Discriminative stimulus properties of the 5-HT1A receptor biased agonists NLX-101 and F13714, in rats trained to discriminate 8-OH-DPAT from saline.
Discriminative stimulus properties of the 5-HT1A receptor biased agonists NLX-101 and F13714, in rats trained to discriminate 8-OH-DPAT from saline.
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DOI：
10.1097/fbp.0000000000000659
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发表时间：
2021-12-01
影响因子：
1.6
通讯作者：
Newman-Tancredi A
中科院分区：
文献类型：
--
作者：
Broadbear JH;Depoortere RY;Vacy K;Ralph D;Tunstall BJ;Newman-Tancredi A
NLX-101和F13714是5-HT 1A受体的选择性、完全有效、偏向性激动剂。NLX-101优先激活皮质突触后5-HT 1A受体，而F13714优先激活中缝核突触前5-HT 1A受体。我们比较了NLX-101和F13714替代由原型、非偏倚5-HT 1A受体激动剂8-OH-DPAT（rachloride）产生的辨别性提示的功效和效力。训练雄性和雌性Sprague-Dawley大鼠辨别8-OH-DPAT（0.1mg/kg腹膜内，预处理20分钟）。8-OH-DPAT（0.01和0.05 mg/kg i.p.）剂量依赖性地替代训练剂量，在0.05 mg/kg时，对8-OH-DPAT相关的杠杆有约50%的响应。F13714完全且非常有效地替代了训练剂量的8-OH-DPAT，从0.018 mg/kg i. p.，而NLX-101仅在0.5 mg/kg腹腔注射时达到完全替代，已知该剂量也激活突触前5-HT 1A受体。5-HT 1A受体部分激动剂丁螺环酮在1和2 mg/kg i. p.时部分取代（~80%），剂量也降低了反应率。F13714在0.05 mg/kg剂量下降低应答率。选择性5-HT 1A受体拮抗剂WAY-100，635（1 mg/kg s.c.，预处理40 min）对8-OH-DPAT相关杠杆本身几乎没有引起反应，但阻断了由8-OH-DPAT（0.1 mg/kg）、F13714（0.025 mg/kg）、NLX-101（0.5 mg/kg）或丁螺环酮（1 mg/kg）给药（预处理20 min）产生的辨别刺激效应。这些数据表明，由0.1 mg/kg i. p. 8-OH-DPAT产生的辨别性线索来自突触前5-HT 1A受体的激活。它们还进一步证明了5-HT 1A受体偏向激动剂的行为模型中的不同特征。
NLX-101 and F13714 are selective, full efficacy, biased agonists of the 5-HT1A receptor. NLX-101 preferentially activates cortical post-synaptic 5-HT1A receptors whereas F13714 preferentially activates Raphe nuclei pre-synaptic 5-HT1A receptors. We compared NLX-101 and F13714 for their efficacy and potency to substitute for the discriminative cue produced by the prototypical, non-biased 5-HT1A receptor agonist, 8-OH-DPAT (racemate). Male and female Sprague-Dawley rats were trained to discriminate 8-OH-DPAT (0.1 mg/kg i.p., 20 min pre-treatment) from saline using a classical two-lever drug-discrimination procedure. 8-OH-DPAT (0.01 and 0.05 mg/kg i.p.) dose-dependently substituted for the training dose, with about 50 % responding on the 8-OH-DPAT-associated lever at 0.05 mg/kg. F13714 fully and very potently substituted for the training dose of 8-OH-DPAT from 0.018 mg/kg i.p., while NLX-101 only achieved full substitution at 0.5 mg/kg i.p., a dose which is known to also activate pre-synaptic 5-HT1A receptors. The 5-HT1A receptor partial agonist, buspirone, partially substituted (~80%) at 1 and 2 mg/kg i.p., doses which also decreased response rates. F13714 decreased response rates at 0.05 mg/kg. The selective 5-HT1A receptor antagonist WAY-100,635 (1 mg/kg s.c., 40 min pre-treatment) elicited almost no responding on the 8-OH-DPAT-associated lever by itself, but blocked the discriminative stimulus effects produced by administration (20 min pretreatment) of 8-OH-DPAT (0.1 mg/kg), F13714 (0.025 mg/kg), NLX-101 (0.5 mg/kg), or buspirone (1 mg/kg). These data suggest that the discriminative cue produced by 0.1 mg/kg i.p. 8-OH-DPAT results from activation of pre-synaptic 5-HT1A receptors. They also further demonstrate the distinct profiles in behavioral models of 5-HT1A receptor biased agonists.