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At least 811 records · Page 45Linked to original sources

PubMed1991

Lack of increase in dopamine transporter binding or function in rat brain tissue after treatment with blockers of neuronal uptake of dopamine.

Rats were pretreated daily for 10 days with a dopamine (DA) uptake blocker ([+]amphetamine, benztropine, cocaine, GBR-12909, mazindol, or nomifensine) or control vehicle and, after 1-4 days of no treatment, striatal tissue was fractionated to provide synaptosomes and membranes for assays of transport of 3H-DA or binding of 3H-GBR-12935. There were no significant increases of apparent maxima for uptake (Vmax) or binding (Bmax) or consistent changes in ligand affinity. Pharmacologic characterization of 3H-GBR-12935 binding extended the impression that this ligand has high affinity and selectivity for many agents which block neuronal uptake of DA uptake and much less for those which interact with DA receptors or other amine transporters. The results suggest that dopamine transporters are not regulated in the same way as receptors, nor influenced similarly toward upregulation and supersensitization by repeated treatment with antagonists.

Animals↗

PubMed1991

Modulation by dopamine of [3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine ([3H]BTCP, a phencyclidine derivative) binding to the dopamine uptake complex.

The modulation by dopamine of the binding of [3H]BTCP to the dopamine (DA) uptake complex was investigated in vivo (in control, reserpine- and L-DOPA-treated mice) and in vitro (on membrane preparations of the striatum of the rat). In both cases increasing doses of DA exerted a non-competitive inhibition of binding of [3H]BTCP, with a Ki value close to its K0.5, determined in competition experiments. Amphetamine and cocaine were also non-competitive inhibitors of the binding of [3H]BTCP, while GBR 12783 was competitive. In the presence of DA, the amount of cocaine required to inhibit the binding of [3H]BTCP was increased both in vitro and in vivo. These results suggest that inhibitors of the uptake of DA, such as BTCP or GBR 12783, modulate allosterically the uptake of DA, by binding to a site different from the DA recognition site. Cocaine, however, seems to share the same recognition site as DA.

Animals↗

PubMed1993

Effects of age and dopamine agonists and antagonists on striatal dopamine release in the rat: an in vivo microdialysis study.

The in vivo microdialysis technique was used to measure the extracellular output of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in adult and aged rats; as well as in response to the perfusion of dopamine agonists and antagonists, high-potassium Ringer solution and 1-methyl-4-phenyl-pyridinium ion (MPP+). The DA basal release before the drug treatment was higher in adult rats compared with the aged animals. The perfusion of dopaminergic drugs (nomifensine, sulpiride and quinpirole) through the probe at 1 microM concentration produced the same effect on DA, DOPAC and HVA outflow in adult and aged rats. 5-HIAA levels were not affected. The application of a high-potassium (60 mM) Ringer solution did not produce any significant difference on DA, DOPAC, HVA and 5-HIAA extracellular content when adult and aged rats were compared. The perfusion of MPP+ (1 mM) for 15 min produced a greater increase in DA release in aged than in adult rats. Greater susceptibility in the adult rats could explain these results.

1-Methyl-4-phenylpyridinium↗

PubMed1994

Differential effects of dopamine depletion on the binding and mRNA levels of dopamine receptors in the shell and core of the rat nucleus accumbens.

In the present study, using quantitative receptor autoradiography and in situ hybridization histochemistry the effects of unilateral 6-hydroxydopamine lesions on the binding density levels of dopamine D1 and D2 receptors and the levels of mRNA encoding D1 and D2 receptors were investigated in the core and shell territories of the nucleus accumbens (Acb) and in the caudate-putamen (CP). The lesions induced contrasting effects on the D1 binding and D1 mRNA in the Acb and CP, i.e. an increase in binding and a decrease in the mRNA levels. For the D2 receptor an increase in both the binding density and mRNA levels was observed. The lesion-induced effects displayed regional differences. For D1 mRNA and D1 and D2 binding, the lesion effect was more pronounced in the core than in the shell of the Acb. For the D2 mRNA levels an increase was observed in the CP but not in the two territories of the Acb. Furthermore, the decrease in D1 mRNA was greater in the rostral than in the caudal parts of the core and shell of the Acb. These results indicate that the core and shell of the Acb and the CP respond differentially to dopamine depletion.

Animals↗

PubMed1993

Endogenous dopamine differently affects N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine and cocaine binding to the dopamine uptake complex.

1. [3H]N-[1-(2-Benzo(b)thiophenyl)cyclohexyl]piperidine ([3H]BTCP) labels in vivo the dopamine uptake complex in the mouse striatum. 2. In mice treated with gamma-butyrolactone (GBL, 400 mg/kg), [3H]BTCP specific binding was increased and ID50 values of BTCP and cocaine for the prevention of [3H]BTCP binding were significantly lowered. 3. In GBL-treated mice, cocaine (5 mg/kg, s.c.) had no effect on the BTCP ID50 value, whereas GBR 12783 (2 mg/kg, s.c.) increased it significantly. 4. Thus in vivo, endogenous dopamine and cocaine are competitive and non-competitive inhibitors, respectively, of the binding of [3H]BTCP.

4-Butyrolactone↗

PubMedDate not supplied

The influence of cholesterol on synaptic fluidity, dopamine D1 binding and dopamine-stimulated adenylate cyclase.

The present study examined the influence of the synaptic cholesterol/phospholipid ratio on fluorescence polarization, the binding of SCH23390 to dopaminergic D1 binding sites and dopamine-stimulated adenylate cyclase activity. The cholesterol/phospholipid ratio of synaptic membranes from bovine caudate was modified by incubating the membranes with a lipid transfer protein and liposomes which were either loaded with or lacking cholesterol. The results of this study demonstrated that the number of binding sites (Bmax) for SCH23390 was insensitive to alterations in the synaptic cholesterol/phospholipid ratio and membrane order. However, when the cholesterol/phospholipid ratio was decreased by 30%, membrane order and binding affinity (Kd) were decreased. Despite the lack of change in the number of D1 binding sites, the activity of dopamine-stimulated adenylate cyclase was markedly inhibited by an elevated cholesterol/phospholipid ratio. The results of these studies are discussed in terms of their potential relevance to aging.

Adenylyl Cyclases↗

PubMed2005

Differential effects of dopamine and psychoactive drugs on dopamine transporter phosphorylation and regulation.

The dopamine transporter (DAT) is a phosphoprotein whose activity and phosphorylation state are acutely regulated by both protein kinase C (PKC) and substrate transport. DAT is a major site of action for psychostimulant and therapeutic drugs that either block transport or are transported substrates, but the effects of such drugs on DAT phosphorylation and regulation are not well understood. To examine these issues we subjected rDAT LLC-PK(1) cells to acute in vitro pretreatments with the endogenous, psychostimulant, and therapeutic compounds dopamine (DA), (-)-cocaine, 2 beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (beta-CFT), GBR 12909, mazindol, and methylphenidate (MPH), in the presence or absence of the PKC activator phorbol 12 myristate 13 acetate (PMA), followed by analysis of DAT metabolic phosphorylation and transport activity. Basal phosphorylation of DAT was not affected by any of the uptake blockers tested, and PMA-stimulated phosphorylation was not affected by cocaine, beta-CFT, mazindol or MPH, but was strongly suppressed by GBR 12909. Pretreatment of cells with cocaine or MPH had no effect on subsequent DA transport activity or the extent of PMA-induced transport down-regulation, whereas GBR 12909 inhibited PMA-induced DAT internalization. These findings indicate that these DAT phosphorylation and down-regulation properties are unaffected by some classes of uptake blocking drugs, but that differential regulatory effects may be exerted by GBR compounds. Pretreatment of cells with DA had no obvious effect on basal or PMA-stimulated DAT phosphorylation but led to cocaine-blockable transport down-regulation. DA-induced down-regulation was blocked by the PKC inhibitor bisindoylmaleimide I and was not additive with down-regulation induced by PMA, consistent with PKC serving as a common step and point of integration for these DA and PMA induced processes. The results of this study provide information on the potential for endogenous and psychoactive compounds to modulate or be modulated by DAT phosphorylation-mediated regulatory mechanisms that may contribute to drug behavioral or therapeutic properties.

Animals↗

PubMed2002

Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative.

Monoamine neurons are believed to use neuronal-specific transporters to remove their own transmitters from the extracellular space and thus terminate transmission to postsynaptic neurons. We report here, for the first time, conclusive evidence that a cross clearance of serotonin into dopamine neurons exists. Such alternative uptake by different neurons is adopted under circumstances when their own transporter function is no longer adequate. When the serotonin transporter (5-HTT) is disrupted in 5-HTT knockout mice, serotonin (5-HT) is found in dopamine (DA) neurons of homozygous (-/-) but not of heterozygous (+/-) mutant mice or their normal littermates. DA neurons containing 5-HT are seen in the substantia nigra and ventral tegmental area (VTA), but not in other brain areas of 5-HTT -/- mice. Normal rats treated with a 5-HT uptake blocker paroxetine also showed similar result. To verify the role of the DA transporter in such ectopic uptake, 5-HTT -/- mice were treated with DA uptake blocker GBR-12935, ectopic 5-HT in DA neurons was disappeared. These data indicate that: (a) 5-HT can be taken into DA neurons in rats and mice when the 5-HTT is not functionally adequate to remove extracellular 5-HT; (b) the 5-HT uptake into DA neurons is not affected by the 5-HT uptake blocker paroxetine; and (c) the DA transporter is responsible for the 5-HT uptake into DA neurons. This study thus demonstrates that cross neuronal type uptake exists and serves as a compensatory backup when a specific transporter is dysfunctional. This study also demonstrates that DA neurons can store 5-HT for possible "false neurotransmitter" or other usage.

Animals↗

PubMed1999

Developmental and age-related changes of dopamine transporter, and dopamine D1 and D2 receptors in human basal ganglia.

The developmental and age-related changes of the dopamine transporter (DAT), and the dopamine D1 and D2 receptor (D1R and D2R) subtypes were investigated in basal ganglia (BG) of human brain. DAT immunostaining was mainly observed in the neuropil, neurons, and glia of the striatum. The DAT-positive neuropil was detectable at 32 GW, a peak being reached at 9-10 years of age, with a decrease to 50-63 years of age. The developmental pattern of DAT immunoreactivity in neuron was similar to that of the neuropil. DAT-positive glia were observed in the BG at 32 GW, which increased slightly at 38-40 GW, and then did not obviously change until 6-8 months after birth. D2R-positive neurons were clearly observed at 19 GW, a peak being reached at 32 GW and 1-3 months of age in the globus pallidus and striatum, respectively, with a decrease after 9-10 years of age. D1R was expressed as early as D2R, but decreased after 6-8 months. Our results suggest that D1R and D2R expression is an intrinsic property of striatal neurons and is independent of dopaminergic innervation. D1R may play a more important role in neuronal maturation of the BG than D2R. D2R may be closely correlated with late neuronal development. The higher expression of DAT during adolescence may be related to function of the BG which learns complex behavioral patterns. The significance of the age-related decreases in DAT, D1R and D2R in the BG remains to be further investigated.

Adolescent↗

PubMed1998

Discriminative stimulus properties of the putative dopamine D3 receptor agonist, (+)-PD 128907: role of presynaptic dopamine D2 autoreceptors.

The putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 microg kg(-1), s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (-) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (+/-)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent alpha-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists > 40 and > 100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.

Animals↗

PubMed2000

Dopamine-opioid interactions in the rat striatum: a modulatory role for dopamine D1 receptors in delta opioid receptor-mediated signal transduction.

Dopaminergic and opioidergic systems interact in the striatum to modulate locomotor and motivated behaviors. The present study investigated the molecular interactions of these two systems by determining the role of dopamine D1 and D2 receptors in the modulation of opioid receptor-mediated signal transduction. Male Fischer rats were injected daily for 10 days with either saline, the D1 receptor agonist SKF 82958, the D2 receptor agonist quinpirole, or both SKF 82958 and quinpirole. Administration of SKF 82958 alone or together with quinpirole attenuated the ability of the delta receptor agonist D-Pen2,D-Pen5-enkephalin (DPDPE) to inhibit adenylyl cyclase activity in the caudate putamen and nucleus accumbens. Quinpirole administration alone had no effect. The efficacy and potency of the mu opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin (DAMGO) to inhibit adenylyl cyclase activity was unaltered following administration of either dopamine receptor agonist. Administration of SKF 82958 had no affect on delta receptor binding, forskolin-stimulated adenylyl cyclase activity, or G protein/adenylyl cyclase coupling. However, the ability of DPDPE to stimulate binding of [35S]GTPgammaS to inhibitory G proteins was attenuated in animals that received SKF 82958. These results suggest that repeated activation of D1 receptors attenuates the functional coupling of delta opioid receptors with adenylyl cyclase due to decreased coupling between delta receptors and G proteins.

Adenylyl Cyclases↗

PubMed2004

Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DAex) and serotonin (5-HT(ex)) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT(ex) in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DAex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT(ex) can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.

Animals↗

PubMed2001

Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum.

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections.

Adenosine↗

PubMed1992

Biphasic dose-dependent effects of dopamine and involvement of dopamine autoreceptors on intra-ocular pressure in the rabbit.

1. This work was conducted to provide new data concerning the possible dose-dependent activity of dopamine (DA) after ocular instillation. Experiments were done in rabbits with normal intraocular pressure (IOP), or after transitory induced ocular hypertension in water-loaded animals. 2. In ocular normotensive animals, a biphasic dose-dependent activity is observed, with no significant effect for 0.001% and 0.003% DA, a decrease in IOP after 0.005% and 0.01% DA instillation, then an important increase in IOP at concentrations from 0.05% onwards. 3. During transitory ocular hypertension, this phenomenon was confirmed, with a marked ocular hypotensive activity for 0.01% DA, no effect after 0.005% DA, then an important ocular hypertension with 0.05% and 0.5% DA as compared to the control group (0.9% NaCl). 4. An immediate and similar ocular hypertensive effect with DA could be reproduced by a subsequent instillation at high concentration (1%), while the hypotensive activity induced at low concentration (0.01%) is followed by a long-lasting refractory period (about 18 h). 5. Such a dose-dependent biphasic effect was also observed with N-methyl-dopamine (NMDA) after ocular instillation. The effects of instilled dopaminergic compounds were tested and ocular hypotensive activities of the S(-)enantiomer of the DA analogues 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), and of thiothixene (TIX) were also demonstrated. 6. The possible relationships to DA1 and DA2 receptors of the dual effect is discussed.

Animals↗

PubMed1996

Decreases in dopamine receptors but not in dopamine transporters in alcoholics.

It has been hypothesized that ethanol's actions on the dopamine (DA) system may participate in addiction. The purpose of this study was to evaluate the DA system in the brain of alcoholics. We evaluated 10 alcoholics and 17 nonalcoholics using positron emission tomography and [11C]raclopride to measure DA D2 receptors. In addition, in 5 of the alcoholics and 16 of the nonalcoholics, we also measured DA transporters with [11C]d-threo methylphenidate. The ratio of the distribution volumes in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as model parameter of DA D2 receptor and transporter availability. Dopamine D2 receptor availability (Bmax/Kd) was significantly lower in alcoholics (2.1 +/- 0.5) than in nonalcoholics (2.7 +/- 0.6) (p < 0.05) and was not correlated with days since last alcohol use. Alcoholics showed DA transporter values similar to those in nonalcoholics. The ratio of DA D2 receptor to transporter availability was significantly higher in nonalcoholics (1.4 +/- 0.1) than in alcoholics (1.1 +/- 0.1) (p < 0.005). Alcoholics showed significant reductions in D2 receptors (postsynaptic marker) but not in DA transporter availability (presynaptic marker) when compared with nonalcoholics. Because D2 receptors in striatum are mainly localized in gamma-aminobutyric acid (GABA) cells these results provide evidence of GABAergic involvement in the dopaminergic abnormalities seen in alcoholics.

Adult↗

PubMed1980

Lack of evidence that the central serotoninergic system plays a role in the activation of prolactin secretion following inhibition of dopamine synthesis or blockade of dopamine receptors in the male rat.

Administration of alpha MT to inhibit catecholamine synthesis or dopamine (DA) receptor blockade with spiroperidol had no effect on the hypothalamic concentration of 5HT or 5HIAA. Fluoxetine to block serotonin uptake had no influence on the elevation of serum prolactin levels induced by alpha MT or DA receptor blockers and conversely alpha MT did not influence the prolactin-releasing action of 5HTP alone or in combination with fluoxetine. Depletion of brain serotonin stores with p-chlorophenylalanine did not affect the prolactin-releasing action of alpha MT or DA receptor blockers. In contrast, the serotonin blocker methysergide, but not cyproheptadine, inhibited the prolactin-releasing effect of alpha MT or alpha-flupentixol, a DA receptor blocker, but not of spiroperidol, another DA receptor blocker. The intensity of the inhibition induced by methysergide paralleled the intensity of inhibition induced by apomorphine. Methysergide conspicuously lowered serum prolactin in animals with electrolytic destruction of the median eminence, whereas cyproheptadine had only a slight effect. The prolactin-inhibiting effect of methysergide could be prevented by pretreatment of the lesioned rats with spiroperidol. It is concluded (1) that elimination of the influence of the DA system does not activate the central serotoninergic system; (2) that activity of the serotoninergic system has no role in the activation of prolactin secretion induced by suppression of the inhibitory dopaminergic influence, and (3) that the inhibiting action of methysergide on the prolactin-releasing effect of alpha MT or alpha-flupentixol is due to its dopamine receptor agonist activity rather than to blockade of serotonin receptors.

5-Hydroxytryptophan↗

PubMed1999

Cationic modulation of human dopamine transporter: dopamine uptake and inhibition of uptake.

Effects of cations on dopamine (DA) uptake into cells expressing the human dopamine transporter and on inhibition of DA uptake by various substrates and inhibitors were investigated by using rotating disk electrode voltammetry. The Na(+) dependence of DA uptake varied with Na(+) substitutes, hyperbolic with Li(+), almost linear at 1 microM DA but hyperbolic at 8 microM DA with choline, and sigmoidal with K(+). With Na(+) substituted by Li(+), K([DA]) decreased and V(app) remained constant with increasing [Na(+)], whereas K([Na+]) decreased and V(app) increased with increasing [DA], suggesting an ordered sequence with Na(+) binding before DA. Similar trends for the Na(+)-DA interactions were observed in the presence of cocaine. Cocaine inhibited DA uptake solely by increasing K([DA]), with its K(i) not significantly different at 55 and 155 mM [Na(+)], whereas it inhibited Na(+) stimulation by reducing V(app) more than K([Na+]) at 1 microM DA, and V(app) only and less potently at 8 microM DA. Thus, cocaine may compete with DA, not with Na(+), for the transporter, and might not follow a strictly ordered reaction with Na(+). With Na(+) substituted by K(+), K([DA]) or K([Na+]) became insensitive to Na(+) or DA. K(+) impaired the DA uptake mainly by reducing V(app,) but affected cocaine inhibition by elevating K(i). Despite their different patterns for inhibiting DA uptake, nontransportable inhibitors cocaine, methylphenidate, mazindol, and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenyl-2-propyl)piperazi ne (GBR12909) showed similarly modest Na(+) dependence in their K(i) values. In contrast, substrates DA, m-tyramine, and amphetamine displayed a similarly stronger Na(+) requirement for their apparent affinities.

Carrier Proteins↗

PubMed2000

Dopamine D3 receptors expressed by all mesencephalic dopamine neurons.

A polyclonal antibody was generated using synthetic peptides designed in a specific sequence of the rat D(3) receptor (D(3)R). Using transfected cells expressing recombinant D(3)R, but not D(2) receptor, this antibody labeled 45-80 kDa species in Western blot analysis, immunoprecipitated a soluble fraction of [(125)I]iodosulpride binding, and generated immunofluorescence, mainly in the cytoplasmic perinuclear region of the cells. In rat brain, the distribution of immunoreactivity matched that of D(3)R binding, revealed using [(125)I]R(+)trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7-trans-OH-PIPAT), with dense signals in the islands of Calleja and mammillary bodies, and moderate to low signals in the shell of nucleus accumbens (AccSh), frontoparietal cortex, substantia nigra (SN), ventral tegmental area (VTA) and lobules 9 and 10 of the cerebellum. Very low or no signals could be detected in other rat brain regions, including dorsal striatum, or in D(3)R-deficient mouse brain. Labeling of perikarya of AccSh and SN/VTA appeared with a characteristic punctuate distribution, mostly at the plasma membrane where it was not associated with synaptic boutons, as revealed by synaptophysin immunoreactivity. In SN/VTA, D(3)R immunoreactivity was found on afferent terminals, arising from AccSh, in which destruction of intrinsic neurons by kainate infusions produced a loss of D(3)R binding in both AccSh and SN/VTA. D(3)R-immunoreactivity was also found in all tyrosine hydroxylase (TH)-positive neurons observed in SN, VTA and A8 retrorubral fields, where it could represent D(3) autoreceptors controlling dopamine neuron activities, in agreement with the elevated dopamine extracellular levels in projection areas of these neurons found in D(3)R-deficient mice.

Animals↗