Modulation of cannabinoid signaling by amygdala α2-adrenergic system in fear conditioning

Abstract

The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Growing evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. In addition, there is an interaction between the cannabinoid and noradrenergic system that has significant functional and behavioral implications. Considering the importance of these systems in forming memories for fearful events, we have investigated the involvement of basolateral amygdala (BLA) α2-adrenoceptors on ACPA (as selective cannabinoid CB1 agonist)-induced inhibition of the acquisition of contextual and auditory conditioned fear. A contextual and auditory fear conditioning apparatus for assess fear memory in adult male NMRI mice was used. Pre-training, intraperitoneal administration of ACPA decreased the percentage freezing time in contextual (at doses of 0.05 and 0.1mg/kg) and auditory (at dose of 0.1 mg/kg) in the fear conditioning task, indicating memory acquisition deficit. The same result was observed with intra-BLA microinjection of clonidine (0.001-0.5 μg/mouse, for both memories), as α2-adrenoceptor agonist and yohimbine (at doses of 0.005 and 0.05 for contextual and at dose of 0.05 μg/mouse for auditory fear memory), as α2-adrenoceptor antagonist. In addition, intra-BLA microinjection of clonidine (0.0005 μg/mouse) did not alter ACPA response in both conditions, while the same dose of yohimbine potentiated ACPA response at the lower dose on contextual fear memory. It is concluded that BLA α2-adrenergic receptors may be involved in context- but not tone-dependent fear memory impairment induced by activation of CB1 receptors.

Role of the amygdala GABA-A receptors in ACPA-induced deficits during conditioned fear learning

“…The administration of ACPA had no effect on the locomotor activity. This observation confirms our previous results in which ACPA impairs the fear memory acquisition both in contextual and tone fear conditions (Nasehi et al, 2016c(Nasehi et al, , 2016d. In line with our results, Pamplona and Takahashi (Pamplona and Takahashi, 2006) showed that the activation of cannabinoid receptors impairs contextual fear memory.…”

“…Surgery was conducted as described previously (Nasehi et al, 2016a(Nasehi et al, , 2016c(Nasehi et al, , 2016d). Mice were anesthetized using ketamine (50 mg/kg, i.p.)…”

Precondition of right frontal region with anodal tDCS can restore the fear memory impairment induced by ACPA in male mice

“…Fear conditioning method was achieved on basis of our earlier studies, (Nasehi et al, 2016[ 40 ][ 41 ]; Shoji et al, 2014[ 56 ]). An acoustic insulated chamber with the dimensions of 55 × 53× 67 cm 3 , which illuminated by 24 watts bulb and equipped with two speakers and a video camera was used for fear conditioning.…”

Endocannabinoids, stress signaling, and the locus coeruleus-norepinephrine system

“…Recent evidence suggests that the eCB and noradrenergic systems play a role together in stress-related memory consolidation (Campolongo et al, 2009; Hill and McEwen, 2010), and eCB signaling also modulates the noradrenergic-mPFC microcircuit where memory extinction occurs (Cathel et al, 2014; McLaughlin et al, 2014; Bedse et al, 2015; Wyrofsky et al, 2015). CB1r activation-induced impairment of context-dependent fear memory acquisition is dependent on α2-AR activation in the BLA {Nasehi et al (2016). Therefore, targeting eCB-noradrenergic interactions could help improve PTSD and anxiety-like behaviors associated with chronic stress.…”