncular nucleus and pars reticulata of the substantia nigra also show marked reductions in binding after striatal ibotenate lesions. Thus, after caudate nucleus lesions, D2 binding in the two pallidal segments declines by approximately 50%, but remains unchanged in the substantia nigra. Binding of the D1 radioligand (which is not measurable in the globus pallidus) declines by about 75% in the affected regions of the entopeduncular nucleus and pars reticulata, and by about 30% in the pars compacta. Lesions of the nigral dopamine neurons reduce D2 receptor-binding by 95% in the pars compacta and 40% in the pars reticulata, but have no effect on the concentration of D1 or D2 radioligand-binding in the striatum or pallidum. Moreover, such lesions failed to alter the uneven patterns of binding in the striatum. These data suggest that most, if not all, D1 receptors in the basal ganglia are associated with cells of the striatum and their axons in the entopeduncular nucleus and substantia nigra, and likewise, a large majority of D2 receptors are associated with striatal cells and their axons in pallidal structures. Nearly all D2 receptors in the substantia nigra are associated with dopamine neurons (autoreceptors). Finally, the heterogeneous patterns of D1 and D2 receptors in the striatum are a consequence of intrinsic neuronal distributions.

Animals↗

PubMed1982

Dopamine agonist-induced restoration of drinking in response to hypertonic saline in adipsic dopamine denervated rats.

Bilateral 6-hydroxydopamine lesions of the ascending dopamine neurones of the nigro-striatal bundle or bilateral electrolytic lesions of the lateral hypothalamus cause a syndrome of aphagia and adipsia. Rats with such lesions do not drink in response to hypertonic saline which causes thirst in intact animals. However, the systemic administration of the direct dopamine receptor agonists apomorphine, piribedil and lergotrile restored drinking in response to hypertonic saline in 6-hydroxydopamine treated rats but not in rats with electrolytic lesions of the lateral hypothalamus. Amphetamine and beta-phenylethylamine failed to restore drinking in response to hypertonic saline in either group of lesioned rats which suggests that these drugs may act indirectly on the dopaminergic system. The restoration of drinking model suggests that dopamine may have a permissive function in thirst, and, in addition, appears to represent a useful test for the screening of new drugs for a direct dopamine receptor stimulating action.

Animals↗

PubMed1994

Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor.

Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines, two binding sites were observed with Kd values of 0.5 and 5 nM in CHO cells and 0.05 and 1.6 nM in BHK cells, respectively. Neither of the receptors affected Ca2+ metabolism whereas they both were coupled in a stimulatory fashion to adenylyl cyclase. The pharmacological profile of both the D1a and D1b receptors as assessed from inhibition of specific [3H]SCH 23390 binding was classical D1-like. Thus, benzazepine derivatives as well as the atypical neuroleptics, clozapine and fluperlapine, exhibited high affinity whereas D2 selective compounds like sulpiride and spiperone had low affinity for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments, dopamine was around 20 fold more potent in stimulating adenylyl cyclase via the D1b receptor as compared to the D1a receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1998

Real time measurement of stimulated dopamine release in the conscious rat using fast cyclic voltammetry: dopamine release is not observed during intracranial self stimulation.

Fast cyclic voltammetry (FCV) was used to measure real time release of electrically stimulated endogenous dopamine in the nucleus accumbens (NAc) of conscious freely moving rats for up to 17 days. The method of electrode construction, implantation, electrical stimulation and recording of changes of extracellular dopamine concentration in the conscious rat are described. Rats trained on a continuous reinforcement schedule to perform intracranial self stimulation (ICSS) were implanted with electrodes for FCV. During ICSS, no faradaic signal was observed at an electrode implanted in the NAc. Decreasing the intensity of the stimulating current abolished ICSS, increasing the stimulating current disrupted ICSS. Operator delivered electrical stimulations using currents greater than those needed for ICSS yielded dopamine signals. It is concluded that during ICSS, sufficient dopamine does not reach the extracellular fluid space to yield a faradaic signal detectable by FCV.

Animals↗

PubMed1988

Preparation of dopamine 3-O-sulphate and dopamine 4-O-sulphate as reference substances and high-performance liquid chromatographic trace determination.

Simple syntheses of the biologically important but hitherto difficult to obtain dopamine sulpho conjugates dopamine 3-O-sulphate (I) and dopamine 4-O-sulphate (II), as analytical reference substances, starting from dopamine hydrochloride are described. A method for the determination of I and II with reversed-phase high-performance liquid chromatographic separation and coulometric detection in human urine together with calibration and current-voltage curves are presented. Detection limits of approximately 100 pg of I or II and unequivocal substance identifications even in very complex substrates such as human urine are reported.

Chemical Phenomena↗

PubMed1987

Dopamine agonists: effects of charged and uncharged analogues of dopamine.

Dopamine, at physiological pH, may exist as either an uncharged amine or a charged ammonium species. In order to gain insight as to which species is better suited for interaction with the dopamine receptor, we have synthesized dopamine analogues in which the nitrogen atom is replaced with a neutral methyl sulfide, a neutral methyl selenide, a charged dimethylsulfonium iodide, and a charged dimethylselenonium iodide. These analogues were tested for their ability to inhibit the K+-stimulated release of [3H]acetylcholine from striatal slices. At 30 microM concentration, the charged sulfonium and selenonium salts possessed significant agonist activity while the corresponding neutral species were inactive, suggesting that a charged species is optimal for dopamine agonist activity. In addition, the methyl sulfide was converted into the corresponding sulfoxide and sulfone; however, neither of these oxidation products possessed significant activity as dopaminergic agonists.

Acetylcholine↗

PubMed2006

Local dopamine production in the dorsal striatum restores goal-directed behavior in dopamine-deficient mice.

To determine whether dopamine signaling in the dorsal striatum is sufficient for performance of goal-directed behaviors, local dopamine production was restored in the dorsal striatum of dopamine-deficient (DD) mice through viral-mediated gene therapy. Virally rescued DD (vrDD) mice were tested for learning of an appetitive T-maze task designed to measure goal-directed behavior. The results indicate that in contrast with the performance of DD mice that have dysregulated dopamine signaling, vrDD mice were able to perform the T-maze task and reverse their behavior as well as sham-operated control mice. The authors conclude that finely tuned dopaminergic signaling within the dorsal striatum is sufficient for performance of goal-directed behavior.

Animals↗

PubMed1969

Release of newly synthesized dopamine from dopamine-containing terminals in the striatum of the rat.

The extraneuronal spontaneous efflux of (3)H-dopamine synthesized endogenously in dopamine terminals has been demonstrated in vitro, by collecting the (3)H amine in superfusates of isolated striatum of the rat previously incubated with (3)H-tyrosine. The (3)H-dopamine newly synthesized appears to be preferentially released. Furthermore, amphetamine and a monoamine oxidase inhibitor (Carton) markedly increased the release of (3)H-dopamine. This effect was also observed with substances normally contained in some striatal neurons: acetylcholine and 5-hydroxytryptamine.

Acetylcholine↗

PubMed1995

Coupling of human D-1 dopamine receptors to different guanine nucleotide binding proteins. Evidence that D-1 dopamine receptors can couple to both Gs and G(o).

Coupling between D-1 dopamine receptors and G proteins in cell lines expressing human D-1 receptors and different G proteins was examined. Pertussis toxin (PTX) treatment of rat pituitary GH4C1 cells significantly reduced, but did not abolish, agonist high affinity binding sites of the D-1 dopamine receptor; in SK-N-MC neuroblastoma cells, PTX failed to have any effect on D-1 high affinity sites. Cholera toxin (CTX) treatment of GH4C1 cells reduced but did not abolish the high affinity sites of D-1 receptors, while in SK-N-MC cells, treatment with CTX abolished all the high affinity sites. Western blot analyses with specific antisera indicated that Gs alpha, Gi1 alpha, Gi3 alpha, and Gq alpha were expressed in both cell lines, while Gi2 alpha and G(o) alpha were expressed in GH4C1 but not SK-N-MC cells. Antisera NEI-805 (anti-Gs alpha) and 9072 (anti-G(o) alpha) immunoprecipitated 24 +/- 4.3 and 34.4 +/- 6.9%, respectively, of G protein-associated D-1 dopamine receptors. Antisera 3646 (anti-Gi1 alpha), 1521 (anti-Gi2 alpha), 1518 (anti-Gi3 alpha), and 0941 (anti-Gq alpha) failed to coimmunoprecipitate appreciable levels of soluble receptors. These data indicate that D-1 dopamine receptors are coupled to both Gs alpha and G(o) alpha but not to Gq alpha.

Animals↗

PubMed1986

Specific inhibition of dopamine D-1-mediated cyclic AMP formation by dopamine D-2, muscarinic cholinergic, and opiate receptor stimulation in rat striatal slices.

The ability of different receptors to mediate inhibition of cyclic AMP accumulation due to a variety of agonists was examined in rat striatal slices. In the presence of 1 mM 3-isobutyl-1-methylxanthine, dopamine D-2, muscarinic cholinergic, and opiate receptor stimulation by RU 24926, carbachol, and morphine (all at 10(-8)-10(-5) M), respectively, inhibited the increase in cyclic AMP accumulation in slices of rat striatum due to dopamine D-1 receptor stimulation by 1 microM SKF 38393. In contrast, these inhibitory agents were unable to reduce the ability of a number of other agonists, including isoprenaline, prostaglandin E1, 2-chloroadenosine, vasoactive intestinal polypeptide, and cholera toxin, to increase cyclic AMP levels in striatal slices. These results suggest that in rat striatum either dopamine D-2, muscarinic cholinergic, and opiate receptors are only functionally linked to dopamine D-1 receptors or that the D-1 and D-2 receptors linked to adenylate cyclase lie on the cells, distinct from other receptors capable of elevating striatal cyclic AMP levels.

1-Methyl-3-isobutylxanthine↗

PubMed1991

Changes in extracellular concentrations of glutamate, aspartate, glycine, dopamine, serotonin, and dopamine metabolites after transient global ischemia in the rabbit brain.

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmitters (e.g., glycine and dopamine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brain's extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1-, 5-, and 13-fold and by 4-, 9-, and 31-fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700-fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4-fold, but remained elevated throughout the 80-min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann-Whitney test). That glutamate and aspartate concentrations in the hippocampus co-vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1979

The cardiovascular pharmacology of 7-propyl-theo-phylline-dopamine (D4975); comparison with dopamine and dobutamine.

1 The effects of a newly developed dopamine-xanthine derivative, 7-propyl-theophylline-dopamine (D4975), have been examined in cats anaesthetized with sodium pentobarbitone. When administered intravenously (in doses as low as 0.5 to 1.0 micrograms/kg) it increased systemic arterial pressure, left ventricular (LV) dP/dtmax, dP/dt at fixed ventricular isovolumic pressures and cardiac output. Heart rate effects were minimal. 2 D4975 was about 5 times more active than dopamine or dobutamine in elevating LV dP/dtmax or dP/dt at common peak isovolumic pressures (CPIP) and about 10 times more active than dopamine at increasing systemic arterial blood pressure. The effects of D4975 were also more prolonged than those of the other two agents. 3 The effects of D4975 on LV dP/dtmax were greatly reduced by the prior administration of propranolol. D4975 has no effect on peripheral beta 2-adrenoceptors. 4 It is suggested that the effects of D4975 on the myocardium involve both beta 1-adrenoceptor stimulation and inhibition of phosphodiesterase and that the marked and prolonged pressor response is due to resistance to enzymatic breakdown by monoamine oxidase. 5 The results suggest that D4975 might prove valuable in the treatment of the hypotension and reduced myocardial contractility of shock, especially as it is possible to select a dose that increases LV dP/dtmax without increasing either heart rate of systemic arterial pressure.

Animals↗

PubMedDate not supplied

First pass metabolism and in vitro metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine in dogs.

To elucidate the first pass metabolism of the dopamine prodrug N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) in the small intestine and liver of dogs, the blood and plasma concentrations of unchanged TA-870 and metabolites in the gastroduodenal vein, portal vein, hepatic vein, and abdominal aorta were measured by HPLC after intraduodenal administration of TA-870. In addition, an in vitro metabolic study of TA-870 was carried out using liver, small intestinal wall, and blood homogenates of dogs. The order of maximal concentration (Cmax 0-30 min) in gastroduodenal blood or plasma was unchanged TA-870 greater than deethoxycarbonylated TA-870 (DEC-TA-870) greater than conjugated dopamine greater than free dopamine (DA) greater than free homovanillic acid (HVA) greater than free 3,4-dihydroxyphenylacetic acid (DOPAC). This result showed that the main pathway of metabolism in the small intestine is catechol ester hydrolysis and minor pathways are amido hydrolysis, oxidative deamination, and catechol 3-O-methylation. The order of Cmax in the hepatic vein and abdominal aorta was conjugated DA greater than free DEC-TA-870 greater than free HVA greater than free DA greater than free DOPAC greater than conjugated DOPAC greater than unchanged TA-870. The main metabolic pathways in the liver were hydrolyses of ester and amido-linkage of TA-870 and conjugation of DA. In the in vitro studies, the main metabolites of TA-870 in liver, small intestinal wall, and blood homogenates were DEC-TA-870, 3- or 4-mono-deethoxycarbonylated TA-870, DA, and an unknown compound.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

[Purification of dopamine-beta-monooxygenase and extremely acidic, copper-containing proteins from the adrenal medulla. Extremely acidic, copper-containing proteins as electron donors for dopamine-beta-monooxygenase].

A procedure for purification of two copper-containing proteins from bovine adrenal medulla has been developed. The method is based on the extraction of proteins with Triton X-100, DEAE-cellulose chromatography and fractionation with polyethylene glycol. The yield of dopamine-beta-monooxygenase and extremely acidic copper-containing protein per 1 kg of brain medullar tissue is 100 and 150 mg, correspondingly. The ability of the reduced extremely acidic copper-containing protein to act as an electron donor in the reactions of side chain hydroxylation of tyramine and dopamine catalyzed by dopamine-beta-monooxygenase was demonstrated. The kinetics of the products formation and oxygen consumption in the course of these reactions and the specific activities of dopamine-beta-monooxygenase were compared, using the reduced extremely acidic copper-containing protein, ascorbate and ferrocyanide as cosubstrates.

Adrenal Medulla↗

PubMed1994

Oligodeoxynucleotide antisense to the D1 dopamine receptor mRNA inhibits D1 dopamine receptor-mediated behaviors in normal mice and in mice lesioned with 6-hydroxydopamine.

The effects of intracerebroventricular (i.c.v.) administration of a 20-mer phosphorothioate oligodeoxynucleotide antisense to the D1 dopamine receptor mRNA (D1 antisense) on D1 dopamine receptor-mediated behaviors were studied in normal mice and in mice with unilateral 6-hydroxydopamine-induced lesions of corpus striatum. Treating mice with D1 antisense inhibited grooming behavior induced by the D1 dopamine receptor agonist SKF 38393 [1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol hydrochloride], the reduction in grooming being related to the amount and length of time D1 antisense was given, with significant reductions in grooming behavior observed within 2 days of repeated injections of D1 antisense. Administering D1 antisense also inhibited rotational behavior induced by SKF 38393 in mice with unilateral 6-hydroxydopamine-induced lesions of corpus striatum. This inhibitory effect on rotational behavior could not be overcome by increasing the dose of SKF 38393. Recovery from inhibition of both grooming and rotational behaviors occurred after cessation of D1 antisense treatment. An oligomer with a similar composition of bases but placed in a random sequence failed to alter grooming or rotational behaviors induced by SKF 38393. In contrast to its effects on D1-mediated behaviors, treatment with D1 antisense had no significant inhibitory effect on stereotyped behavior induced by the D2 dopamine receptor agonist quinpirole [trans-(-)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H(or 2H)-pyrazolo- (3,4g)-quinoline dihydrochloride] in normal mice and produced no significant inhibition of rotational behavior induced either by quinpirole or by the muscarinic cholinergic agonist oxotremorine in 6-hydroxydopamine-lesioned mice.(ABSTRACT TRUNCATED AT 250 WORDS)

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