Disease relevance of Drd1a

• The primary effect of exposure to METH is elevation of the level of extracellular DA; therefore, we assessed the role of the DA D1 receptor (D1R) and neurokinin-1 receptor (NK-1R) on the expression of toxicity [1].
• Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors [2].
• The D1 agonist SKF83959 was identified as a specific agonist for the heteromer that activated G(q)/11 by functioning as a full agonist for the D1 receptor and a high-affinity partial agonist for a pertussis toxin-resistant D2 receptor within the complex [3].
• The neuroleptic responsive and NNR mice have differed for at least eight generations by an order of magnitude in their sensitivity (ED50s) to catalepsy induced by neuroleptics with a high D2/D1 receptor activity profile [4].
• The selective D-2 receptor agonists, quinpirole and LY 163502, and the mixed D-1/D-2 agonist, apomorphine, induced a dose-dependent hypothermia, whereas the selective D-1 receptor agonists, SK&F 81297, SK&F 38393 and SK&F 75670, induced hyperthermia [5].

Psychiatry related information on Drd1a

• The present study investigated the specific contribution of dopamine D1 receptor (D1R) in mediating reward, locomotor activity, and spatial associative processes and in regulating NAc neural responses [6].
• To determine whether the dopamine D1 receptor plays a crucial role in the behavioral effects of psychostimulants, we tested both the locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control mice after cocaine and amphetamine treatments [7].
• An agent such as A-86929 (or its prodrug ABT-431), which selectively stimulates the D1 receptor, may represent a novel mechanism for Parkinson's disease therapy with the potential for an improved side-effect profile and, consequently, improved patient compliance [8].
• Mice of both lines were administered 0, 1, 3, or 10 mg/kg (SC) of the full efficacy D1 receptor agonist dihydrexidine, and their behavior was assessed in a social interaction test [9].
• In the hot-plate test D1 receptor deficient (-/-) and wild-type (+/+) mice showed similar reaction times under basal conditions [10].

High impact information on Drd1a

• Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses [11].
• These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity [11].
• These results demonstrate the essential role of the D1 receptor in the locomotor stimulant effects of cocaine and in dopamine-mediated neurophysiological effects within the nucleus accumbens [12].
• In one model system-in utero exposure to cocaine-specific and robust alterations are seen in dopamine-rich areas of the cerebral cortex, such as the anterior cingulate cortex: D1 receptor-G protein coupling is greatly reduced, the GABAergic system is altered and pyramidal dendrites undergo excessive growth [13].
• The cosegregation with hypertension of an impaired D1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D1A alleles suggest a causal relationship of the D1A receptor gene with hypertension [14].

Chemical compound and disease context of Drd1a

• The neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) selected lines of mice differ more than 10-fold in the ED50 for catalepsy induced by a wide variety of neuroleptics with a high dopamine D2/D1 receptor activity ratio, e.g., haloperidol [15].
• Pretreatment with either the selective D-1 receptor antagonist SCH 23390 or the D-2 receptor antagonist (-)-sulpiride converted the hyperalgesia produced by the D-1 agonist into an antinociceptive response whereas the effect of the D-2 receptor agonist was significantly antagonised [16].
• The potency and efficacy of the selective dopamine D2 receptor agonist quinpirole, the mixed D1/D2 agonist apomorphine, and the selective D1 receptor agonist SKF 38393 in producing hypothermia and changes in locomotor activity were evaluated in four strains of mice: CBA/J, C57BL/6J, ICR Swiss and CF1 [17].
• The effect was blocked by either the D2-receptor antagonist sulpiride or the D1-receptor antagonist SCH 23 390, indicating that motor activity is dependent on simultaneous activation of both dopamine receptor types [18].
• Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpine-treated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine [19].

Biological context of Drd1a

• Furthermore, for D2 mutants, immunoprecipitation experiments revealed increased basal and D1-agonist-stimulated phosphorylation of D1-receptor proteins at serine residues [20].
• The lack of development of up-regulation of Drd1 and Drd2 genes after repeated treatment with amphetamine probably explains the reduced place conditioning in CCK(2) receptor deficient mice [21].
• D1R mutants do not become locomotor activated with cocaine or show upregulated immediate early gene (IEG) expression, but D2 receptor-dependent IEG changes are intact [22].
• The data also show that cAMP second messenger cascade is not engaged in the D1R-induced regulation of the levels of these three proteins [23].
• Previously, we demonstrated that dopamine D1 receptor (D1R) agonists inhibit epidermal growth factor (EGF)-induced passage of mouse fetal cerebral cortical precursor cells from the G1 phase to the S phase of the cell cycle [23].

Anatomical context of Drd1a

• Mice lacking dopamine D2 receptors exhibit a significantly decreased agonist-promoted forebrain neocortical D1 receptor activation that occurs without changes in D1 receptor expression levels [20].
• In wild-type mice, acute treatment with a dopamine D1-receptor agonist results in activation of extracellular signal-regulated kinase in the nucleus accumbens without activation in the dorsal striatum [24].
• There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum [25].
• In D1 receptor null mice, D1R-/-, DA dose-dependently depolarized both LA and FS interneurons [26].
• Results show that although D1 dopamine receptor-mediated product on of cAMP is completely absent in membranes of D1A-deficient mice, D1 receptor-mediated accumulation of inositol phosphate is identical in tissues of mutant and wild-type animals [27].

Associations of Drd1a with chemical compounds

• CD1 mice were bilaterally microinjected in the PFC with either the D1 receptor antagonist, SCH23390 (SCH 6.25; 12.5; 50 ng), or the D2 receptor antagonist, sulpiride (SULP 12.5; 50; 100 ng) and placed into an open field containing five different objects [28].
• Compared to wild types, preference and consumption of ethanol were decreased in D1A2A receptor knockout mice, the reduction in ethanol consumption greater even than that seen in D1 receptor-deficient mice [29].
• Surprisingly, D1R-deficient mice retain cocaine-conditioned place preference [22].
• Pretreatment with the D1R antagonist SCH-23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu [1].
• Acute cocaine administration increases substance P levels, suggesting that striatal expression of this neuropeptide can be modulated by D1R-independent processes [22].

Physical interactions of Drd1a

• The hyperdopaminergic state of GABAB1-/- mice is accompanied by molecular changes, including reduced levels of tyrosine hydroxylase mRNA, D1 receptor binding-sites and Ser40 phosphorylation of tyrosine hydroxylase [30].

Enzymatic interactions of Drd1a

• However, the absence of normal DA tone generated significant alterations in DA D1-receptor signalling as indicated by increased mutant striatal levels of phosphorylated DARPP-32 and by an altered motor response to amphetamine [31].

Regulatory relationships of Drd1a

• After lesions of dopaminergic neurons, dopamine D1-receptor agonists activate extracellular signal-regulated kinase in the dorsal striatum, something not observed in intact animals [24].
• Mice with targeted mutations at the D1 receptor (D1R) are growth-retarded and show downregulated expression of dynorphin and substance P [22].
• A dopamine/D1 receptor/protein kinase A/dopamine- and cAMP-regulated phosphoprotein (Mr 32 kDa)/protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor [32].
• This observation is consistent with the concept that M4 receptors exert inhibitory control over D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are known to be coexpressed [33].
• To determine if selective potentiation of cortical-limbic D1 receptor-expressing (D1+) neurons increases seizure susceptibility, we administered pentylenetetrazole (PTZ) to mice that express a neuropotentiating transgene only in a glutamatergic, cortical-limbic subset of D1+ neurons (D1CT-7 line) [34].

Other interactions of Drd1a

• 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 [25].
• Hyperactivity and dopamine D1 receptor activation in mice lacking girk2 channels [35].
• Dopamine-deficient mice, in which the tyrosine hydroxylase gene is specifically inactivated in dopaminergic neurons, were used to investigate dopamine D1-receptor-mediated activation of extracellular signal-regulated kinase [24].
• Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice [24].
• Here, we report that this action of D1R agonists may involve regulation of cyclin D, and P27, which respectively promote and suppress the G1 to S transition [23].

Analytical, diagnostic and therapeutic context of Drd1a

• To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice [11].
• On PND, 60 male offsprings received an intraperitoneal injection of the D1 receptor agonist 2,3,4,5-tetra-hydro-7,8-diol-1-phenyl-(1H)-3-benzazepine (SKF 38393) (0, 3, and 10 mg/kg), and spontaneous behavior was assessed in an automated activity chamber for 40 min [36].
• The importance of rebinding to receptors in influencing the kinetics of in vivo binding of PET and SPECT radiotracers was evaluated by examining the binding of a high-affinity D1 receptor radiotracer, [3H]SCH 23390, in tissue homogenates, living brain slices, and in vivo [37].
• To examine this possibility, we have started to combine the use of D1 receptor mutant mice with cDNA microarrays to identify gene expression changes mediated through the D1 receptors induced by repeated cocaine administration [38].

References