Disease relevance of Drd3

• Male Drd3-/- mice have increased body weight and body fat when given access to high fat (HF) diet but not standard rodent chow [1].
• In D3 receptor expressing AtT-20 cells, application of the D2/D3 receptor agonist, quinpirole, induces pertussis toxin-sensitive inward rectifying K+ currents that are blocked by barium [2].
• However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice [3].
• The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease [4].

Psychiatry related information on Drd3

• While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01-1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice [5].
• The dopamine D3 receptor (D3R) has been implicated in schizophrenia, drug addiction, depression and Parkinson's disease [6].

High impact information on Drd3

• Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal [7].
• Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes [8].
• These responses were accompanied by dopamine D2/D3 receptor supersensitivity [9].
• Thus, disruption of the D3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension [10].
• However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation [11].

Chemical compound and disease context of Drd3

• The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling [5].
• Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D3 receptor [12].

Biological context of Drd3

• In the present study, we sought to characterize body weight, body fat and food intake regulation in a mouse with a targeted disruption of the dopamine-3 receptor gene (Drd3) [1].
• DA D1 or D3 receptor homozygous knockout (D1-/- or D3-/-) mice offer the opportunity to test the roles of these specific receptors in regulating MOP-r gene expression in response to cocaine [13].
• Restriction and sequence analysis reveal the presence of six introns, in contrast to the five introns previously reported for the rat D3 receptor [14].
• Finally, a marked increase in D3 receptor mRNA levels was observed concomitant with a significant increase in D3 binding sites [15].
• Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice [16].

Anatomical context of Drd3

• C57BL/6J mice exhibited lower D3R binding density (-32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (-26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice [5].
• Post-transfection, the Bmax for D3 receptor expression was 1.9, 1.1 and 0.4 pmol/mg protein in the CHO-K1, SK-N-MC and CCL1.3 cell lines, respectively [17].
• Also, D3 receptor activation neither potentiated ATP-stimulated arachidonic acid release from CHO cells nor stimulated inositol phosphate production in CCL1.3-cells although both of these responses were elicited by D2 agonists in D2-transfected cells [17].
• These results show that the D3r expression is not restricted to neurons but it is also expressed in differentiating oligodendrocytes before terminal maturation [18].
• Confocal microscopic analysis indicated that D3r was associated with cell bodies and cell membranes but not with the processes emanating from cell somas [18].

Associations of Drd3 with chemical compounds

• C57BL/6J mice exhibit reduced dopamine D3 receptor-mediated locomotor-inhibitory function relative to DBA/2J mice [5].
• The D3 receptor expressed in CHO-K1 and CCL1.3 cells exhibited similar radioligand binding profiles, especially for the D3-selective compound, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) [17].
• In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes [19].
• CONCLUSIONS: Taken together, these studies suggest that the D2 receptor rather than the D3 receptor is important for the antidepressant-like activity observed for pramipexole in the mouse forced swim test [20].
• Cocaine-conditioned hyperactivity was inhibited by BP 897 or SB-277011-A, D3R-selective partial agonist and antagonist, respectively [21].

Regulatory relationships of Drd3

• Accumulating evidence suggests that dopamine D3 receptor (D3R) stimulation is inhibitory to spontaneous and psychostimulant-induced locomotion through opposition of concurrent D1R and D2R-mediated signaling [22].
• The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption [23].

Other interactions of Drd3

• We conclude that the signalling properties of the D3 receptor differ from those of its closest homolog, the D2 receptor [17].
• In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion [19].
• Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice [24].
• The receptor's entire coding region was contained within a 6 kb EcoRI genomic fragment, indicating that the murine D4 receptor gene is significantly smaller than the corresponding D2 and D3 receptor genes, the coding regions of which each stretch over 30 kb [25].
• D3R-deficient mice displayed other neuroadaptive changes, including decreased tyrosine hydroxylase, increased dopamine transporter mRNAs and increased dopamine reuptake in striatum [6].

Analytical, diagnostic and therapeutic context of Drd3

• This possibility was tested with mice lacking the D3 receptor as a result of gene targeting [26].
• Expression of the D3r mRNA, but not D2r mRNA, was detected as early as 5 d in vitro (DIV) by RT-PCR [18].
• Immunohistochemistry of brain sections revealed the presence of D3r in some oligodendrocytes located mainly within the genu and radiato of the corpus callosum during the active period of myelination [18].
• Double immunofluorescence analysis for the D3r and for surface markers of specific stages of oligodendrocyte development indicated that D3r expression occurred in precursors and in immature oligodendrocytes but not in mature oligodendrocytes (i.e. , A2B5(+) 007(-) 01(-) and A2B5(+) 007(+) 01(-) cells but not A2B5(-) 007(+) 01(+) cells) [18].
• Northern blot analysis shows the mouse D3 receptor to be most abundant in the olfactory tubercle [27].

References