Similar to the hypothesis that induction of endocannabinoid signaling in response to stress may limit activation of the HPA axis, there is also evidence that endocannabinoid signaling may constrain activation of specific neuronal populations in response to stress. Using the immediate early gene c-fos as a marker of neuronal activation, it has been found that pharmacological antagonism of the CB1 receptor can potentiate stress-induced neuronal activation in a subset of forebrain regions such as the cingulate cortex, lateral septum and the nucleus accumbens (Patel et al., 2005). This would suggest that in response to stress, an induction of endocannabinoid signaling curbs neuronal activation in these structures, possibly through a regulation of glutamate release (Patel et al., 2005). Similarly, microdialysis studies have found that the ability of stress to promote acetylcholine release in the hippocampus is facilitated in mice lacking the CB1 receptor (despite no differences in basal acetylcholine levels; (Degroot et al., 2006)). These data indicate that a mobilization of endocannabinoid signaling in response to stress functions to limit transmitter release and neuronal activation in limbic structures.
