Dopamine D2 Receptors In Striatum Research Articles

Dystonia: Sparse Synapses for D2 Receptors in Striatum of a DYT1 Knock-out Mouse Model.

Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a DYT1 Tor1a mouse model. Adult control Tor1a+/+ and mutant Tor1a+/− mice were used. The brains were perfused and free-floating sections of basal ganglia were incubated with polyclonal anti-D2 antibody, followed by secondary immune-fluorescent antibody. Confocal microscopy was used to detect immune-fluorescent signals. The same primary antibody was used to evaluate D2 receptor expression by western blot. The D2 receptor immune-fluorescence appeared circumscribed in small disks (~0.3–0.5 µm diameter), likely representing D2 synapse aggregates, densely distributed in the striatum of Tor1a+/+ mice. In the Tor1a+/− mice the D2 aggregates were significantly smaller (µm2 2.4 ± SE 0.16, compared to µm2 6.73 ± SE 3.41 in Tor1a+/+) and sparse, with ~30% less number per microscopic field, value correspondent to the amount of reduced D2 expression in western blotting analysis. In DYT1 mutant mice the sparse and small D2 synapses in the striatum may be insufficient to “gate” the amount of presynaptic dopamine release diffusing in peri-synaptic space, and this consequently may result in a timing and spatially larger nonselective sphere of influence of dopamine action.

Dopamine in drug abuse and addiction: results from imaging studies and treatment implications.

The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted (decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus (neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration.

In VivoEvidence for the Involvement of Dopamine-D2Receptors in Striatum and Anterior Cingulate Gyrus in Major Depression

The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2receptors were characterized in 13 patients with major depression using the dopamine-D2receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2receptor binding during serotonin reuptake inhibition was found in striatum and anterior cingulate gyrus in treatment responders, but not in nonresponders. The increase in dopamine-D2receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r=0.59 for right and left striatum respectively,P<0.05;r=0.79 for the anterior cingulate gyrus,P<0.05 after Bonferroni correction). Qualitatively similar correlations were observed in the precentral gyrus, the medial frontal gyrus, the inferior frontal gyrus, and the frontal part of the opercular gyrus, but these correlations failed to reach statistical significance after correction for the effects of multiple testing. No such correlations were found in the superior frontal gyrus, the orbitofrontal gyrus, the gyrus rectus, the superior parietal gyrus, or the superior temporal gyrus. The data strengthen the concept that the striatum and the anterior cingulate gyrus are involved in mood regulation. Dopamine-D2receptors may constitute a central role in this domain.

INTRASTRIATAL ADMINISTRATION OF AN OLIGODEOXYNUCLEOTIDE ANTISENSE TO THE D2 DOPAMINE RECEPTOR mRNA INHIBITS D2 DOPAMINE RECEPTOR-MEDIATED BEHAVIOR AND D2 DOPAMINE RECEPTORS IN NORMAL MICE AND IN MICE LESIONED WITH 6-HYDROXYDOPAMINE

Previous studies have shown that the intracerebroventricular injection of antisense oligodeoxynucleotides targeted to the mRNAs encoding the different subtypes of dopamine receptors inhibited behaviors mediated by these receptors. The present studies were designed to determine whether such antisense oligodeoxynucleotides could produce similar effects when injected into a discrete brain area. A D2 dopamine receptor antisense oligodeoxynucleotide (D2 antisense) was repeatedly injected into one corpus striatum of either normal mice or mice with unilateral lesions of the striatum induced by 6-hydroxydopamine. In the latter, intrastriatal injection of D2 antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D2 dopamine receptor agonist quinpirole. The inhibitory effect of D2 antisense was dose- and time-related and was reversed upon cessation of D2 antisense treatment. This inhibitory effect was also selective in that D2 antisense treatment inhibited the rotational behavior induced by quinpirole but not that induced by the D1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D2 antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D2 antisense was injected. No such rotational behavior was seen when similarly treated mice were challenged with SKF 38393 or oxotremorine. The quinpirole-induced rotational behavior in mice given intrastriatal injections of D2 antisense disappeared upon cessation of D2 antisense treatment. Repeated intrastriatal administration of D2 antisense also caused a significant reduction in the levels of D2, but not D1, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D2 dopamine receptors returned to normal upon cessation of D2 antisense treatment. Intrastriatal administration of an oligodeoxynucleotide with randomly placed nucleotides failed to alter the rotational response to quinpirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D2 dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D2 dopamine receptors can be achieved by the direct injection of a D2 antisense oligodeoxynucleotide into a discrete brain area. Copyright © 1996 Elsevier Science Ltd

MR-PET image coregistration for quantitation of striatal dopamine D2 receptors.

Our goal was to assess the utility of MR-PET image coregistration to quantify dopamine D2 receptors in striatum. Twenty-nine normal subjects were investigated with PET and [11C]raclopride and with MRI. D2 receptors were quantified using the ratio of the distribution volume in striatum to that in cerebellum. Measures obtained using regions selected directly from the PET images were compared with those obtained from MR images and then projected to coregistered PET images. There were no differences between measures selected from the PET images (3.9 +/- 0.5) and those from the MR images (3.9 +/- 0.65). The values for these two measures were significantly correlated and corresponded to r = 0.9, p < 0.0001. Regions of interest selected directly from PET images, where there is a large contrast between the region of interest and background, as for the case of dopamine D2 ligands, are almost identical to those obtained from coregistered MR images.

3H-spiperone labels sigma receptors, not dopamine D2 receptors, in rat and human lymphocytes

3H-Spiperone binds to dopamine D2 receptors in striatum and, under the assumption that it labels the same receptors in lymphocytes, this binding site has been suggested as a biological marker for schizophrenia. Recent studies, however, have raised questions about the existence of dopamine receptor changes in drug-free schizophrenic patients, as well as on the presence and/or dopaminergic nature of lymphocytic 3H-spiperone bindin the present study we have conducted an investigation of the binding of 3H-spiperone to rat and human lymphocytes. We found that 3H-spiperone binds in a specific, saturable and reversible manner to a site in lymphocytes; however, its dissociation constant Kd (9 nM) is about 40-fold higher than in striatum. An extensive investigation of the 3H-spiperone sites indicated that their pharmacological profile was not that of a dopamine D2 site, but rather that of sigma receptors, a novel class of non-dopaminergic, non-opioid receptors which bind with high affinity antipsychotic drugs. Sigma receptors were also identified in lymphocytes using the specific ligand 3H-DTG (1,3-di-o-tolyl-guanidine), whose binding characteristics were comparable to those of sigma receptors in rat brain. Receptor density and the pharmacological profile of 3H-spiperone and 3H-DTG were similar. Both compounds also labelled a higher number of sites in B cells than in T cells and a good correlation was found between the lymphocytic binding of both ligands in a group of 58 people. These findings indicate that sigma receptors are present in lymphocytes and suggest that 3H-spiperone binding in these cells occurs to sigma sites and not to dopamine D2 sites.

Effect of Repeated Treatment with Antidepressant Drugs and Electroconvulsive Shock (ECS) on the D2 Dopaminergic Receptor Turnover in the Rat Brain*

The effect of repeated treatment with citalopram, (+)oxaprotiline, (-)oxaprotiline, imipramine and ECS on the turnover of dopamine D2 receptors in the rat brain was measured using an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced irreversible receptor inactivation method. Repeated treatment with citalopram and ECS, but not with (+) and (-) enantiomers of oxaprotiline and imipramine, significantly decreased the turnover of D2 receptors in the striatum. Neither of the applied repeated treatments changed the turnover of D2 receptors in the limbic system. The results suggest that changes in the turnover of D2 dopamine receptors in striatum may participate in the mechanism of antidepressant action of ECS and citalopram, but not that of (+) or (-)oxaprotiline or imipramine.

Increased uptake sites for serotonin and dopamine with decreased S2 serotonin receptors in microencephalic rat brain

Methylazoxymethanol (MAM)-induced cerebral hypoplasia resulted in a significant increase in densities of both serotonin uptake sites in frontal cortex and dopamine uptake sites in striatum, suggesting serotonergic and dopaminergic axons terminals were compressed in the smaller brain volumes. The density of S2 serotonin receptors in MAM-lesioned frontal cortex was decreased probably due to down-regulation, while densities of D1 and D2 dopamine receptors in striatum were identical between MAM-lesioned rats and control rats.

Repeated administration of lisuride down-regulates dopamine D-2 receptor function in mesostriatal and in mesolimbocortical rat brain regions

Functional modifications of both D-1 and D-2 dopamine (DA) receptor subtypes following repeated administration of lisuride, a DA agonist that acts selectively on D-2 DA receptors were studied. The functional state of D-1 and D-2 DA receptors was evaluated from measurements of SKF 82526-stimulated and bromocriptine-inhibited adenylate cyclase activity in different brain regions of rats treated daily for 26 days with saline or lisuride (100 μg/kg i.p.). Persistent stimulation by lisuride of DA receptors in striatum, nucleus accumbens, substantia nigra, frontal cortex, hippocampus and pituitary gland induced a down-regulation of D-2 receptors without changing the functional activity of D-1 receptors.

Repeated administration of (−) sulpiride and SCH 23390 differentially up-regulate D-1 and D-2 dopamine receptor function in rat mesostriatal areas but not in cortical-limbic brain regions

We studied the possible function modifications of both D-1 and D-2 dopamine (DA) receptor subtypes following repeated administration of DA antagonists that act selectively on a single class of DA receptors. The functional state of D-1 and D-2 DA receptors in particular was evaluated by measuring SKF 82526-stimulated and bromocriptine-inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (−)sulpiride for 21 days. The results indicate that chronic blockade of D-1 DA receptors in striatum, nucleus accumbens, and substantia nigra by SCH 23390 induced up-regulation of the D-1 receptors without changing the functional activity of D-2 receptors. Likewise, chronic blockade of D-2 DA receptors by (−) sulpiride caused up-regulation of D-2 but not D-1 DA receptors in striatum, nucleus accumbens, substantia nigra and pituitary. SCH 23390 or (−)sulpiride did not modify the functional activity of either D-1 or D-2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that chronic treatment with selective D-1 or D-2 DA receptor blockers induces a receptor-specific up-regulation which involves the DA receptors located in the nigrostriatal system and pituitary but not those in the limbic-cortical areas.

Differential up‐regulation of D‐1 and D‐2 dopamine receptor function in mesostriatal areas but not in cortical‐limbic brain regions of rats chronically treated with (—)sulpiride and SCH 23390

AbstractIn the present study, the possible functional modifications of both D‐1 and D‐2 dopamine (DA) receptor subtypes have been studied following chronic treatment with DA antagonists that selectively act on a single class of DA receptors. Particularly, the functional state of D‐1 and D‐2 receptors has been evaluated by measuring SKF 82526‐stimulated and bromocriptine‐inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (−)sulpiride for 35 days.The results indicate that in striatum, nucleus accumbens, and substantia nigra, chronic blockade of D‐1 DA receptors by SCH 23390 induces up‐regulation of D‐1 receptors without changing the functional activity of D‐2 receptors. Likewise, chronic blockade of D‐2 DA receptors by (−)sulpiride causes an up‐regulation of D‐2 but not D‐1 DA receptors in striatum, nucleus accumbens, and substantia nigra. SCH 23390 or (−)sulpiride did not modify the functional activity of either D‐1 or D‐2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that treatment with selective D‐1 or D‐2 DA receptor blockade for 5 weeks induces a receptor‐specific up‐regulation which involves the DA receptors located in the nigrostriatal system but not those present in the limbic‐cortical areas.