Marek Gerard J, Ramos Brian P
Department of Psychiatry, School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, Yale University, New Haven, CT, United States.
Astellas Pharma Global Development, Inc., Global Medical Science, CNS and Pain, Northbrook, IL, United States.
Front Pharmacol. 2018 Feb 8;9:89. doi: 10.3389/fphar.2018.00089. eCollection 2018.
5-Hydroxytryptamine (5-HT) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α-adrenergic and orexin) or suppress (metabotropic glutamate [mGlu], adenosine A, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3-10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3-3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β-adrenergic receptor antagonist ICI-118,553 (0.01-1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While G/G-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT receptor activation in the mPFC, the present work appears to extend this suppressant action to a G-coupled GPCR. Furthermore, the modulation of 5-HT receptor activation-induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs.
5-羟色胺（5-HT）受体在大鼠前额叶皮质和新皮质的I层和Va层中富集，其激活会增加作用于V层锥体细胞的谷氨酸能兴奋性突触后电位/电流（EPSP/Cs）的频率。许多其他G蛋白偶联受体（GPCR）也在皮质I层和Va层中富集，它们要么诱导（α-肾上腺素能和食欲素），要么抑制（代谢型谷氨酸[mGlu]、腺苷A、μ-阿片样物质）5-HT诱导的EPSCs以及苯乙胺类致幻剂2,5-二甲氧基-4-碘苯丙胺（DOI）诱导的头部抽搐或摇头。另一种也定位于大鼠前额叶皮质和新皮质I层和Va层明显丘脑皮质传入纤维的神经递质受体是β-肾上腺素能受体。因此，我们用大鼠脑片进行了初步电生理实验，研究浴加DOI（3μM）后肾上腺素对电诱发EPSP的影响。肾上腺素（0.3 - 10μM）抑制电刺激和DOI产生的晚期EPSP。选择性β-肾上腺素能受体拮抗剂ICI - 118,551（300 nM）导致肾上腺素浓度 - 反应关系向右移位。我们还测试了选择性β-肾上腺素能受体激动剂克伦特罗和拮抗剂ICI - 118,551对DOI诱导的头部抽搐的影响。克伦特罗（0.3 - 3 mg/kg，腹腔注射）抑制DOI（1.25 mg/kg，腹腔注射）诱导的头部抽搐。选择性β-肾上腺素能受体拮抗剂ICI - 118,553（0.01 - 1 mg/kg，腹腔注射）似乎至少部分逆转了这种克伦特罗效应，在0.1和1 mg/kg剂量时逆转显著。因此，β-肾上腺素能受体激活可逆转大鼠前额叶皮质中苯乙胺类致幻剂的作用。虽然之前已表明G/G偶联的GPCR可抑制内侧前额叶皮质中5-HT受体激活的电生理和行为效应，但目前的工作似乎将这种抑制作用扩展到了G偶联的GPCR。此外，在大鼠脑片中，一系列GPCR对5-HT受体激活诱导的谷氨酸释放到内侧前额叶皮质V层锥体细胞顶端树突上进行调节，这在筛选新型中枢神经系统治疗药物时似乎会产生具有行为显著性的相关效应。
