Murai T, Yoshida Y, Koide S, Takada K, Misaki T, Koshikawa N, Cools A R
Department of Dental Anesthesiology, Nihon University School of Dentistry, Tokyo, Japan.
Pharmacol Biochem Behav. 1998 Jul;60(3):695-701. doi: 10.1016/s0091-3057(98)00050-1.
The effects of clonidine, an alpha2 adrenoceptor agonist, on extracellular concentrations of dopamine and gamma-aminobutyric acid (GABA) in the nucleus accumbens of rats were studied by using in vivo brain microdialysis. Clonidine (5 microg/kg i.v.) significantly decreased the brain microdialysate concentration of dopamine in the nucleus accumbens up to a maximum of 16% at its peak effect. This effect was inhibited by a dose of idazoxan (10 microg/kg i.v.), an alpha2-adrenoceptor antagonist. which itself did not affect the efflux of dopamine. A smaller dose of clonidine (1 microg/kg i.v.), which had no significant effect on dopamine efflux per se, decreased the dopamine efflux (21% reduction) when given together with an ineffective dose of midazolam (0.075 mg/kg i.v.), a benzodiazepine receptor agonist. The effect of clonidine (5 microg/kg i.v.) on mesolimbic dopamine efflux was abolished by bicuculline (1 mg/kg i.v.), a GABA(A) receptor antagonist, counteracted by beta-carboline-3-carboxylate ethyl ester (beta-CCE, 3 mg/kg i.p.), a benzodiazepine receptor inverse agonist, but not affected by flumazenil (6 microg/kg i.v.), a benzodiazepine receptor antagonist. Clonidine (5 microg/kg i.v.) increased the dialysate concentration of GABA in the nucleus accumbens up to a maximum of 250% at its peak effect, but not in the ventral tegmental area. It is hypothesized that GABA(A) binding sites in the nucleus accumbens form part of the sequence of events that is triggered by clonidine in an alpha2-adrenergic-specific manner and that ultimately results in a decreased release of dopamine in the nucleus accumbens.
采用体内脑微透析技术，研究了α2肾上腺素能受体激动剂可乐定对大鼠伏隔核细胞外多巴胺和γ-氨基丁酸（GABA）浓度的影响。静脉注射可乐定（5μg/kg）可使伏隔核脑微透析液中多巴胺浓度显著降低，在其峰值效应时最大降幅达16%。α2肾上腺素能受体拮抗剂咪唑克生（静脉注射10μg/kg）可抑制此效应，而咪唑克生本身并不影响多巴胺的流出。静脉注射较小剂量的可乐定（1μg/kg）本身对多巴胺流出无显著影响，但与无效剂量的苯二氮䓬受体激动剂咪达唑仑（静脉注射0.075mg/kg）合用时，可使多巴胺流出量减少（降低21%）。GABA(A)受体拮抗剂荷包牡丹碱（静脉注射1mg/kg）可消除静脉注射可乐定（5μg/kg）对中脑边缘多巴胺流出的影响，苯二氮䓬受体反向激动剂β-CCE（腹腔注射3mg/kg）可对抗此效应，而苯二氮䓬受体拮抗剂氟马西尼（静脉注射6μg/kg）对此无影响。静脉注射可乐定（5μg/kg）可使伏隔核透析液中GABA浓度在峰值效应时最高增加250%，但在腹侧被盖区则无此作用。据推测，伏隔核中的GABA(A)结合位点是可乐定以α2肾上腺素能特异性方式触发的一系列事件的一部分，最终导致伏隔核中多巴胺释放减少。
