Increased sensitivity to restraint stress and novelty-induced emotionality following long-term, high dose cannabinoid...

Cannabinoids have long been known to affect anxiety, emotionality and stress responsivity; however, the direction of this effect has been controversial. This research aimed to compare the effects of chronic administration of both a very low dose (5 microg/kg) and a very high dose (100 microg/kg) of the potent cannabinoid CB(1) receptor agonist HU-210 on emotionality and stress responsivity. Twelve day administration of the high dose of HU-210 increased anxiety-like behavior as indicated by a significant reduction in time spent in the central quadrant and an increase in fecal boli in the open field test. However, neither dose of HU-210 elicited any significant behavioral effect in the elevated plus maze. Stress responsivity appeared to be sensitized in animals that had received high dose HU-210 treatment, as 30 min of restraint resulted in significantly higher plasma corticosterone levels in these subjects than in stressed controls or those receiving the low dose treatment. Furthermore, restraint stress elicited a non-significant increase in c-fos induction in the central amygdala, which was significantly potentiated following high-dose treatment with HU-210. This interaction was not seen in the basolateral amygdala. Together, these findings suggest that chronic high dose, but not low dose, cannabinoid administration may result in increased emotionality and sensitization of the stress axis.