Cannabidiol prevents fear extinction deficits caused by single prolonged stress in rats: possible involvement of serotoninergic, cannabinoid, and nitric mechanisms.

Abstract

Post-traumatic stress disorder (PTSD) involves impaired extinction learning, autonomic and neuroendocrine dysregulation, and first-line selective serotonin reuptake inhibitors (SSRIs) show limited efficacy. We investigated effects and mechanisms of cannabidiol (CBD) on fear deficits induced by the single prolonged stress (SPS) model in male Wistar rats. SPS sensitized conditioned fear, impaired extinction recall, enhanced cardiovascular reactivity to trauma-related cues, and produced a trend toward a biphasic corticosterone response. Repeated post-SPS paroxetine (an SSRI, 10 mg/kg, 7 days) prevented these behavioral deficits. Repeated CBD (5 and 10 mg/kg, 7 days) prevented extinction memory impairments, and these effects were attenuated by the 5-HT1A antagonist WAY-100635 and the CB1 antagonist AM281. In the prelimbic medial prefrontal cortex (PL-mPFC), SPS increased neuronal nitric oxide synthase (nNOS) phosphorylation after extinction recall, which repeated CBD normalized, an effect prevented by WAY-100635 and attenuated by AM281. A single post-SPS injection of the competitive and preferential nNOS inhibitor 7-nitroindazole (7-NI, 30 and 60 mg/kg), used as a pharmacological tool, also prevented fear sensitization and extinction deficits. A single dose of CBD was effective at 30 mg/kg, but not at 5 or 10 mg/kg, and reduced nNOS phosphorylation. Neither CBD regimen altered total nNOS, CB1, or 5-HT1A levels. Both compounds remained effective in a stress-restress paradigm with a forced swim trauma reminder, although neither normalized the SPS-induced increase in total nNOS. These findings indicate that CBD prevents SPS-induced extinction deficits through 5-HT1A- and CB1-dependent mechanisms, identify nNOS as a candidate downstream substrate, and support CBD as a multi-target candidate for PTSD treatment.