Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors.

Previous studies have implicated cannabinoids in extinction of conditioned fear. We have recently showed that intraventricular infusion of the phytocannabinoid cannabidiol (CBD) facilitates fear extinction, but the brain regions underlying this effect remained unknown. Here we demonstrate that repeated microinjections of CBD into the infralimbic cortex (IL) facilitated fear extinction, as indicated by reduced levels of freezing during extinction test. Systemic administration of the CB1 receptor antagonist rimonabant blocked the effects of intra-IL CBD, suggesting that CBD acts through CB1 receptors to facilitate fear extinction. Our findings suggest a potential therapeutic use of CBD for extinction-based therapies of aversive memories in humans.

Olfactory fear conditioning paradigm in rats: effects of midazolam, propranolol or scopolamine.

In rodents, fear conditioned responses are more pronounced toward olfactory stimulus, since olfaction is a dominant sense in these subjects. The present study was outlined to investigate if the association between coffee odor (CS1) and electrical footshock (US) would be an effective model for the study of fear-induced behavior and whether compounds used in humans for emotional-related disorders such as midazolam, propranolol, or scopolamine, applied during the different stages of fear conditioning (acquisition, consolidation and expression), affect the defensive responses to both, the olfactory CS1, and the context (CS2) where the CS1 had been presented (second order conditioning). The results revealed that five pairings between coffee odor (CS1) and electrical footshock (US) were able to elicit consistent defensive responses and a second order conditioning to the context (CS2). Midazolam (0.375-0.5 mg/kg; i.p.) treatment was able to interfere with the CS1-US association and with the consolidation of the aversive information. The propranolol (5-10 mg/kg; i.p.) treatment interfered with the CS1-US association, with the retention of fear memory and with the CS1-CS2 association. Propranolol also attenuated the expression of conditioned fear responses when applied before the CS1 test session. Scopolamine (0.6-1.2 mg/kg; i.p.) treatment impaired the acquisition of CS1-US and CS1-CS2 associations, and also disrupted the expression of conditioned fear responses when injected prior to the CS1 test session. These findings have pointed out the usefulness for the olfactory fear conditioning paradigm to investigate drug effects on the acquisition, consolidation and expression of fear conditioned responses.

Sensing danger through the olfactory system: the role of the hypothalamic dorsal premammillary nucleus.

The dorsal premammillary nucleus (PMd) has a critical role on the expression of defensive responses to predator odor. Anatomical evidence suggests that the PMd should also modulate memory processing through a projecting branch to the anterior thalamus. By using a pharmacological blockade of the PMd with the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5), we were able to confirm its role in the expression of unconditioned defensive responses, and further revealed that the nucleus is also involved in influencing associative mechanisms linking predatory threats to the related context. We have also tested whether olfactory fear conditioning, using coffee odor as CS, would be useful to model predator odor. Similar to cat odor, shock-paired coffee odor produced robust defensive behavior during exposure to the odor and to the associated context. Shock-paired coffee odor also up-regulated Fos expression in the PMd, and, as with cat odor, we showed that this nucleus is involved in the conditioned defensive responses to the shock-paired coffee odor and the contextual responses to the associated environment.