A synthetic predator odor (TMT) enhances conditioned analgesia and fear when paired with a benzodiazepine receptor inverse agonist (FG-7142)

Benzodiazepine receptor inverse agonists, such as B-carboline-3-carboxylic acid n-methylamide (FG-7142), induce a state of fear and analgesia. These reactions can be conditioned to novel stimuli during drug administration. The present experiment was conducted to determine if FG-7142 is similar to other stressors such that certain ethologically relevant stimuli are more likely to become conditioned to a state of fear than are others. 2,5-Dihydro-2,4,5-trimethylthiazoline (TMT), a compound previously isolated from the feces of the predator fox, and butyric acid (BA) were presented to male rats as novel odors after administration of FG-7142 or vehicle. A method of ensuring that equal amounts of these odors were presented to the subjects was employed. Six hours after one conditioning trial with drug or vehicle, the same nonodor or chemical odors were present during formalin tests for analgesia and fear-induced freezing. Compared with no-odor and BA groups, the TMT group showed significantly enhanced conditioned analgesia and fear when FG-7142 was administered during the conditioning session. However, relative to the other odor conditions, the TMT condition produced significantly higher levels of analgesia and freezing in the absence of the benzodiazepine inverse agonist, suggesting that this odor acts as an unconditioned stressor by itself.