Enhancing Cannabinoid Neurotransmission Augments the Extinction of Conditioned Fear

Abstract

The endogenous cannabinoid (eCB) system represents a major therapeutic target for the treatment of a variety of anxiety-related disorders. A recent study has demonstrated that pharmacologic or genetic disruption of CB1-receptor-mediated neurotransmission decreases the extinction of conditioned fear in mice. Here, we examined whether CB1 blockade would similarly disrupt extinction in rats, using fear-potentiated startle as a measure of conditioned fear. We also examined whether pharmacologic enhancement of CB1 activation would lead to enhancements in extinction. Our results indicate that systemic administration of the CB1 antagonist rimonabant (SR141716A) prior to extinction training led to significant, dose-dependent decreases in extinction. While the administration of the CB1 agonist WIN 55,212-2 did not appear to affect extinction, administration of AM404, an inhibitor of eCB breakdown and reuptake, led to dose-dependent enhancements in extinction. In addition to showing decreased fear 1 and 24 h after extinction training, AM404-treated animals showed decreased shock-induced reinstatement of fear. Control experiments demonstrated that the effects of AM404 could not be attributed to alterations in the expression of conditioned fear, locomotion, shock reactivity, or baseline startle, as these parameters seemed unchanged by AM404. Furthermore, coadministration of rimonabant with AM404 blocked this enhancement of extinction, suggesting that AM404 was acting to increase CB1 receptor activation during extinction training. These results demonstrate that the eCB system can be modulated to enhance emotional learning, and suggest that eCB modulators may be therapeutically useful as adjuncts for exposure-based psychotherapies such as those used to treat Post-Traumatic Stress Disorder and other anxiety disorders.

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

“…Consequently, we evaluated whether OL-135 administered only before each extinction trial would facilitate this process, and showed that elevated levels of FAAs were only required during the extinction trials themselves. This effect is consistent with a recent report in which AM404, a purported inhibitor of the putative anandamide transporter that also inhibits FAAH (Beltramo et al, 1997;Jarrahian et al, 2000;Glaser et al, 2003;Hillard and Jarrahian, 2005) potentiated extinction of a conditioned fear response (startle) in rats (Chhatwal et al, 2005).…”

“…However this interpretation is somewhat limited by the fact that SR141716 given alone delayed extinction. As previously described in a similar water maze task (Varvel et al, 2005a) and in conditioned fear paradigms (Marsicano et al, 2002;Suzuki et al, 2004;Chhatwal et al, 2005), SR141716 robustly attenuated extinction in the present experiment. The effect of SR141716 presented here replicates our previously published report, with some minor procedural differences such as the weekly extinction trials (as opposed to bi-weekly trials) and the inclusion of the quadrant data.…”

“…We have recently reported that FAAH (À/À) mice acquired a fixed-platform water maze task normally, and displayed a slight, but significant, enhancement in the acquisition of a repeated acquisition (ie, working memory) task (Varvel et al, 2005b). Another recent report showed that AM404, which inhibits FAAH and is purportedly an inhibitor of the controversial anandamide uptake transporter (Beltramo et al, 1997;Jarrahian et al, 2000;Glaser et al, 2003;Hillard and Jarrahian, 2005), enhanced the extinction of a fearpotentiated startle response (Chhatwal et al, 2005). Thus the present experiments were conducted to test the hypothesis that elevating endogenous levels of anandamide would enhance extinction.…”

Mechanisms of fear extinction

“…It has been suggested that the apparent facilitation of extinction by cannabinoid agonists or reuptake inhibitors is in fact due to an impairment of memory reconsolidation by these compounds, 236 although it is somewhat difficult to compare this study to that of Chhatwal 234 because of the different routes of administration employed (systemic vs intra-amygdala) as well as the finding of a significant effect of WIN 55,21202 in one case 236 and not the in other. 234 Kamprath et al 237 have argued that endogenous cannabinoids modulate nonassociative learning processes including habituation, and are involved in fear extinction only to the extent that habituation is a component of extinction. That is, endogenous cannabinoid release is not a mechanism of fear extinction per se but rather occurs under conditions in which habituation occurs, which include, but are not specific to, extinction.…”

“…The impairment of LTDi was mimicked in slices obtained from wild-type mice and superfused with SR141716A. Impairment of fear extinction by pre-extinction training administration of SR141716A has been reported by several other groups as well 168,234,235 Chhatwal et al, 234 in a study of extinction of fearpotentiated startle in rats, examined SR141716A as well as positive modulators of cannabinoid neurotransmission. The CB1 agonist WIN 55,212-2 had no effect on extinction retention when administered systemically before extinction training, but AM404, an inhibitor of cannabinoid reuptake and enzymatic degradation, dose-dependently facilitated extinction retention measured 1 and 24 h after extinction training and impaired subsequent reinstatement following exposure to unsignaled footshock.…”