Cannabinoid use is enhanced by stress and changes conditioned stress responses.

Individuals diagnosed with post-traumatic stress disorder (PTSD) are often comorbid for substance use disorders. Cannabis is widely used by PSTD patients, and the literature is mixed on whether cannabis use ameliorates or exacerbates patient responses to stress-associated conditioned stimuli (stress-CS). We determined if cannabis use affects responsivity to stress-CS in rats receiving 2 h stress in the presence of an odor stress-CS. Three weeks after acute stress, rats self-administered cannabinoids (delta9-tetrahydrocannabinol + cannabidiol; THC + CBD) for 15 days, and the stressed males consumed more THC + CBD than sham males. We then used the stress-CS or a novel odor (stress-NS) to reinstate THC + CBD seeking. Surprisingly, the stress-NS reinstated THC + CBD seeking, an effect blocked by N-acetylcysteine. Moreover, the stress-CS inhibited THC + CBD-CS induced reinstatement. To determine if the unexpected effects of stress-NS and -CS resulted from THC + CBD altering conditioned stress, the effect of THC + CBD use on stress-NS/CS-induced coping behaviors and spine morphology was quantified. In THC + CBD-treated rats, stress-NS increased active coping (burying). Conversely, stress-CS reduced active coping and increased passive coping (immobility) and other behavioral parameters associated with stress responses, including self-grooming and defecation. Transient spine head expansion in nucleus accumbens core is necessary for cue-induced drug seeking, and THC + CBD self-administration prevented the increase in head diameter by stress-CS in control rats. These data show THC + CBD self-administration altered the salience of environmental cues, causing neutral cues to promote active behavior (drug seeking and burying) and stress-CS to switch from active to passive behavior (inhibiting drug seeking and immobilization). We hypothesize that cannabis may exacerbate conditioned stress responses.