In vivo evidence for preferential role of dopamine D-3 receptor in the presynaptic regulation of dopamine release but not synthesis
In vivo evidence for preferential role of dopamine D-3 receptor in the presynaptic regulation of dopamine release but not synthesis
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DOI：
10.1016/0014-2999(96)00300-7
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发表时间：
1996-07-25
影响因子：
5
通讯作者：
Rayevsky, KS
中科院分区：
文献类型：
--
作者：
Gainetdinov, RR;Sotnikova, TD;Rayevsky, KS
采用脑微透析技术，观察了多巴胺D-3受体激动剂（+/-）-7-羟基-N，N-二正丙基-2-氨基四氢萘（7-OH-DPAT）对清醒大鼠背侧纹状体和延髓背侧核多巴胺释放、代谢和合成的影响。ip给药的药物剂量依赖性地降低了两个脑区多巴胺的释放、代谢和合成。发现7-OH-DPAT降低多巴胺释放的效力在中脑核中比在背侧纹状体中更高（中脑核的艾德（50）为0.0096 mg/kg，i. p.;背侧纹状体0.068 mg/kg，i. p.）。多巴胺代谢（通过测量细胞外3，4-二羟基苯乙酸水平进行评估）和多巴胺合成（用L-芳香酸脱羧酶抑制剂3-羟基苄肼（10（-5）M）灌注后3，4-二羟基苯丙氨酸输出测定）在7-OH-DPAT的较高剂量范围内降低（艾德（50）降低3，丘脑核4-二羟苯丙氨酸输出量0.124 mg/kg，腹腔注射;背侧纹状体0.101 mg/kg，i. p.）。0.002-0.25 mg/kg，i.p.，与丘脑核多巴胺释放减少有关。用假定的多巴胺D-3受体“选择性”剂量0.05 mg/kg的7-OH-DPAT预处理动物，腹膜内，在自由活动的大鼠背侧纹状体中，发现（+）-AJ 76、顺式-（+）-（1 S，2 R）-5-甲氧基-1-甲基-2-（正丙基氨基）四氢萘盐酸盐（7 mg/kg，i. p.）和氟哌啶醇（0.1mg/kg，i. p.）。与背侧纹状体相比，通过添加到灌注介质中的7-OH-DPAT的局部应用也导致中脑核中多巴胺释放的优先减少（中脑核的EC（50）为1.9 nM;背侧纹状体为11.3 nM）。这些结果进一步支持了多巴胺D-3自身受体优先参与突触前多巴胺释放的调节，而D-2自身受体控制多巴胺合成的假说。
Brain microdialysis was used to investigate the effects of the putative dopamine D-3 receptor agonist (+/-)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on dopamine release, metabolism and synthesis in the dorsal striatum and nucleus accumbens of awake rats. The drug administered i.p. dose dependently decreased the release, metabolism and synthesis of dopamine in both brain areas. The potency of 7-OH-DPAT to decrease dopamine release was found to be higher in the nucleus accumbens than in the dorsal striatum (ED(50) for nucleus accumbens 0.0096 mg/kg, i.p.; for dorsal striatum 0.068 mg/kg, i.p.). Dopamine metabolism, assessed by measuring 3,4-dihydroxyphenylacetic acid extracellular levels, and dopamine synthesis, determined as 3,4-dihydroxyphenylalanine output following perfusion with the L-aromatic acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (10(-5) M), were decreased at higher dose ranges of 7-OH-DPAT (ED(50) for decrease of 3,4-dihydroxyphenylalanine output in nucleus accumbens 0.124 mg/kg, i.p.; in dorsal striatum 0.101 mg/kg, i.p.). The hypomotility of rats induced by 7-OH-DPAT in doses of 0.002-0.25 mg/kg, i.p., was shown to correlate with the decreased dopamine release in the nucleus accumbens. Pretreatment of animals with 7-OH-DPAT at the putative dopamine D-3 receptor 'selective' dose of 0.05 mg/kg, i.p., was found to prevent the increase of dopamine release but not the increase in metabolism in the dorsal striatum of freely moving rats induced by (+)-AJ76, cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin HCl (7 mg/kg, i.p.) and haloperidol (0.1 mg/kg, i.p.). Local application of 7-OH-DPAT by addition into the perfusing medium also resulted in a preferential decrease of dopamine release in the nucleus accumbens as compared with the dorsal striatum (EC(50) for nucleus accumbens 1.9 nM; for dorsal striatum 11.3 nM). The present results give further support to the hypothesis that the dopamine D-3 autoreceptor is preferentialy involved in the presynaptic regulation of dopamine release, while the D-2 autoreceptor controls dopamine synthesis.