Functional characterization of cannabidiol effect on the serotonergic neurons of the dorsal raphe nucleus in rat brain slices

Abstract

Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects via the 5-HT1A receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT1A receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT1A 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-HT1A 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-HT1A 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 [Ca2+]i or the inhibitory effect of ipsapirone (1 μM, 4 min) on KCl-evoked [Ca2+]i. In conclusion, CBD does not activate 5-HT1A autoreceptors, but it hindered the inhibitory effect produced by selective 5-HT1A receptor agonists on the firing activity of DRN 5-HT cells through a mechanism that does not involve CB1, 5-HT2A, or GABAA receptors. Our data support a negative allosteric modulation of DRN somatodendritic 5-HT1A receptor by CBD.

The ameliorative effects of cannabidiol on methotrexate‐induced neuroinflammation and neuronal apoptosis via inhibiting endoplasmic reticulum and mitochondrial stress

“…[ 39 ] Cognitive and neuropsychiatric disorders, movement and balance disorders are seen due to the deterioration of serotonergic innervation. [ 9 ] In a study by Aitziber et al, [ 40 ] it was found that CBD reduced the competitive inhibitory effect of serotonin receptor agonists. Keeping serotonin levels high is important in the treatment of depression as well as learning and memory functions.…”

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders

“…The most studied receptors in this system are TRPV1, 5-HT 1A , PPARγ and PPARα, although some studies have assessed the role of two G protein-coupled receptors (GPRs), the orphan G protein-coupled receptor (GPR) 55 and G protein-coupled receptor 18 (GPR18). [75][76][77][78][79][80] TRPV1 is a cation-permeable ion channel activated by heat, acidic pH and capsaicin (the pungent compound in the pepper Capsicum frutescens). It is a vanilloid receptor or "transient receptor potential cationic channel, subfamily V, member 1" 81 located on GABAergic and glutamatergic terminals; other perikarya in some limbic system structures with relevant mnemonic functions, such as the hippocampus; motor system-related structures, such as the basal nuclei and cerebellum; and elsewhere.…”

“…In addition to CB1 and CB2 receptors, the eCS may include additional ligands, and some cannabinoid drugs, such as CBD, bind directly or indirectly to noncannabinoid receptors. The most studied receptors in this system are TRPV1, 5‐HT 1A , PPARγ and PPARα, although some studies have assessed the role of two G protein‐coupled receptors (GPRs), the orphan G protein‐coupled receptor (GPR) 55 and G protein‐coupled receptor 18 (GPR18) 75–80 …”

Evidence suggesting creatine as a new central neurotransmitter: presence in synaptic vesicles, release upon stimulation, effects on cortical neurons and uptake into synaptosomes and synaptic vesicles

“…In previous reports, 100 μM to 2 mM of GABA [226][227][228] , 50 μM to 2 mM of Glu 229,230 , 1 to 100 μM of DA 229 , 0.1-100 μM of 5-HT [231][232][233][234][235][236] were bath applied to investigate the physiological functions of neurotransmitters. Our results revealed that, when bath applied, Cr could inhibit cortical neurons at 100 μM within several minutes, with a time course similar to that of 5-HT 237 234 236 and DA 229 , but significantly slower than that of Glu 230 , GABA 48,227 and 5-HT 233 . We speculate that Cr may act on G-protein coupled receptors (GPCRs), rather than the fast acting ligand-gated ion channels, such as AMPA or NMDA receptors for Glu and GABA A receptor for GABA.…”

“…Here we report that Cr, at a concentration comparable to classical neurotransmitters, inhibits pyramidal neurons in specific regions of the mouse brain, with approximate 1/3 of pyramidal neurons responding to 100 μM Cr (Figure 7). In previous reports, 100 μM to 2 mM of GABA [226][227][228] , 50 μM to 2 mM of Glu 229,230 , 1 to 100 μM of DA 229 , 0.1-100 μM of 5-HT [231][232][233][234][235][236] were bath applied to investigate the physiological functions of neurotransmitters. Our results revealed that, when bath applied, Cr could inhibit cortical neurons at 100 μM within several minutes, with a time course similar to that of 5-HT 237 234 236 and DA 229 , but significantly slower than that of Glu 230 , GABA 48,227 and 5-HT 233 .…”