Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.

The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.

Estrogen disrupts the inhibition of fear in female rats, possibly through the antagonistic effects of estrogen receptor alpha (ERalpha) and ERbeta.

The ambiguous role of estrogen in emotional learning may result from opposing actions of estrogen receptor alpha (ERalpha) and ERbeta. Using a fear-conditioning paradigm called the AX+, BX- discrimination, in which cue A comes to elicit fear and cue B becomes a safety signal, we examined the effect of 17beta-estradiol (E) and selective ERalpha and ERbeta agonists on excitatory and inhibitory fear learning. Gonadectomized (GDX) male and female rats implanted with E or selective ERalpha or ERbeta agonists were trained on the AX+, BX- discrimination and tested periodically to A, B, and AB. GDX sham-implanted male and female rats and GDX E-implanted males, but not GDX E-implanted females, exhibited less fear to AB than to A, suggesting that estrogen interferes with generalization of safety signals in female rats. ERalpha and ERbeta agonists disrupted discrimination learning in both sexes. ERalpha-implanted groups had higher fear responses to all cues than did ERbeta-implanted groups, suggesting that these two receptors have opposing effects in aversive discrimination learning. In contrast, neither E nor ERalpha and ERbeta agonists affected single-cue fear conditioning in either sex. These data suggest that E does not enhance fear in emotional learning but acts to disrupt the inhibition of fear in females only.