Mendiguren Aitziber, Aostri Erik, Alberdi Elena, Pérez-Samartín Alberto, Pineda Joseba
Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
Achucarro Basque Center for Neuroscience, Department of Neuroscience, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
Front Pharmacol. 2022 Sep 6;13:956886. doi: 10.3389/fphar.2022.956886. eCollection 2022.
Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects the 5-HT receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT autoreceptors have not been characterized. Our aim was to study the effect of CBD on the firing activity of DRN 5-HT cells and the 5-HT autoreceptor activation by electrophysiological and calcium imaging techniques in male Sprague-Dawley rat brain slices. Perfusion with CBD (30 μM, 10 min) did not significantly change the firing rate of DRN 5-HT cells or the inhibitory effect of 5-HT (50-100 μM, 1 min). However, in the presence of CBD (30 μM, 10 min), the inhibitory effects of 8-OH-DPAT (10 nM) and ipsapirone (100 nM) were reduced by 66% and 53%, respectively. CBD failed to reverse ipsapirone-induced inhibition, whereas perfusion with the 5-HT receptor antagonist WAY100635 (30 nM) completely restored by 97.05 ± 14.63% the firing activity of 5-HT cells. Administration of AM251 (1 µM), MDL100907 (30 nM), or picrotoxin (20 μM) did not change the blockade produced by CBD (30 μM) on ipsapirone-induced inhibition. Our study also shows that CBD failed to modify the KCl (15 mM, 4 min)-evoked increase in [Ca] or the inhibitory effect of ipsapirone (1 μM, 4 min) on KCl-evoked [Ca]. In conclusion, CBD does not activate 5-HT autoreceptors, but it hindered the inhibitory effect produced by selective 5-HT receptor agonists on the firing activity of DRN 5-HT cells through a mechanism that does not involve CB, 5-HT or GABA receptors. Our data support a negative allosteric modulation of DRN somatodendritic 5-HT receptor by CBD.
大麻二酚（CBD）是大麻植物中主要的非精神活性大麻素，对5-羟色胺（5-HT）受体具有多种药理作用。中缝背核（DRN）是大脑中主要的表达5-HT受体的血清素能神经元集群。迄今为止，CBD对DRN 5-HT细胞神经元活动的影响及其与躯体树突状5-HT自身受体的相互作用尚未得到明确。我们的目的是通过电生理和钙成像技术，研究CBD对雄性Sprague-Dawley大鼠脑片中DRN 5-HT细胞放电活动和5-HT自身受体激活的影响。用CBD（30μM，10分钟）灌注并未显著改变DRN 5-HT细胞的放电率或5-HT（50 - 100μM，1分钟）的抑制作用。然而，在存在CBD（30μM，10分钟）的情况下，8-OH-DPAT（10 nM）和 ipsapirone（100 nM）的抑制作用分别降低了66%和53%。CBD未能逆转ipsapirone诱导的抑制作用，而用5-HT受体拮抗剂WAY100635（30 nM）灌注可使5-HT细胞的放电活动完全恢复97.05±14.6%。给予AM251（1μM）、MDL100907（30 nM）或苦味毒素（20μM）并未改变CBD（30μM）对ipsapirone诱导抑制的阻断作用。我们的研究还表明，CBD未能改变氯化钾（15 mM，4分钟）诱发的[Ca]升高或ipsapirone（1μM，4分钟）对氯化钾诱发的[Ca]的抑制作用。总之，CBD不会激活5-HT自身受体，但它通过一种不涉及CB、5-HT或GABA受体的机制，阻碍了选择性血清素能受体激动剂对DRN 5-HT细胞放电活动产生的抑制作用。我们的数据支持CBD对DRN躯体树突状5-HT受体的负变构调节作用。
