Marijuana has been used by humans for more than 2,500 years as a medicinal agent and social drug. Cannabinoids are the chemicals in marijuana that are responsible for its effects on the body. A long-standing interest of our laboratory is the study of the mechanisms by which the cannabinoids affect the function of the brain. Delta-9-tetrahydrocannabinol (THC) is the cannabinoid in marijuana that is responsible for its mood- and sensation-altering effects. THC targets two receptors: the CB1 receptor present on neurons and the CB2 receptor that is present primarily on immune cells. Although THC targets these receptors when a person is exposed to the drug from the outside, we know that at least two “endogenous” (or, from the self) molecules also target these receptors. These two molecules are named the endocannabinoids. 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-arachidonoylglycerol. 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. One of our goals is to biochemically understand these processes and to develop inhibitors.
2. Studies of the role of endocannabinoid signaling in the regulation of mood and responses 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. In addition, the endocannabinoid system is itself turned on or, in some cases, turned off by stress. Our goal in these studies is to examine the mechanistic relationships between stress and the endocannabinoids. While most of our studies are carried out using rodent models, we are also exploring these processes in human subjects exposed to periods of psychological stress through collaborations with other investigators.
3. Studies of the effects of cannabinoids on metabolic functions in the brain.
THC and the other cannabinoids in marijuana also affect enzymes and processes that are essential for brain energy utilization and neuronal survival. One enzyme that is known to play an important role in the brain is glycogen synthase kinase 3 (GSK3). Interestingly, over-activation of this enzyme has been shown to produce detrimental effects in the adult brain. In fact, inhibition of this enzyme is a good treatment for bipolar disorder. It is also interesting that there is a very high amount of cannabis use among people with bipolar disorder. These facts together have lead us to hypothesize that cannabis use contributes to the likelihood of developing bipolar disorder because cannabinoids in the plant increase the activity of GSK3. We are testing this hypothesis using cellular, biochemical and animal models.
Pazos MR, Mohammed N, Lafuente H, Santos M, Martinez-Pinilla E, Moreno E, Valdizan E, Romero J, Pazos A, Franco R, Hillard CJ, Alvarez FJ, Martinez-Orgado J. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: Role of 5HT1A and CB2 receptors. Neuropharmacology 71:282-291, 2013
McLaughlin RJ, Hill MN, Sang SS, Wainwright SR, Galea LA, Hillard CJ, Gorzalka BB. Upregulation of CB(1) receptor binding in the ventromedial prefrontal cortex promotes proactive stress-coping strategies following chronic stress exposure. Behav Brain Res 237:333-337, 2013
Dlugos A, Childs E., Stuhr KL, Hillard CJ*, de Wit, H: Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans. Neuropsychopharmacol. 37:2416-27, 2012
Ho WS, Hill MN, Miller GE, Gorzalka BB and Hillard CJ: Serum contents of endocannabinoids are correlated with blood pressure in depressed women. Lipids in Health and Disease 11:32 (9 pages), 2012
Roberts CJ, Stuhr KL and Hillard CJ: Swim stress differentially affects limbic contents of 2-arachidonoylglycerol and 2-oleoylglycerol. Neuroscience 204:74-82, 2012
Hill, M.N., McLaughlin, R.J., Bingham, B., Shrestha, L., Lee, T.T., Gray, J.M., Hillard, C.J., Gorzalka, B.B. and Viau, V.: Endogenous cannabinoid signaling is essential for stress adaptation. Proc. Natl. Acad. Sci. 107: 9408-11, 2010.
Chen, C.Y., Bonham, A.C., Dean, C., Hopp, F.A., Hillard, C.J. and Seagard, J.L.: Retrograde release of endocannabinoids inhibits presynaptic GABA release to second-order baroreceptive neurons in NTS. Auton. Neurosci. 158:(1-2):44-50 2010. (e pub July 1).
Vaughn, L.K., Denning, G., Stuhr, K.L., de Wit, H., Hill, M.N., and Hillard, C.J.: Endocannabinoid signaling: has it got rhythm? Br J Pharmacol. 160: 530-43, 2010.
Ho, W.S., Patel, S., Thompson, J.R., Roberts, C.J., Stuhr, K.L., and Hillard, C.J.: Endocannabinoid modulation of hyperaemia evoked by physiologically relevant stimuli in the rat brain primary somatosensory cortex. Br J Pharmacol. 160: 736-46, 2010.
Wang, W., Sun, D., Pan, B., Roberts, C.J., Sun, X., Hillard, C.J., and Liu, Q.S.: Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress. Neuropsychopharmacol. 35: 2249-61, 2010.
Evanson, N.K., Tasker, J.G., Hill, M.N., Hillard, C.J., and Herman, J.P.: Fast Feedback Inhibition of the HPA Axis by Glucocorticoids Is Mediated by Endocannabinoid Signaling. Endocrinology 151: 4811-19, 2010.
Krebs-Kraft DL, Hill MN, Hillard CJ, McCarthy MM: Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior. Proc Natl Acad Sci U S A. 107:20535-40, 2010.