Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus
The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.
This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.
A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-d-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH.
The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH.
These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.
KeywordsCannabidiol CB1 receptor Panic attack-like behaviour Endocannabinoid system Unconditioned fear-induced antinociception Ventromedial hypothalamus
The authors thank Daoud Hibrahim Elias-Filho for his expert technical assistance.
A. U. Khan performed the experiments and wrote the manuscript. L. L. Falconi-Sobrinho and T. dos Anjos-Garcia wrote the manuscript, analysed and interpreted the data, revised figures and performed morphometry. N.C. Coimbra designed the experiments, the enriched polygonal arena, analysed and interpreted the data, wrote the manuscript and approved the final manuscript. M. de F. dos Santos Sampaio performed morphometry. L. Menescal-de-Oliveira interpreted the data and J.A.S. Crippa analysed and interpreted the data. All authors have approved the final version of the manuscript. We are entirely responsible for the scientific content of this paper.
This research was supported by FAPESP (Research grants 2007/01174-1 and 2012/03798-0 and 2017/11855-8) and CNPq (Research grants 483763/2010-1, 474853/2013-6 and 427397/2018-9). A. U. Khan was supported by The World Academy of Sciences for the Advancement of Science in Developing Countries (TWAS)-CNPq (Scientiae Doctor Fellowship CNPq grant 1902229/2014-4). L.L. Falconi-Sobrinho was supported by FAPESP (Magister Scientiae grant 2013/ 10984-8) and CNPq (M.Sc. fellowship grant 134267/2013-3; Sc. D. fellowship grant 145258/2015-7). T. dos Anjos-Garcia was financially supported by CNPq (M.Sc. fellowship, process 130124/2012-5; Sc. D. fellowship, process 141124/2014-8) and is a postdoctoral researcher supported by FAPESP (grant 2017/22647-7). M. de Fátima dos Santos Sampaio is a postdoctoral researcher supported by CNPq (PDJ grant 155489/2018-6). N.C. Coimbra is a researcher (level 1A) at CNPq (Science Productivity grants 301905/2010-0 and 301341/215-0). D.H. Elias-Filho is supported by CNPq (grant 372877/2010-9).
Compliance with ethical standards
All experimental trials complied with the Ethical Commission in Animal Experimentation of the FMRP-USP, which fulfils the principles of ethics for animal research adopted by the National Council for Control of Animal Experimentation (CONCEA) and were approved by the Commission of Ethics in Animal Research (CEUA-FMRP-USP) (process 107/2012).
Conflict of interest
The authors declare that there are no conflicts of interest.
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