Although the output of the lateral habenula (LHb) controls the activity of midbrain dopamine (DA) and 5-hydroxytryptamine (5-HT) containing systems, which are implicated in the pathophysiology of anxiety, it is not clear how activation and blockade of LHb D₄ receptors affects anxiety-like behaviors, particularly in Parkinson's disease related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced anxiety-like behaviors, which attribute to hyperactivity of LHb neurons and decrease in the level of DA in the medial prefrontal cortex (mPFC), amygdala and ventral hippocampus (vHip) compared to sham-operated rats. Intra-LHb injection of D₄ receptor agonist A412997 induced or increased the expression of anxiety-like behaviors, while injection of D₄ receptor antagonist L741742 showed anxiolytic effects in sham-operated and the SNc-lesioned rats. However, the doses producing behavioral effects in the lesioned rats were higher than those of sham-operated rats. Intra-LHb injection of A412997 increased firing rate of LHb neurons, and decreased levels of DA and 5-HT in the mPFC, amygdala and vHip; conversely, L741742 decreased firing rate of LHb neurons, and increased levels of DA and 5-HT in two groups of rats. Compared to sham-operated rats, the duration of A412997 and L741742 action on the firing rate of neurons was markedly shortened in the lesioned rats. Collectively, these findings suggest that D₄ receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway down-regulates function and/or expression of these receptors.

2012-11-01·Journal of Attention Disorders2区 · 医学

A Randomized, Double-Blind, Crossover Comparison of MK-0929 and Placebo in the Treatment of Adults With ADHD

2区 · 医学

Article

作者: Adler, Lenard A. ; Hutson, Pete H. ; Reimherr, Fred W. ; Watt, Alan P. ; Rosah, Thomas ; Wang, Xiaojing J. ; Alexander, Robert C. ; Rivkin, Anna ; Snavely, Duane B. ; Knighton, Jennifer

Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD. Method: A randomized, double-blind, placebo-controlled, crossover study was conducted in adults with primary ADHD. The primary end point was changed from baseline in total score on the Adult ADHD Investigator Symptom Rating Scale following a 4-week treatment regimen. Additional measures included Clinical Global Impression–Severity Scale, Hospital Anxiety and Depression Scale, and Brown Attention Deficit Disorder Scale and D4 genotype analysis. Results: No statistically significant treatment differences were found between MK-0929 and placebo in any of the primary or secondary assessments. Conclusion: Results from this study suggest that blockade of the D4 receptor alone is not efficacious in the treatment of adult ADHD.

2005-07-01·Neuropsychopharmacology1区 · 医学

Antidepressant-Like Effect of D2/3 Receptor-, but not D4 Receptor-Activation in the Rat Forced Swim Test

1区 · 医学

Article

作者: Decker, Michael W. ; Moreland, Robert B. ; Brioni, Jorge D. ; Gallagher, Kelly B. ; Hsieh, Gin C. ; Drescher, Karla ; Fox, Gerard B. ; Basso, Ana M. ; Bratcher, Natalie A. ; Rueter, Lynne E.

Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D(2)-like receptor subtypes (D(2), D(3), D(4)) to depression is not known. We present evidence that activation of D(2)/D(3), but not D(4) receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 micromol/kg); quinpirole, a D(2)-like receptor and agonist (0.4, 1.0, and 2.0 micromol/kg); PD 12,8907, a preferential D(3) receptor agonist (0.17, 0.35, and 0.7 micromol/kg); PD 168077 (0.1, 0.3, and 1.0 micromol/kg) and CP 226269 (0.3, 1.0, and 3.0 micromol/kg), both selective D(4) receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D(2)-like receptor antagonist (0.27 micromol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D(3) receptor antagonist (17.46 micromol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D(4) receptor antagonist (1.15 micromol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D(2) and to a lesser extent by D(3) but not D(4) receptors.

100 项与 D4 receptor antagonists(University of Bari) 相关的药物交易

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