Cannabinoids are the chemicals in marijuana that are responsible for its psychoactive effects. Marijuana has been used by humans for more than 2,500 years as a medicinal agent and social drug and scientists are in the process of determining how these interesting chemicals affect the brain. It is likely that the target of the cannabinoids are two different receptors, CB1 on neurons and CB2 on immune cells. About 15 years ago, a laboratory in Israel identified a very scarce brain lipid as an "endocannabinoid", that is, a chemical made by the brain for the purpose of activating the CB1 and CB2 receptors. Our research focuses on the cannabinoids, the receptors with which they interact and the role of the endocannabinoids in brain function. We have three major research projects.
1. Studies of the biochemical mechanisms involved in the synthesis, release and degradation of the endocannabinoids.
At least two lipid molecules are thought to act as endocannabinoids, anandamide and 2-arachidonylglycerol. Both can be synthesized by neurons but our knowledge of the mechanisms that regulate their synthesis is lacking in detail. One goal of our work is to develop inhibitors of these pathways to help us understand the physiological roles of endocannabinoids. We are also studying the processes by which the endocannabinoids are inactivated. We know that they are catabolized by enzymes and that they are substrates for transporters that act in plasma membranes. As above, one of our goals is to biochemically understand these processes and to develop inhibitors.
2. Studies of the physiological roles of endocannabinoids and cannabinoid receptors in the regulation of cerebral blood flow.
An important question regarding the endocannabinoid/cannabinoid receptor signaling system is what is its role in the functioning of the brain? We are focused on several of the many diverse systems that are affected by endocannabinoid tone. We have found that cerebral artery smooth muscle cells have CB1 receptors and that when activated, they result in an increase in blood vessel diameter and blood flow. This finding suggests that the endocannabinoid system could function as an endogenous mechanism for the regulation of the delivery of blood to the brain. We are currently studying the cellular source of endocannabinoids that activate this receptor and the distribution of the CB1 receptor throughout the cerebral vasculature. We are also very interested in exploring the role of this cannabinoid receptor in the sequelae of stroke or during other disease states that affect blood flow to the brain.
3. Studies of the role of endocannabinoid signaling in the regulation of mood and responses of animals to stress.
Several laboratories, including ours, have demonstrated that one very important function of the endocannabinoids is to regulate the response of the brain to stress. Animals and humans need to cope with physical and psychological stresses in order to survive, but stress responses have a cost. For example, we know that long term stress exposure results in depression and post traumatic stress disorder in humans. The endogenous cannabinoid system is a stress buffer, it turns down the hormonal and behavioral responses to stress. We are studying this hypothesis in animals and in humans.
Brightfield photomicrographs of double-labeled cells within parabrachial pigmented nucleus (PBP) of the ventral tegmental area of the mouse brain. Fos protein was visualized using black reaction product (DAB + Ni/Co heavy metal intensification), tyrosine hydroxylase, a marker of dopaminergic neurons, was visualized using brown reaction product (plain DAB). Intensely Fos-expressing dopaminergic cells within the PBP (black arrows) and less intensely stained Fos-expressing dopaminergic neurons (red arrows) are visible.
Recent Publications
Patel, S. and Hillard, C.J.: Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304-311, 2006.
Carrier, E.J., Auchampach, J.A. and Hillard, C.J.: Inhibition of an equilibrative nucleoside transporter by cannabidiol: a novel mechanism of cannabinoid immunosuppression. Proc Natl. Acad. Sci. U.S.A. 103: 7895-900. 2006.
Hill, M.N., Ho, W.-S. V., Sinopoli, K., Viau, V., Hillard, C.J. and Gorzalka, B.B.: Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacol. 31:2591-2599, 2006.
Rademacher, D.J and Hillard, C.J.: Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward. Prog Neuropsychopharmacol Biol Psychiatry 31:633-41, 2007.
Maresz, K., Pryce, G., Ponomarev, E.D., Marsicano, G., Croxford, J.L., Shriver, L.P., Ledent, C., Cheng, X., Carrier, E.J., Mann, M.K., Giovannoni, G., Pertwee R.G., Yamamura, T., Buckley, N.E., Hillard, C.J., Lutz, B., Baker, D. and Dittel, B.N.: Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 autoreactive T cells. Nature Med. 13: 492-497, 2007.
Benito, C., Romero, J.P., Tolon, R.M., Hillard, C.J. , Guaza, C., and Romero, J.: Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque-associated cells in human multiple sclerosis. J. Neurosci. 27: 2396-402, 2007.