CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity During Extinction of Conditioned Fear in Mice

Abstract

Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1 . We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.

Mechanisms of fear extinction

“…Cannich et al 288 reported upregulation in extinguished wild-type mice relative to nonextinguished controls, and interestingly, found that pMAPK actually decreased in cannabinoid receptor knockout (CB1À/À) mice that exhibit a profound impairment in extinction. Yang and Lu 173 reported a modest increase in pMAPK within the BLA in rats exposed to an extinction training protocol that was not sufficient to produce significant behavioral extinction, and a larger and statistically significant increase in rats trained with the same protocol after administration of DCS.…”

“…290,291 Studies employing measurement of pAkt levels within the BLA following extinction training have produced very inconsistent results. Cannich et al 288 reported no significant increase in pAkt in the BLA of extinguished wild-type or cannabinoid receptor knockout (CB1À/À) mice relative to nonextinguished controls, although the ratio of pAkt levels in extinguished vs nonextinguished animals was significantly greater in the knockouts (which exhibit a profound extinction impairment) than in the wild types. Yang and Lu 173 reported a modest increase in BLA pAkt in rats following exposure to an extinction training protocol that was not sufficient to produce measurable behavioral extinction, but a significant increase in animals trained with the same protocol under the influence of DCS.…”

“…Calcineurin dephosphorylates (inactivates) many of the kinases that are phosphorylated during fear consolidation 305 and has been implicated in the induction of synaptic depotentiation, a physiological reversal of LTP that may be a cellular correlate of forgetting. 306,307 Po-Wu Gean and co-workers have reported that both amygdalar depotentiation in vitro and fear extinction in behaving animals are associated with increased BLA calcineurin protein and enzymatic activity, 167 (see also Cannich et al 288 and Lin et al 292 ) and both are blocked by preadministration of calcineurin inhibitors. 292,306 Like fear extinction, depotentiation also is blocked by NMDA receptor antagonists and L-VGCC inhibitors.…”

Chronic cannabinoid administration in vivo compromises extinction of fear memory

“…ERK is known to be required for several forms of synaptic plasticity and learning and memory (English and Sweatt 1997;Impey et al 1998;Atkins et al 1998;Coogan et al 1999;Schafe and LeDoux 2000). In the mPFC, the phosphorylated level of ERK44 was significantly increased after extinction training (Cannich et al 2004). Infusion of ERK inhibitor into the mPFC immediately after extinction training blocked extinction, suggesting the requirement of ERK activation in the behavioral process of extinction (Hugues et al 2004).…”

Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice

“…The samples were treated as previously described [24] . Loading buffer (16% glycerol, 20% β-mercaptoethanol and 0.05% bromophenol blue) was added to each sample (3:1, sample/ loading buffer) before boiling for 3 min.…”