Endogenous Cannabinoid Regulation of the Hypothalamic-Pituitary-Adrenal Axis and of Neuroendocrine Reactivity to Acute and Repeated Stress

Deleterious effects of stress contribute to many mind/body ills and precipitate substantial individual and societal burden. The endogenous cannabinoid (endocannabinoid, eCB) system is widely expressed in the brain and body, and contributes to psychoneuroendocrine regulation. Inhibitory CB1 receptors on neurons afford the \u22toning down\u22 of conscious experience that makes cannabis a popular relaxant. In normal waking consciousness, the eCB ligands anandamide and 2-AG both bind at this predominantly presynaptic receptor and function as a negative feedback mechanism for neurotransmission. Peripheral eCB activity is less explored in stress research and is of interest in metabolic regulation. Excessive elevations of stress-induced cortisol and excitatory neurotransmission are interacting pathological influences that may be regulated by the eCB system in both acute and repeated stress. We initially demonstrated that systemic antagonism of CB1 receptors potentiates some measures of neural and hypothalamic-pituitary-adrenal (HPA) axis response to acute loud noise stress, and that antagonism of CB1 receptors alone directly stimulated activity in a select subset of neural regions, and elevated plasma corticosterone (CORT, the rodent equivalent of cortisol). We have explored involvement of CB1 receptors in inhibition of central and peripheral psychoneuroendocrine stress reactivity in acute and repeated stress, and in contributing to constitutive tonic inhibition in regions including the amygdala and adrenal glands