Gainetdinov R R, Sotnikova T D, Grekhova T V, Rayevsky K S
Laboratory of Neurochemical Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia.
Eur J Pharmacol. 1996 Jul 25;308(3):261-9. doi: 10.1016/0014-2999(96)00300-7.
Brain microdialysis was used to investigate the effects of the putative dopamine D3 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 (ED50 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 (ED50 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 D3 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-1-2-(n-propylamino)tetralin HCI (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 (EC50 for nucleus accumbens 1.9 nM; for dorsal striatum 11.3 nM). The present results give further support to the hypothesis that the dopamine D3 autoreceptor is preferentially involved in the presynaptic regulation of dopamine release, while the D2 autoreceptor controls dopamine synthesis.
采用脑微透析技术研究了假定的多巴胺D3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伏隔核中多巴胺释放、代谢及合成的影响。腹腔注射该药物可剂量依赖性地降低两个脑区中多巴胺的释放、代谢及合成。结果发现，7-OH-DPAT降低伏隔核中多巴胺释放的效力高于背侧纹状体（伏隔核的腹腔注射半数有效剂量为0.0096mg/kg；背侧纹状体的腹腔注射半数有效剂量为0.068mg/kg）。通过测量3,4-二羟基苯乙酸细胞外水平评估的多巴胺代谢以及在灌注L-芳香酸脱羧酶抑制剂3-羟基苄肼（10⁻⁵M）后测定的3,4-二羟基苯丙氨酸输出量所确定的多巴胺合成，在7-OH-DPAT的较高剂量范围内均降低（伏隔核中3,4-二羟基苯丙氨酸输出量降低的腹腔注射半数有效剂量为0.124mg/kg；背侧纹状体中为0.101mg/kg）。腹腔注射0.002 - 0.25mg/kg剂量的7-OH-DPAT诱导的大鼠运动减少与伏隔核中多巴胺释放减少相关。在假定的多巴胺D3受体“选择性”剂量0.05mg/kg腹腔注射7-OH-DPAT预处理动物，发现可阻止由（+）-AJ76、顺式（+）-（1S，2R）-5-甲氧基-1-甲基-1-2-（正丙基氨基）四氢萘盐酸盐（腹腔注射7mg/kg）和氟哌啶醇（腹腔注射0.1mg/kg）诱导的自由活动大鼠背侧纹状体中多巴胺释放的增加，但不能阻止代谢的增加。通过向灌注介质中添加7-OH-DPAT进行局部应用，与背侧纹状体相比，也导致伏隔核中多巴胺释放优先减少（伏隔核的半数有效浓度为1.9nM；背侧纹状体为11.3nM）。目前的结果进一步支持了以下假说：多巴胺D3自身受体优先参与多巴胺释放的突触前调节，而D2自身受体控制多巴胺合成。
