Role of endocannabinoid signaling in stress-coping behavior

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Stress contributes to the etiology of addiction, but the mechanisms underlying this phenomenon are still unknown. The endocannabinoids (eCBs) - anandamide and 2-arachidonoylglycerol (2-AG) - and their attending cannabinoid (CB) receptors are thought to play important roles in the regulation of stress-coping behaviors. Project 5 will examine whether changes in eCB signaling contribute to the neurobehavioral alterations induced by stress. We hypothesize that the eCB system enhances stress-coping responses by acting as a downstream regulator of corticotrophin-releasing factor (CRF), a neuropeptide implicated in stress-related disorders. We have four specific aims: 1. To determine the effects of CRF on brain eCB mobilization. Initial results indicate that administration of CRF in rats alters brain eCB levels. We propose to characterize this response by identifying the CRF receptor subtype(s) involved, their brain localization, and the biochemical mechanism through which they influence eCB mobilization. 2. To examine the role of the eCB system in CRF-induced behaviors. Preliminary findings suggest that brain eCB mobilization modulates the neurobehavioral actions of CRF. To test this idea, we will examine whether agents that either increase eCB levels (the anandamide degradation inhibitor URB597) or block CB receptors (the B! antagonist rimonabant) affect three actions of CRF that closely mimic those elicited by acute stress: inhibition of feeding, enhancement of anxiety-related behaviors and elevation of plasma corticosterone levels. 3. To assess the contribution of the eCB system to stress-induced behaviors mediated by CRF. We will determine the effects of URB597 and rimonabant on three neurobehavioral outcomes of acute restraint stress that are mediated by CRF: inhibition of feeding, enhancement of anxiety-related behaviors and elevation of plasma corticosterone levels. Chronic exposure to stress disrupts behavior, reducing the ability to cope with normally manageable stressful stimuli. To test whether such disturbances are due to a disruption in the normal balance between CRF and anandamide signaling in the brain, we will 4. determine the impact of chronic stress on brain eCB signaling. To this end, we will (i) identify the molecular mechanisms underlying such alterations; and (ii) determine whether they are associated with changes in CB1 receptor expression. The results of these studies should facilitate the development of innovative therapies for stress-related disorders such as addiction, anxiety and depression. Development of new therapies will be of great benefit to decreasing the public health costs related to addiction.