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PubMed1995

The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase.

Segregation analyses have shown that Gilles de la Tourette Syndrome (GTS) is transmitted as an autosomal dominant gene disorder indicating that classical linkage analysis should be able to identify susceptibility loci. Previous studies of GTS have included investigations of neuroreceptor function, neurotransmitters, and their metabolites as well as neurotransmitter-related enzymes in an attempt to determine the pathophysiology of GTS. The neurotransmitter systems most often thought to be involved in GTS include those involving adrenaline, noradrenaline, and dopamine. We have carried out research to test the hypothesis that genes encoding proteins in the catecholamine pathways may contribute to the genetic etiology of GTS. Polymorphic markers at or near the D1, D2, D3, D4, D5 neuroreceptor gene loci as well as at the genes encoding dopamine beta hydroxylase (DBH), tyrosinase (TY) and tyrosine hydroxylase (TH) were studied in one large multiple affected pedigree. The linkage results of this investigation exclude a major role of these candidate genes in the etiology of GTS in the pedigree.

Chromosome Aberrations↗

PubMed1982

Evidence for dopamine autoreceptors controlling dopamine synthesis in the substantia nigra.

The effect of apomorphine and haloperidol on DOPA accumulation after inhibition of DOPA decarboxylase activity with NSD 1015 was compared in the substantia nigra (SN) and caudate nucleus (CN) of normal rats and rats deprived of nigral afferences from the striatum by means of intrastriatal kainic acid. In normal rats apomorphine decreased DOPA accumulation to the same extent in both the SN and CN. However, haloperidol produced a more pronounced increase in DOPA accumulation in the CN than in the SN. The effect of both drugs still persisted in the SN and CN after destruction of the neuronal strionigral feedback loop with kainic acid. The results provide evidence for the existence of nigral dopamine autoreceptors controlling dopamine synthesis in the SN.

Animals↗

PubMed1984

(+)- and (-)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis.

Both enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP; 0.5-32 mg/kg s.c.) dose dependently reduced the increase in striatal dopamine (DA) synthesis rate produced by gamma-butyrolactone (GBL). Whereas (+)-3-PPP completely prevented the action of GBL, (-)-3-PPP was only partially effective. In addition, (-)-3-PPP partially antagonised the inhibitory action of apomorphine on the GBL-induced increase in DA synthesis rate. These findings suggest that (+)- and (-)-3-PPP act as full and partial agonists respectively, at striatal DA autoreceptors controlling DA synthesis.

4-Butyrolactone↗

PubMed1985

Regional distribution of the dopamine D2 receptors in the mesotelencephalic dopamine neuron system of human brain.

Using the [3H]spiroperidol binding technique, we performed a regional distribution of the D2 receptors in the human mesotelencephalic dopamine neuron system. D2 receptors were found in decreasing order of concentration in caudate nucleus greater than putamen greater than nucleus accumbens greater than globus pallidus greater than amygdala greater than substantia nigra. D2 receptors could not be detected in any cortical region. The nigrostriatal and mesolimbic components of the mesotelencephalic dopamine neuron system are easily to reconstitute. If there exists a mesocortical component in man, its actions appear not to be mediated by D2 receptors.

Aged↗

PubMed1985

Dopamine-beta-hydroxylase inhibition acutely stimulates rats hypothalamic noradrenaline and dopamine neuronal activity as assessed from metabolic ratios and circulating glucose and ACTH responses.

Because central noradrenaline neuronal activity is tonically inhibited by noradrenaline (NA) itself via an action at prejunctional alpha 2-adrenoceptors, it was hypothesised that the blockade of central NA synthesis following acute dopamine-beta -hydroxylase (DBH) inhibition might primarily deplete prejunctional NA levels and result in an increase in central NA neuronal activity through reduced NA autoinhibition. This hypothesis was tested in the rat following the acute administration of the DBH inhibitors diethyldithiocarbamate (DDC) and cysteamine (CSH). Computerised gas chromatography/mass spectrometry was used to precisely measure the hypothalamic levels of NA and dopamine (DA) together with those of their primary neuronal metabolites dihydroxyphenylethyleneglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), respectively. Both DDC (at 4 h) and CSH (at 30 min.) caused approximately a 50% reduction of hypothalamic NA concentrations. However this was associated with marked and highly significant increases in hypothalamic DHPG levels (by 50-100%) and in the hypothalamic ratio DHPG/NA. Also, when measured after CSH, the hypothalamic levels of the DHPG metabolite 3-methoxy-4-hydroxyphenylethyleneglycol were highly significantly increased. Consistent with increased DA neuronal activity, both DBH inhibitors raised DA and DOPAC levels and also the ratio DOPAC/DA in the hypothalami of treated rats and markedly suppressed serum prolactin levels (all p less than 0.01). The rise in hypothalamic concentrations of DHPG indicates that an increase in hypothalamic NA neuronal activity occurs following DBH inhibition. Significant elevations of blood glucose, corticosterone and ACTH were also observed after DBH inhibition. As we have previously demonstrated that increased central NA activity is associated with elevations of blood glucose, corticosterone and ACTH, these data provide further evidence for a functional increase in central NA activity caused by acute DBH inhibition. It is proposed that the increase in hypothalamic NA activity after DBH inhibition results from a primary depletion of the prejunctional alpha 2-active autoregulatory pool of NA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

D2 dopamine receptor involvement in spinal dopamine-produced antinociception.

Experiments were performed on 79 lightly pentobarbital-anesthetized rats. Rats displayed a dose-dependent increase in tail-flick latencies following the injection of dopamine (DA) into the lumbar subarachnoid space through an intrathecal tube. Sulpiride, a D2-subtype receptor antagonist, antagonized the DA-induced analgesia (antinociceptive) effect; while SCH-23390, a D1-subtype receptor antagonist, had no effect even in a higher dose. To further investigate whether the well-known spinal serotonergic, noradrenergic and opioidergic receptor systems were involved in DA-induced antinociception, their antagonists, methysergide, phentolamine, and naloxone were tested respectively. The results showed that phentolamine, but not methysergide or naloxone, could block the DA-induced antinociception. The present data provide evidence that DA exerts antinociceptive effects through D2-subtype dopamine receptor(s) at the spinal level, and that spinal alpha-adrenergic receptors may mediate this effect.

Animals↗

PubMed1989

Yawning induced by the selective dopamine D2 agonist N-0437 is blocked by the selective dopamine autoreceptor antagonist (+)-UH 232.

Yawning and stretching responses were elicited in rats by a small dose (0.3 mg/kg) of the highly selective dopamine D2 agonist, N-0437. The responses were blocked by the highly selective dopamine autoreceptor antagonist, (+)-UH 232 (3.0 mg/kg), but not by raclopride at a dose which selectively blocks postsynaptic D2 receptors. The results strongly confirm the view that yawning and stretching are behavioral responses elicited by stimulation of presynaptic D2 receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Opposite effects of SK&F 38393, a dopamine D-1 agonist, and SCH 23390, a dopamine D-1 antagonist, in tests of salt preference/aversion in the rehydrating rat.

Male rats were adapted to a 22-hr water-deprivation schedule, and to a 15-min choice test, in which water was available in one drinking tube, and water, 0.064%, 0.16%, 0.4%, 1.0%, or 2.5% NaCl solution, respectively, was available in a second. A typical saline preference-aversion function was obtained. The selective dopamine D-1 agonist, SK&F 38393 (3.0 mg/kg, IP), significantly depressed choice of hypertonic saline solutions (1.0% and 2.5% NaCl solutions), without affecting preference for hypotonic saline solutions. In contrast, the selective dopamine D-1 antagonist, SCH 23390 (0.1 mg/kg, SC), significantly increased the preference measure in the case of hypertonic solutions. These data indicate a role for D-1 receptors in dopaminergic mediation of the descending limb of the saline preference-aversion function.

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

PubMed1995

Rats self-inject a dopamine antagonist in the lateral hypothalamus where it acts to increase extracellular dopamine in the nucleus accumbens.

Local injection of sulpiride to block dopamine (primarily D2-type) receptors in the perifornical lateral hypothalamus (pf-LH) can induce locomotion, feeding, and drinking, and in the present study, local sulpiride induced reward and dopamine (DA) release in the nucleus accumbens. Sulpiride injected bilaterally (4, 8, and 16 micrograms/0.3 microliters), ipsilaterally, or contralaterally (8 micrograms) in the pf-LH increased extracellular levels of DA and its metabolites in the accumbens. Bilateral sulpiride injected posterior and medial to the pf-LH controlled for diffusion to the ventricle or ventral midbrain. Rats self-injected sulpiride (210 ng/21 nl/2 s) in the pf-LH (111 resp/2 h on drug lever vs. 20 resp on a blank lever). Thus, cells in the pf-LH establish connections with mesolimbic DA neurons involved in the behavior reinforcement process. Evidently hypothalamic cells with DA receptors normally inhibit aspects of behavior reinforcement. Disinhibition with hypothalamic sulpiride is reward for self-injection and cause of overeating that can lead to obesity.

Animals↗

PubMed1989

Time course of postmortem modifications in synaptosomal [3H]dopamine uptake and [3H]GBR 12783 binding to the dopamine uptake complex in the rat striatum.

The present study focuses on the changes of two biochemical markers of the striatal dopaminergic innervation evaluated after different postmortem storage periods of rat heads either at room temperature (21 degrees C) or at 4 degrees C: (i) the uptake of [3H]dopamine (DA) into striatal synaptosomes and (ii) the specific binding of [3H]GBR 12783, a selective ligand for the neuronal dopamine uptake sites, to a striatal membrane fraction. The uptake of [3H]DA was completely abolished after 24 and 72 h storage of the tissue at 21 degrees C and 4 degrees C, respectively, whereas in the same conditions, the binding of [3H]GBR 12783 was slightly decreased. The Km and Kd of these two processes were virtually unchanged after the different storage periods considered, whereas the Vmax and Bmax were markedly decreased.

Animals↗

PubMed1988

DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein in tanycytes of the mediobasal hypothalamus: distribution and relation to dopamine and luteinizing hormone-releasing hormone neurons and other glial elements.

The distribution of a dopamine- and cyclic adenosine-3':5'-monophosphate (cAMP)-regulated phosphoprotein with an apparent molecular weight of 32,000 (DARPP-32) was investigated in the rat diencephalon and monkey hypothalamus by use of immunohistochemical techniques. In addition to single cells located peri- and paraventricularly in hypothalamus and thalamus in the rat, and ependymal cells, DARPP-32-immunoreactivity was found to be present in a subpopulation of ependymal tanycytes. These DARPP-32-positive tanycytes lined the walls and floor of the third ventricle, sending processes towards the arcuate nucleus, surrounding blood vessels in this nucleus, and continuing towards the median eminence, where they abutted on portal vessels. A second group of DARPP-32-positive tanycytes with cell bodies within the median eminence was also observed. Simultaneous labeling with antiserum against tyrosine hydroxylase, a presumptive marker for tuberoinfundibular dopamine neurons, revealed a close relation to DARPP-32-containing tanycytes in several anatomical locations. Thus, in the periventricular area DARPP-32-positive tanycytes ensheathed tyrosine hydroxylase-positive processes. These processes, presumably representing dopaminergic dendrites, virtually penetrated between the ependymal cells to the ventricular space and thus perhaps established direct contact with the cerebrospinal fluid. Tyrosine hydroxylase-terminals were also observed in close association with DARPP-32-immunoreactive tanycytes in the rat median eminence. However, in view of the density of DARPP-32-positive processes in the external layer of the median eminence, the DARPP-32 processes may be related to a number of other types of nerve endings, including luteinizing hormone-releasing hormone, as shown in this study. The close association of DARPP-32-immunoreactive processes with tyrosine hydroxylase- and luteinizing hormone-releasing hormone-immunoreactive nerve endings in the rat was directly visualized at the ultrastructural level using triple-labeling immunocytochemistry. Both the ultrastructural analysis and immunohistochemistry at the light microscopic level, comparing the distribution of DARPP-32 and glial fibrillary acidic protein, indicated the presence of two types of glial processes in the median eminence. The electron microscopic studies also suggested the presence of both DARPP-32-positive and DARPP-32-negative glial processes in the external layer of the median eminence.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

1-Methyl-4-phenylpyridinium-induced down-regulation of dopamine transporter function correlates with a reduction in dopamine transporter cell surface expression.

The mechanisms whereby 1-methyl-4-phenylpyridinium (MPP(+)) mediates cell death and Parkinsonism are still unclear. We have shown that dopamine transporter (DAT) is required for MPP(+)-mediated cytotoxicity in HEK-293 cells stably transfected with human DAT. Furthermore, MPP(+) produced a concentration- and time-dependent reduction in the uptake of [3H]dopamine. We observed a significant decrease in [3H]WIN 35428 binding in the intact cells with MPP(+). The saturation analysis of the [3H]WIN 35428 binding obtained from total membrane fractions revealed a decrease in the transporter density (B(max)) with an increase in the dissociation equilibrium constant (K(d)) after MPP(+) treatment. Furthermore, biotinylation assays confirmed that MPP(+) reduced both plasma membrane and intracellular DAT immunoreactivity. Taken together, these findings suggest that the reduction in cell surface DAT protein expression in response to MPP(+) may be a contributory factor in the down-regulation of DAT function while enhanced lysosomal degradation of DAT may signal events leading to cellular toxicity.

1-Methyl-4-phenylpyridinium↗

PubMed2006

Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors.

Proper regulation of brain dopaminergic activity is essential for maintaining normal mental functions. In this study, the regulatory properties of five different dopamine receptor subtypes and alternative splicing variants of dopamine D2 and D4 were examined. The stimulation of D1R, D2R, D5R but not D3R, D4R caused the robust translocation of beta-arrestin to the plasma membrane. When D1R or D3R were co-expressed with D2R, D1R significantly inhibited the sequestration of D2R, suggesting that the inhibitory effects of D1R on the D2R sequestration could explain the synergistic activity between two receptors. The sequestration of alternatively spliced isoforms of D2R was differently regulated by GRKs and beta-arrestins. Three alternative splicing variants of D4R produced a similar level of beta-arrestin translocation, and the studies with the deletion mutants of D4R within the third cytoplasmic loop revealed that the regions containing the SH3-binding domains are responsible for the beta-arrestin translocation.

Animals↗

PubMed2004

Effect of 1,2,3,4,-tetrahydroisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [3H]GBR 12,935 to dopamine transporter in the rat nigrostriatal, dopaminergic system.

Current concepts of Parkinson's disease (PD) postulate that interaction between neurotoxins and specific genetic background may play an important role in pathogenesis of PD. Therefore, the effect of multiple administration of 1,2,3,4-tetrahydroisoquinoline (TIQ) under conditions of CYP2D blockade on the expression of key markers of PD was studied in the rat striatum (STR) and substantia nigra (SN). TIQ administered alone (50 mg/kg i.p. twice daily for 14 days) markedly decreased the level of tyrosine hydroxylase protein (TH) in the STR; however, this effect was not accompanied by reduction of dopamine (DA) concentration and [(3)H]GBR 12,935 binding to dopamine transporter (DAT). Administration of CYP2D inhibitor, quinine, jointly with TIQ lowered the levels of TH and DA in that structure, but slightly increased DAT binding. In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [(3)H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc). Neither the TH level nor DA concentration was affected by the combined treatment, although DAT binding was still reduced in the SN. TIQ did not change the total DA catabolism in the STR, but caused its inhibition in the SN. It strongly depressed the levels of intraneuronal DA metabolite DOPAC and enhanced that of extraneuronal 3-MT in either structure. TIQ more weakly affected the levels of both DA metabolites in the presence of quinine. Our results suggest that endogenous TIQ may act rather as neuromodulator but not as parkinsonism-inducing neurotoxin in the rat brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine.

Pharmacological alterations in dopamine transporter (DAT) function not only modulate dopamine reuptake, but they can induce rapid changes in the plasmalemmal expression of the transporter. By modifying transporter membrane expression, drugs may alter the maximum rate of neurotransmitter clearance, shifting cellular transport capacity and disrupting normal receptor stimulation. DAT-interacting drugs include the illicit and highly abused psychostimulants amphetamine and cocaine. Regulation of transporter activity and plasma membrane expression by these drugs has been implicated in the long-term processes of reward and addiction. This review summarizes the regulation of DAT by transporter substrates and blockers with particular emphasis on the modulation of DAT cell surface expression by acute exposure to amphetamine and cocaine.

Amphetamine↗

PubMed2005

D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4+ -T cells.

The expression of dopamine receptors was examined in purified human neutrophils, monocytes, B cells, natural killer cells and CD4+ - and CD8+ -T lymphocytes by RT-PCR. In healthy subjects, D1 and D2 receptors were not expressed in leukocytes. Real Time PCR for dopamine receptors D3 and D4 disclosed that D3 receptors are expressed in T cells and natural killer cells and D4 receptors in CD4+ -T cells. The comparison of schizophrenic patients with sex- and age-matched controls revealed a significantly higher expression of D3 receptor mRNA in T cells of schizophrenic patients, whereas D4 receptor mRNA in CD4+ -T cells was downregulated.

Adult↗

PubMed2006

Slow isomerization step in the interaction between mouse dopamine transporter and dopamine re-uptake inhibitor N-(3-iodoprop-2E-enyl)-2beta-carbo-[3H]methoxy-3beta-(4'-methylphenyl)nortropane.

The kinetics of the association and dissociation of the tritium-labeled selective and potent dopamine transporter inhibitor N-(3-iodoprop-2E-enyl)-2beta-carbo-[3H]methoxy-3beta-(4'-methylphenyl)nortropane ([3H]PE2I) with the transporter of mouse striatal membranes was studied. The analysis revealed that the specific binding of [3H]PE2I occurs within a homogeneous population of binding sites in these membranes. The relatively slow binding process was characterized by the pseudo-first-order rate constant kobs. The plot of these rate constants versus free radioligand concentration was hyperbolic, demonstrating that at least two kinetically distinguishable steps can be identified in the interaction of dopamine transporter with this inhibitor. The fast and reversible binding step, characterized by dissociation constant KA = 51 +/- 23 nM, is followed by a slow but also reversible isomerization step of the complex, characterized by the isomerization rate constant ki = (7 +/- 2)10(-2) s(-1) and by the rate constant k(-i) = (3.9 +/- 0.5)10(-3) s(-1) for the reverse process. This isomerization step increases the apparent affinity of the ligand and probably consists of a conformational transition of the transporter protein, induced by the inhibitor molecule.

Animals↗

PubMed2004

Striatal adenosine A(2A) receptor blockade increases extracellular dopamine release following l-DOPA administration in intact and dopamine-denervated rats.

The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinson's disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously.

3,4-Dihydroxyphenylacetic Acid↗