Aono Yuri, Saigusa Tadashi, Mizoguchi Naoko, Iwakami Tomoyo, Takada Koji, Gionhaku Nobuhito, Oi Yoshiyuki, Ueda Koichiro, Koshikawa Noriaki, Cools Alexander R
Department of Pharmacology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Tokyo 101-8310, Japan.
Eur J Pharmacol. 2008 Feb 2;580(1-2):87-94. doi: 10.1016/j.ejphar.2007.10.020. Epub 2007 Oct 25.
In vivo microdialysis was used to study the effects of the locally applied GABA(A) receptor agonist muscimol and GABA(A) receptor antagonist bicuculline on the basal dopamine efflux as well as on the endomorphin-1- and endomorphin-2-induced dopamine efflux in the nucleus accumbens of freely moving rats. Muscimol (2500 pmol) and bicuculline (5 and 10 nmol) increased basal dopamine efflux. Bicuculline (50 pmol) inhibited the muscimol (2500 pmol)-induced dopamine efflux. Muscimol (250 pmol), but not bicuculline (50 and 500 pmol), enhanced the endomorphin-1 (25 nmol)-induced dopamine efflux. Bicuculline (50 pmol) counteracted the muscimol (250 pmol)-induced increase of the endomorphin-1-elicited dopamine efflux. Neither muscimol (25 and 250 pmol) nor bicuculline (50 and 500 pmol) affected the endomorphin-2 (25 nmol)-induced dopamine efflux. The doses mentioned are the total amount of drug over the infusion period (25 or 50 min) that varied across the drugs. The finding that muscimol and bicuculline increased basal dopamine efflux may imply that these drugs acted at different sites. It is suggested that (1) muscimol acts at GABA(A) receptors on GABA-ergic neurons that exert an inhibitory control of dopaminergic neurons and, accordingly, disinhibits these dopaminergic neurons, and that (2) bicuculline acts directly at GABA(A) receptors on dopaminergic neurons and, accordingly, removes the inhibitory control of these dopaminergic neurons. The finding that an agonist, but not antagonist, of GABA(A) receptors enhanced the endomorphin-1's effects might indicate that endomorphin-1 produced a floor effect at the level of GABA(A) receptors located on presynaptic, dopaminergic terminals. Finally, the present results support our earlier reported notion that endomorphin-1 and endomorphin-2 increase accumbal dopamine efflux by different mechanisms.
采用体内微透析技术，研究局部应用γ-氨基丁酸A（GABA(A)）受体激动剂蝇蕈醇和GABA(A)受体拮抗剂荷包牡丹碱对自由活动大鼠伏隔核基础多巴胺外流以及内吗啡肽-1和内吗啡肽-2诱导的多巴胺外流的影响。蝇蕈醇（2500皮摩尔）和荷包牡丹碱（5和10纳摩尔）增加基础多巴胺外流。荷包牡丹碱（50皮摩尔）抑制蝇蕈醇（2500皮摩尔）诱导的多巴胺外流。蝇蕈醇（250皮摩尔）增强内吗啡肽-1（25纳摩尔）诱导的多巴胺外流，但荷包牡丹碱（50和500皮摩尔）无此作用。荷包牡丹碱（50皮摩尔）抵消蝇蕈醇（250皮摩尔）诱导的内吗啡肽-1引发的多巴胺外流增加。蝇蕈醇（25和250皮摩尔）和荷包牡丹碱（50和500皮摩尔）均不影响内吗啡肽-2（25纳摩尔）诱导的多巴胺外流。上述剂量是输注期（25或50分钟）内药物的总量，不同药物的输注期有所不同。蝇蕈醇和荷包牡丹碱增加基础多巴胺外流这一发现可能意味着这些药物作用于不同位点。提示：（1）蝇蕈醇作用于对多巴胺能神经元发挥抑制性控制的GABA能神经元上的GABA(A)受体，从而解除对这些多巴胺能神经元的抑制；（2）荷包牡丹碱直接作用于多巴胺能神经元上的GABA(A)受体，从而消除对这些多巴胺能神经元的抑制性控制。GABA(A)受体激动剂而非拮抗剂增强内吗啡肽-1的作用这一发现可能表明，内吗啡肽-1在突触前多巴胺能终末的GABA(A)受体水平产生了下限效应。最后，本研究结果支持我们之前报道的观点，即内吗啡肽-1和内吗啡肽-2通过不同机制增加伏隔核多巴胺外流。
