Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

Abstract

BACKGROUND AND PURPOSECannabidiol (CBD) has emerged as an interesting compound with therapeutic potential in several CNS disorders. However, whether it can modulate synaptic activity in the CNS remains unclear. Here, we have investigated whether CBD modulates synaptic transmission in rat hippocampal cultures and acute slices. EXPERIMENTAL APPROACHThe effect of CBD on synaptic transmission was examined in rat hippocampal cultures and acute slices using whole cell patch clamp and standard extracellular recordings respectively. KEY RESULTSCannabidiol decreased synaptic activity in hippocampal cultures in a concentration-dependent and Pertussis toxin-sensitive manner. The effects of CBD in culture were significantly reduced in the presence of the cannabinoid receptor (CB1) inverse agonist, LY320135 but were unaffected by the 5-HT1A receptor antagonist, WAY100135. In hippocampal slices, CBD inhibited basal synaptic transmission, an effect that was abolished by the proposed CB1 receptor antagonist, AM251, in addition to LY320135 and WAY100135. CONCLUSIONS AND IMPLICATIONSCannabidiol reduces synaptic transmission in hippocampal in vitro preparations and we propose a role for both 5-HT1A and CB1 receptors in these CBD-mediated effects. These data offer some mechanistic insights into the effects of CBD and emphasize that further investigations into the actions of CBD in the CNS are required in order to elucidate the full therapeutic potential of CBD.Abbreviations aCSF, artificial cerebrospinal fluid; AP5, (2R)-amino-5-phosphonovaleric acid; CB1, cannabinoid receptor; CBD, cannabidiol; DIV, days in vitro; fEPSP, field excitatory postsynaptic potentials; GPCR, G-protein coupled receptor; HBS, HEPES-buffered saline; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide; 8-OH-DPAT, 8-hydroxy-2(di-N-propylamino)tetralin; THC, D 9 -tetrahydrocannabinol

Endocannabinoids

“…For example, CBD acts as a ligand of the serotonin receptor 5HT 1A (Russo et al 2005;Magen et al 2010) and may also reduce glutamatergic neurotransmission through this pathway. Indeed, the 5HT 1A receptor antagonist WAY100135 has been shown to reduce the inhibitory effect of CBD on hippocampal glutamatergic transmission (Ledgerwood et al 2011). This is also entirely consistent with finding that 5HT 1A knockout mice show increased seizure activity (Sarnyai et al 2000).…”

“…In this respect, further studies are required as some reports suggest that the anticonvulsant potential of CBD is CB 1 -independent ( Fig. 1) (Ledgerwood et al 2011). This raises the possibility that CBD may produce its beneficial effects in part via the same mechanism as low-dose THC.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…CBD can increase also the levels of the other endocannabinoid, 2-arachidonoylglycerol (2-AG), as seen in the mouse periaqueductal grey (519), or colorectal cancer cells (24). Accordingly, some CBD effects are blocked by CB1 or CB2 receptor inverse agonists (79,113,115,124,183,464,519,715), or are absent in CB1 receptor knockout mice (922).…”

Chemically induced synaptic activity between mixed primary hippocampal co-cultures in a microfluidic system

“…Mixed primary cultures, including both neurons and astrocytes, have proven to be a useful method associated with neurobiological research. 6,7 However, it is difficult to gain control over the parameters that influence the cellular microenvironment and neuronal connectivity. Indeed, creation of patterned neuronal networks that are environmentally isolated or the localised transfection of cell populations is difficult to achieve using conventional cell culture techniques.…”