Sensing the chemical warnings present in the environment is essential for species survival. In mammals, this form of danger communication occurs via the release of natural predator scents that can involuntarily warn the prey or by the production of alarm pheromones by the stressed prey alerting its conspecifics. Although we previously identified the olfactory Grueneberg ganglion as the sensory organ through which mammalian alarm pheromones signal a threatening situation, the chemical nature of these cues remains elusive. We here identify, through chemical analysis in combination with a series of physiological and behavioral tests, the chemical structure of a mouse alarm pheromone. To successfully recognize the volatile cues that signal danger, we based our selection on their activation of the mouse olfactory Grueneberg ganglion and the concomitant display of innate fear reactions. Interestingly, we found that the chemical structure of the identified mouse alarm pheromone has similar features as the sulfur-containing volatiles that are released by predating carnivores. Our findings thus not only reveal a chemical Leitmotiv that underlies signaling of fear, but also point to a double role for the olfactory Grueneberg ganglion in intraspecies as well as interspecies communication of danger.olfaction | animal communication | behavior | calcium imaging

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Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

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