Activation of TRPV1 receptors by AEA appears to be the mechanism underlying this synaptic depression. The catabolic enzyme for 2-AG is monoacylglycerol lipase . Inhibition of MAGL by the JZL184 compound inhibits repetitive stimulus-driven dopamine release, as previously described for FAAH inhibition . Inhibitors of MAGL have little effect on synaptic transmission when applied alone, but prolong eCB-mediated depolarization-induced suppression of inhibitory and excitatory transmission. This is one key piece of evidence indicating that 2-AG mediates the synaptic depression observed in this experimental paradigm. Interestingly, similar effects are seen at some synapses with inhibitors of the COX-2 enzyme that can also contribute to 2-AG degradation Impairment of LTP has been observed during application of full CB1 agonists to brain slices . The initial characterization of this effect was in brain slices from prefrontal cortex, outdoor cannabis grow where application of a full CB1 agonist reduced the incidence of LTP at synapses onto projection neurons, while increasing the incidence of LTD .
Subsequent studies of LTP in the hippocampal CA1 subregion produced similar findings, in this case during application of highly efficacious CB1 agonists found in spice-like drugs . This finding suggests that activation of these CB1 receptors at or near maximal efficacy has effects different from partial receptor activation. One possible mechanism underlying LTP disruption by CB1 activation is inhibition of glutamatergic transmission that is needed for LTP induction . The synaptic effects of THC have been studied , but not to the same extent as full CB1 agonists, mainly due to difficulty in obtaining this highly controlled substance and the very low solubility of this compound . A biphasic concentration-response was observed in the hippocampal CA1 region, with potentiation of a field potential population spike and prolongation of the duration of LTP at low-moderate concentrations, changing to inhibition of the PS and shortening of LTP duration at higher concentrations . However, it was difficult to ascertain the synaptic changes underlying these THC actions, as only extracellular field potential recordings were performed.
When GABAergic IPSCs are measured with whole-cell recording in hippocampal CA1 slices, inhibition by THC is comparable to that of full CB1 agonists . These findings are consistent with findings indicating that CB1 receptors are most abundant on GABAergic terminals in hippocampal CA1 . However, it is notable that THC also produces substantial inhibition of glutamatergic synaptic responses at Schaffer collateral-CA1 pyramidal neurons in hippocampal slices . Strong inhibition of glutamatergic transmission by THC has also been observed in hippocampal cultures , and striatal slices . However, it should be noted that Straiker and Mackie did not observe inhibition of glutamatergic transmission in hippocampal autaptic cultures but did find that THC blocked the effect of other CB1 agonists. Thus, despite the fact that THC is a partial CB1 agonist it can have profound effects on both excitatory and inhibitory synaptic transmission. Other synaptic sites of THC action have been suggested, including ionotropic glycine receptors . The acute synaptic effects of CBD have been the subject of increasing research activity in recent years . One proposed molecular CBD target is the G protein-coupled lysophosphatidy linositol receptor known as GPR55 . In hippocampal brain slices CBD enhances GABAergic synaptic responses in dentate gyrus granule neurons cannabis grow equipment. This effect is mimicked and prevented by the GPR55 antagonist DIC 16020046, supporting a role for antagonism of this receptor in the CBD action. Other synaptic receptors implicated in CBD action include the 5-HT-1A receptor , the ionotropic glycine receptor , and several transient receptor potential ionotropic channels .
Depending on the TRP channel subtypes, CBD can have varying effects on channel activation. For example, TRPV1 and 2, as well as TRPA1 are activated by CBD, whereas CBD acts as an antagonist at TRPM8 . The CBD actions involving the 5-HT1A receptor have been suggested to underlie in vivo actions of the drug, including potential uses in treatment of Parkinson’s Disease symptoms . There is also evidence that CBD can inhibit adenosine uptake . However, there is little data indicating if CBD alters synaptic transmission mediated by these receptors in in situ preparations or the intact brain. The synaptic effects of CBD may contribute to the antiepileptiform and antiseizure effects of the drug . The related cannabis constituent cannabidivarin has also been shown to activate TRP channels . This compound also inhibits epileptiform activity in hippocampal slices, and this effect in intact tissue appears to involve TRPV1. The “subacute” effects of THC and other cannabinoid drugs are defined herein as synaptic changes observed within hours of a few days following a single in vivo drug exposure.