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Prefrontal endocannabinoid signaling mediates neuroendocrine and behavioral coping responses to stress

University of British Columbia

Major depression is a heterogeneous disease often precipitated by dysfunction within the neuroendocrine stress circuitry, leading to profound deficits in prefrontocortical function. The endocannabinoid system has recently emerged as a vital component of the stress response; however, the mechanisms by which endocannabinoid signaling in the prefrontal cortex (PFC) modulates neuroendocrine and behavioral responses to stress has yet to be elucidated. In Chapter 2, genetic deletion of the CB₁ receptor prolonged corticosterone secretion following cessation of stress, which was recapitulated by CB₁ receptor antagonism within the medial PFC. Acute stress produced a delayed elevation in 2-arachidonoylglycerol (2-AG) content in the medial PFC that was reversed by glucocorticoid receptor antagonism. Immunohistochemical and electrophysiological data demonstrated the presence of CB₁ receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the medial PFC. Furthermore, application of corticosterone to prefrontocortical slices suppressed γ-aminobutyric acid release onto layer V principal neurons, which was prevented by CB₁ receptor antagonism. Hence, the ability of glucocorticoids to terminate HPA axis activity is mediated by local recruitment of 2-AG in the medial PFC. In Chapter 3, forced swim stress rapidly suppressed anandamide (AEA) content in the medial PFC. Local inhibition of AEA hydrolysis decreased passive coping and increased active coping strategies in the forced swim test (FST) in a CB₁ receptor-dependent and serotonin-mediated manner. Furthermore, local inhibition of AEA hydrolysis increased the firing rate of serotonin neurons, suggesting that prefrontocortical AEA signaling modulates stress coping behaviors via regulation of serotonergic neurotransmission. In Chapter 4, rats exposed to chronic unpredictable stress (CUS) displayed increased CB₁ receptor binding specifically within the ventromedial PFC. CUS exposure increased passive coping and decreased active coping strategies in the FST, which was further augmented by ventromedial PFC CB₁ receptor blockade. Thus, the increase in CB₁ receptor binding observed in the ventromedial PFC of CUS-exposed rodents serves a compensatory role that maintains proactive coping strategies under chronically stressful conditions. Collectively, this body of research indicates that prefrontocortical endocannabinoid signaling is a critical mediator of neuroendocrine and behavioral stress responses and may represent an appealing target for future therapeutic strategies aimed at combating stress-related disorders.

Text

2012-04-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42054

Psychology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/