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. 2023 Jan 20;24(3):2052.
doi: 10.3390/ijms24032052.

Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression

Uri Bright  1   2 , Irit Akirav  1   2
Affiliations

Cannabidiol Modulates Alterations in PFC microRNAs in a Rat Model of Depression

Uri Bright et al. Int J Mol Sci. .

Abstract

Cannabidiol (CBD) is a potential antidepressant agent. We examined the association between the antidepressant effects of CBD and alterations in brain microRNAs in the unpredictable chronic mild stress (UCMS) model for depression. UCMS male rats were injected with vehicle or CBD (10 mg/kg) and tested for immobility time in the forced swim test. Alterations in miRNAs (miR16, miR124, miR135a) and genes that encode for the 5HT1a receptor, the serotonergic transporter SERT, β-catenin, and CB1 were examined. UCMS increased immobility time in a forced swim test (i.e., depressive-like behavior) and altered the expression of miRNAs and mRNA in the ventromedial prefrontal cortex (vmPFC), raphe nucleus, and nucleus accumbens. Importantly, CBD restored UCMS-induced upregulation in miR-16 and miR-135 in the vmPFC as well as the increase in immobility time. CBD also restored the UCMS-induced decrease in htr1a, the gene that encodes for the serotonergic 5HT1a receptor; using a pharmacological approach, we found that the 5HT1a receptor antagonist WAY100135 blocked the antidepressant-like effect of CBD on immobility time. Our findings suggest that the antidepressant effects of CBD in a rat model for depression are associated with alterations in miR-16 and miR-135 in the vmPFC and are mediated by the 5HT1a receptor.

Keywords: 5-HT1a receptor; CB1 receptor; cannabidiol; depression; microRNAs; prefrontal cortex.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The effects of CBD treatment on behavior in rats exposed to UCMS. (a) FST: UCMS rats treated with a vehicle spent more time immobile than the No UCMS groups and UCMS rats treated with CBD. (b) OFT total distance: No UCMS rats treated with the vehicle covered less distance compared to all groups. (c) OFT time in the center: no differences between groups were observed. FST—forced swim test; OFT—open field test; UCMS: unpredictable chronic mild stress; CBD: cannabidiol. *, p < 0.05, **, p < 0.01, ***, p < 0.001.
Figure 2
Figure 2
The effects of CBD treatment on miRNA expression in the vmPFC, NAc, and raphe nucleus in rats exposed to UCMS. miR-16. (a) vmPFC: UCMS rats treated with a vehicle demonstrated miR-16 upregulation compared to all groups. (b) NAc: UCMS rats treated with a vehicle demonstrated miR-16 upregulation compared to No UCMS rats treated with a vehicle. (c) Raphe: UCMS (vehicle, CBD) downregulated miR-16 compared to UCMS rats treated with a vehicle. miR-124: (d) vmPFC: UCMS rats treated with CBD demonstrated miR-124 upregulation compared to No UCMS rats treated with CBD. (e) NAc: UCMS downregulated miR-124 compared to No UCMS. (f) Raphe: UCMS downregulated miR-124 compared to No UCMS. miR-135: (g) vmPFC: UCMS rats treated with a vehicle demonstrated miR-135 upregulation compared to all groups. (h) NAc: UCMS rats treated with CBD demonstrated miR-135 upregulation compared to all groups. (i) Raphe: UCMS upregulated miR-135 compared to No UCMS. vmPFC: ventromedial prefrontal cortex; NAc: nucleus accumbens; miR: microRNA; UCMS: unpredictable chronic mild stress; CBD: cannabidiol. *, p < 0.05, **, p < 0.01, ***, p < 0.001.
Figure 3
Figure 3
The effects of CBD treatment on serotonergic, β-catenin, and CB1 mRNA expression in the vmPFC, NAc, and raphe nucleus in rats exposed to UCMS. htr1a: (a) vmPFC: UCMS-vehicle downregulated htr1a levels compared to all groups. (b) NAc: UCMS rats treated with a vehicle or CBD and No UCMS rats treated with CBD demonstrated htr1a downregulation compared to No UCMS rats treated with a vehicle. (c) Raphe: no differences were observed between the groups. slc6a4: (d) vmPFC: UCMS rats treated with a vehicle or CBD demonstrated downregulation compared to No UCMS rats treated with a vehicle. (e) NAc: no differences were observed between the groups. (f) Raphe: UCMS-vehicle rats demonstrated upregulation of slc6a4 compared to No UCMS-CBD rats. Ctnnb1: (g) vmPFC: UCMS-vehicle rats demonstrated Ctnnb1 downregulation compared to No UCMS-vehicle rats. (h) NAc: UCMS downregulated Ctnnb1 compared to No UCMS rats treated with a vehicle or CBD. (i) Raphe: no differences were observed between the groups. Cnr1: (j) vmPFC: UCMS rats that were treated with a vehicle or CBD demonstrated Cnr1 downregulation compared to No UCMS rats treated with a vehicle or CBD. (k) NAc: no differences were observed between the groups. (l) Raphe: no differences were observed between the groups. vmPFC: ventromedial prefrontal cortex; NAc: nucleus accumbens; UCMS: unpredictable chronic mild stress; CBD: cannabidiol. *, p < 0.05, **, p < 0.01.
Figure 4
Figure 4
The effects of the 5-HT1a antagonist WAY100635 on behavior in rats exposed to UCMS and treated with CBD. (a) FST: UCMS rats that were treated with CBD, spent less time immobile than UCMS rats that were treated with vehicle, WAY, or CBD + WAY. Furthermore, UCMS rats treated with vehicle, WAY, or CBD + WAY, showed increased immobility compared to No UCMS rats injected with vehicle, WAY, or CBD + WAY, respectively. (b) OFT: UCMS rats traveled more than No UCMS rats. (c) OFT time in the center: no differences between groups were observed. FST—forced swim test; OFT—open field test; UCMS: unpredictable chronic mild stress; CBD: cannabidiol; WAY: WAY100635, *, p < 0.05; **, p < 0.01; ***, p < 0.001; compared to UCMS-CBD group ◻ *, p < 0.05, ◻◻ **, p < 0.01, ◻◻◻ ***, p < 0.001 white aquares indicate statistical significance in UCMS vs. NO UCMS groups.
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References

    1. Maletic V., Robinson M., Oakes T., Iyengar S., Ball S.G., Russell J. Neurobiology of depression: An integrated view of key findings. Int. J. Clin. Pract. 2007;61:2030–2040. doi: 10.1111/j.1742-1241.2007.01602.x. - DOI - PMC - PubMed
    1. Pigott H.E., Leventhal A.M., Alter G.S., Boren J.J. Efficacy and effectiveness of antidepressants: Current status of research. Psychother. Psychosom. 2010;79:267–279. doi: 10.1159/000318293. - DOI - PubMed
    1. Shbiro L., Hen-Shoval D., Hazut N., Rapps K., Dar S., Zalsman G., Mechoulam R., Weller A., Shoval G. Effects of cannabidiol in males and females in two different rat models of depression. Physiol. Behav. 2019;201:59–63. doi: 10.1016/j.physbeh.2018.12.019. - DOI - PubMed
    1. Zanelati T.V., Biojone C., Moreira F.A., Guimarães F.S., Joca S.R.L. Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors. Br. J. Pharmacol. 2010;159:122–128. doi: 10.1111/j.1476-5381.2009.00521.x. - DOI - PMC - PubMed
    1. Réus G.Z., Stringari R.B., Ribeiro K.F., Luft T., Abelaira H.M., Fries G.R., Aguiar B.W., Kapczinski F., Hallak J.E., Zuardi A.W., et al. Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala. Acta Neuropsychiatr. 2011;23:241–248. doi: 10.1111/j.1601-5215.2011.00579.x. - DOI - PubMed

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