Hypothermic Effects of Δ9‐THC and Nicotine in Kynurenine‐3‐Monooxygenase (KMO) Knockout Mice

Abstract

Kynurenic acid, a metabolic product of the tryptophan‐kynurenine synthesis pathway, is both a competitive antagonist at the glycine co‐agonist site of NMDA receptors and a negative allosteric modulator at α7 nicotinic acetylcholine receptors (nAChRs). α7 nAChRs are important for mediating the effects of nicotine, but have also recently been implicated in the effects of Δ9‐tetrahydrocannabinol (Δ9‐THC), the primary psychoactive component of Cannabis. Transgenic mice lacking kynurenine‐3‐monooxygenase (KMO) exhibit increased levels of kynurenic acid and thus presumably decreased function of α7 nAChRs. The current study examined the extent to which the hypothermic effects of nicotine and Δ9‐THC are modified in KMO knockout mice (n=7) as compared to wild‐type C57BL/6J controls (n=7). Δ9‐THC (10 mg/kg) produced a maximum decrease in temperature of 3.0°C at 60 min; hypothermia was no longer evident at 240 min. Nicotine (1.78 mg/kg base) produced a maximum hypothermic effect of 7.2°C at 30 min; this effect was no longer evident at 90 min. The magnitude of effect and the time course of hypothermia produced by Δ9‐THC and nicotine were not significantly different between KMO knockout and wild‐type mice. These data suggest that at least some of the in vivo effects of Δ9‐THC and nicotine are not affected by differences in endogenous levels of kynurenic acid. Supported by USPHS grant DA25267 and MH090127.