The activitydependent production and release of eCBs from postsynaptic cells leads to the activation of presynaptic CB1 receptors that inhibit neurotransmi er release. eCB production is increased by either electrical activity or activation of GPCRs such as the M1 and M3 receptors that couple to PLCb, the enzyme involved in the production of 2-arachidonoylglycerol, the most abundant eCB. Previous studies on the role of CB1 receptors in the pilocarpine model of epilepsy have focused on the role of this receptor after the induction of seizures. These studies examined the role of CB1 receptors during the latent phase following the initial seizures or the chronic phase of spontaneous seizures, which is well past the time when muscarinic receptor activity is necessary for seizures. Therefore, in order to examine the effect of CB1 receptor activity on the induction of seizures by activation of muscarinic receptors, we determined the effects of administration of CB1 receptor agonists and antagonists and of the deletion of the CB1 receptor gene on the induction of pilocarpine-induced seizures. Activation of CB1 receptors has been shown to reduce the severity of seizures in a variety of models of epilepsy, and decreased activation of CB1 receptors Coptisine-chloride increases the severity of spontaneous, kainic acid-induced, and electroshock-induced seizures. We show here that the loss of CB1 receptor activity, due to genetic deletion in knockout animals or by administration of CB1 receptor antagonists, causes an increased sensitivity to pilocarpine-induced seizures. Previous studies have shown that activation of M1 and M3 receptors stimulate the production of endocannabinoids. The increased sensitivity to pilocarpine-induced seizures following administration of a CB1 antagonist and when the CB1 gene is deleted indicates that eCBs acting at the CB1 receptor modulate the severity of pilocarpineinduced seizures. Induction of SE causes many changes in the brain, including increased neurogenesis, gliosis, mossy fiber sprouting, and cell death. We confirmed that pilocarpine-induced SE caused the expected increases in cell proliferation and cell death in the hilus in mice that had experienced SE. SE-induced damage was not modified by the loss of CB1 receptor activity during the seizure period, suggesting that changes in cell proliferation and cell death are not due directly to CB1 receptor activity but rather reflect the effect of CB1 receptor activity on seizure severity and ensuing cell proliferation and cell death. Previous studies using kainic acid reported that loss of CB1 receptor activity caused a decrease in neurogenesis and an increase in cell death and gliosis. In the study by Aguado et al., 10 mM kainic acid was sufficient to significantly increase neurogenesis in a CB1-dependent manner in vitro. However, when tested in vivo, Aguado et al. did not indicate whether the dose of kainic acid used in WT and CB1 KO mice evoked seizures or the severity of any seizures evoked. Therefore the decrease in neurogenesis due to loss of CB1 receptor activity in their study may be mostly or Isoacteoside entirely seizureindependent. Marsicano et al. also did not indicate whether the quantification of cell death in their study was performed on mice that had experienced SE or not.