Short-Term Adaptation of Conditioned Fear Responses Through Endocannabinoid Signaling in the Central Amygdala

Abstract

The cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are both known to have crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. In this study we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol, no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA. Taken together, our data show the existence of CB1 proteins in the CeA, and their critical role for ensuring short-term adaptation of responses to fearful events, thereby suggesting a potential therapeutic target to accompany habituation-based therapies of post-traumatic symptoms.

Bimodal Control of Fear-Coping Strategies by CB1Cannabinoid Receptors

“…6 A). Notably, the control exerted by CB 1 receptors signaling on both inhibitory and excitatory amygdalar neurotransmissions has been recently associated with the temporal adaptation of conditioned freezing responses (Kamprath et al, 2011) and in the control of synaptic plasticity (Marsicano et al, 2002;Azad et al, 2004). Thus, we asked whether the selective expression of CB 1 receptors within the amygdala would be sufficient to induce a pattern of fear responses similar to that observed in wild-type animals.…”

“…The medial prefrontal cortex (mPFC), the hippocampus, and the amygdala as well as downstream nuclei, including the hypothalamus and the periaqueducal gray (PAG), act in concert to mediate appropriate freezing responses (Laviolette et al, 2005;Myers and Davis, 2007;Resstel et al, 2009;Roozendaal et al, 2009;SotresBayon and Quirk, 2010). CB 1 receptors are enriched in these brain structures and they modulate conditioned freezing in a region-dependent manner (Laviolette and Grace, 2006;Resstel et al, 2009;Kamprath et al, 2011;Terzian et al, 2011;Dubreucq et al, 2012). However, the mechanisms by which CB 1 receptors modulate active versus passive fear coping strategies have been poorly studied so far.…”

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

“…As well, there is emerging evidence for endocannabinoid roles in various forms of learning and memory outside the hippocampus, e.g. fear conditioning extinction and the amygdale [23,24], and habit learning and the basal ganglia [25].…”

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

“…Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition (Katona et al, 2001;Marsicano et al, 2002;Azad et al, 2003Azad et al, , 2004Kamprath et al, 2011;Lin et al, 2011;Uriguen et al, 2011), we hypothesize that the anatomical colocalization of CCK and Cnr1 indicates a potential functional relationship that may be critical for extinction learning. We propose that activation of presynaptic Cnr1 during extinction causes a decrease in probability of release (Pertwee, 1997;Schlicker and Kathmann, 2001) at GABAergic CCK terminals, inhibiting CCK transmission.…”