Disease relevance of Drd4

• Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity [1].

Psychiatry related information on Drd4

• The recently described D4 receptor homozygous mutants exhibit a reduction in baseline locomotor activity and were shown to be supersensitive to the locomotor activating effects of alcohol and psychostimulant drugs [2].
• The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder [3].
• We examined whether dopamine D4 receptor is involved in morphine dependence in mice [4].

High impact information on Drd4

• Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R-/- mice [5].
• Although less active in open field tests, D4R-/- mice outperformed wild-type mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine [5].
• The modulation by D4 ligands of the dark level of light-sensitive cAMP in photoreceptors demonstrates the physiological coupling of the D4 receptor subtype [6].
• Of the known Ptx-sensitive G-protein alpha subunits, MN9D-expressed Galphai2, GalphaoA, and GalphaoB; however, none of these coupled to the D4 receptor [7].
• Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain neurons were reduced to the same extent in both genotypes, Drd4(-/-) mice lesioned with 6-OHDA did not develop hyperactivity [3].

Chemical compound and disease context of Drd4

• Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice [8].
• Sulpiride, a dopamine D2 receptor antagonist, and clozapine, a dopamine D4 receptor antagonist, which decreased spontaneous locomotor activity, did not prevent the locomotor stimulatory effects of (+)MK-801 [9].

Biological context of Drd4

• To determine whether the D4R plays a role in these behavioral phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4(-/-)) [3].
• The murine D4 receptor gene has three introns and four exons, in common with the rat and human D4 receptor genes [10].
• The D4 receptor gene encoded an open reading frame consisting of 387 amino acids, interrupted by three introns [11].
• Genomic structure and tissue distribution of the mouse dopamine D4 receptor [11].
• The mouse dopamine D4 receptor gene was isolated from a genomic DNA library by plaque hybridization [11].

Anatomical context of Drd4

• Dopamine D4 receptor-induced postsynaptic inhibition of GABAergic currents in mouse globus pallidus neurons [12].
• The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area [13].
• D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P < 0.05) [1].
• Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls [14].
• Despite the similar inhibition of cAMP synthesis, the effect of light is directly on the photoreceptors and independent of dopamine modulation, because it was unaffected by application of the D4 receptor antagonist l-745,870 [15].

Associations of Drd4 with chemical compounds

• Although Drd4-/- mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test [13].
• Similarly, the D4R antagonist PNU-101387G prevented hyperactivity in wild-type 6-OHDA-lesioned mice [3].
• However, D3R or D4R stimulation with quinpirole showed no change in NF-kappaB-Luci activity, although forskolin-induced cyclic AMP responsive element-Luci activation was attenuated by quinpirole treatment in NGD2LR, NGD3R and NGD4R cells [16].
• Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu], (N-methyl-d-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls [14].
• In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D4 receptor-deficient (D4(-/-)) mice and in tenth-generation D4(-/-) mice compared with D4 wild-type (D4(+/+)) littermates [17].

Other interactions of Drd4

• Immunohistochemical study and RT-PCR analysis revealed the expression of the D2 receptor in the basal epidermis and the D4 receptor in the uppermost layer of the epidermis [18].
• 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 [10].
• To investigate whether other dopamine receptor subtypes regulate NF-kappaB, we established NG108-15 cells stably expressing D3R, D4R and D5R (NGD3R, NGD4R and NGD5R) [16].
• A dopamine D2/D4 receptor agonist, quinpirole, reduced cAMP levels in dark-adapted normal retinas in vitro, but not in rds/rds retinas [19].
• In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays [20].

Analytical, diagnostic and therapeutic context of Drd4

• Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections [1].
• The antibodies also detected a single protein of 36 kDa in Western blot of HEK 293 cells transiently transfected with the mouse D4 receptor [21].
• [(123)I]-3-(4-iodobenzyl)-1,2,3,4-tetrahydro-8-hydroxychromeno[3,4-c]pyridin-5-one ([(123)I]-ITCP), a presumed radioligand for visualization of the dopamine D4 receptor by single photon emission computed tomography, was evaluated in vivo in mice and rabbits [22].
• D4 receptor protein was also localized exclusively to the CCD and medullary collecting ducts by immunohistochemistry [23].

References