Identification of the CART neuropeptide circuitry processing TMT-induced predator stress.

Abundance of cocaine- and amphetamine-regulated transcript (CART) neuropeptide in the limbic areas like the olfactory system, central nucleus of amygdala (CeA), ventral bed nucleus of stria terminalis (vBNST) and the hypothalamus suggests involvement of the peptide in emotive processing. We examined the role of CART in mediating fear, a strong emotion with profound survival value. Rats, exposed to 2,4,5-trimethyl-3-thiazoline (TMT), a predator related cue extracted from fox feces, showed significant increase in freezing, escape and risk assessment behavior, whereas grooming was reduced. Neuronal activity was up-regulated in the CeA and vBNST in terms of increased immunoreactivity in CART elements and c-Fos expression. Increased expression of both the markers was also seen in some discrete magnocellular as well as parvicellular subdivisions of the paraventricular nucleus (PVN). However, CART containing mitral cells in the main or accessory olfactory bulb did not respond. CART antibody was stereotaxically injected bilaterally into the CeA to locally immunoneutralize endogenous CART. On exposure to TMT, these rats showed reduced freezing, risk assessment and escape behavior while grooming was restored to normal value. We suggest that the CART signaling in the CeA and vBNST, but not in the olfactory system, might be an important component of the innate fear processing, and expression of stereotypic behavior, while CART in the PVN subdivisions might mediate the neuroendocrine response to predator stress.

Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors.

Acetaminophen (Paracetamol), a most commonly used antipyretic/analgesic agent, is metabolized to AM404 (N-arachidonoylphenolamine) that inhibits uptake and degradation of anandamide which is reported to mediate the analgesic action of acetaminophen via CB1 receptor. AM404 and anandamide are also reported to produce anxiolytic-like behavior. In view of the implication of endocannabinoids in the effect of acetaminophen, we contemplated that acetaminophen may have anxiolytic-like effect. Therefore, this possibility was tested by observing the effects of various doses of acetaminophen in mice on anxiety-related indices of Vogel conflict test and social interaction test. The results from both the tests indicated that acetaminophen (50, 100, or 200 mg/kg, i.p.) or anandamide (10 or 20 microg/mouse, i.c.v.) dose dependently elicited anxiolytic-like effect, that was comparable to diazepam (2 mg/kg, i.p.). Moreover, co-administration of sub-effective dose of acetaminophen (25 mg/kg, i.p.) and anandamide (5 microg/mouse, i.c.v) produced similar anxiolytic effect. Further, pre-treatment with AM251 (a CB1 receptor antagonist; 1 mg/kg, i.p.) antagonized the effects of acetaminophen and anandamide with no per se effect at 1 mg/kg dose, while anxiogenic effect was evident at a higher dose (5 mg/kg, i.p.). None of the treatment/s was found to induce any antinociceptive or locomotor impairment effects. In conclusion, the findings suggested that acetaminophen (50, 100, or 200 mg/kg, i.p.) exhibited dose dependent anxiolytic effect in mice and probably involved endocannabinoid-mediated mechanism in its effect.