Patel Smita, Chapman Kerry L, Marston Deborah, Hutson Peter H, Ragan C Ian
Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Rd, Harlow, Essex, UK.
Neuropharmacology. 2003 Jun;44(8):1038-46. doi: 10.1016/s0028-3908(03)00112-6.
In the retina, activation of dopamine receptors, particularly the D2-like family (D2, D3, D4 receptor subtypes), with quinpirole suppresses the light sensitive cAMP pool and inhibits melatonin synthesis in photoreceptor cells. We have characterised rat retinal D4 receptors using the D4 selective radioligand [(125)I] L-750667 which bound specifically and saturably to rat retinal membranes with high affinity (K(d) 0.06+/-0.02 nM) and exhibited a D4 receptor pharmacology. Comparison of the binding kinetics of [(125)I] L-750667 and [(3)H] spiperone revealed B(max) values of 134+/-27 fmol/mg and 219+/-47 fmol/mg respectively, indicating that the dopamine D4 receptor is a major component of D2-like dopamine receptors in the rat retina. Modulation of retinal cAMP levels by quinpirole was used to evaluate the functional relevance of rat retinal dopamine D4 receptors. Quinpirole (0.03-3 micro ) produced a dose-related decrease of the light sensitive cAMP pool which was reversed by haloperidol, clozapine and the D4 selective antagonist, L-745870 with a rank order of potency suggesting that the quinpirole effect is due to activation of the dopamine D4 receptors. The D2 selective ligand L-741626 had no effect on the quinpirole response confirming that the D4 receptor is the major receptor subtype mediating dopamine induced suppression of adenylate cyclase in the retina.
在视网膜中，喹吡罗激活多巴胺受体，尤其是D2样家族（D2、D3、D4受体亚型），可抑制光敏感的环磷酸腺苷（cAMP）池，并抑制感光细胞中的褪黑素合成。我们使用D4选择性放射性配体[（125）I]L-750667对大鼠视网膜D4受体进行了表征，该配体以高亲和力（K（d）0.06±0.02 nM）特异性且饱和地结合到大鼠视网膜膜上，并表现出D4受体药理学特性。[（125）I]L-750667和[（3）H]螺哌隆结合动力学的比较显示，B（max）值分别为134±27 fmol/mg和219±47 fmol/mg，表明多巴胺D4受体是大鼠视网膜中D2样多巴胺受体的主要成分。喹吡罗对视网膜cAMP水平的调节用于评估大鼠视网膜多巴胺D4受体的功能相关性。喹吡罗（0.03 - 3微摩尔）导致光敏感cAMP池呈剂量相关的减少，氟哌啶醇、氯氮平和D4选择性拮抗剂L-745870可逆转这种减少，其效力顺序表明喹吡罗的作用是由于多巴胺D4受体的激活。D2选择性配体L-741626对喹吡罗反应无影响，证实D4受体是介导多巴胺诱导的视网膜腺苷酸环化酶抑制的主要受体亚型。
