Department of
Psychological and Brain Sciences

• Neuroscience

• Regulation of CB1 cannabinoid receptor signaling
• Regulation of endocannabinoid production
• Role of endocannabinoids in synaptic plasticity
• Novel cannabinoid receptors

The Mackie lab examines the role and function of the endocannabinoid system by using a combination of electrophysiological, imaging, biochemical and immunological approaches. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that regulate the production and degradation of endocannabinoids. ?9THC, the principal psychoactive component of cannabis, interacts with this system to produce the classic effects of cannabis intoxication. In addition, this system is widely involved in multiple physiologically important processes including memory, motivation, movement, analgesia, and emesis. Through our studies, we hope to better understand the implications of social and therapeutic use of drugs that influence this fascinating system.

Morgan, D.J., B.J. Davis, C.S. Kearn, D. Marcus, A.J. Cook, J. Wager-Miller, A. Straiker, M.H. Myoga, J. Karduck, E. Leishman, L.J. Sim-Selley, T.A. Czyzyk, H.B. Bradshaw, D.E. Selley, and K. Mackie, Mutation of Putative GRK Phosphorylation Sites in the Cannabinoid Receptor 1 (CB1R) Confers Resistance to Cannabinoid Tolerance and Hypersensitivity to Cannabinoids in Mice. J Neurosci, 2014. 34(15): p. 5152-63.

Ramikie, T.S., R. Nyilas, R.J. Bluett, J.C. Gamble-George, N.D. Hartley, K. Mackie, M. Watanabe, I. Katona, and S. Patel, Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron, 2014. 81(5): p. 1111-25.

O'Donnell, B.F. and K. Mackie, The mismatch negativity: a translational probe of auditory processing in cannabis users. Biol Psychiatry, 2014. 75(6): p. 428-9.

Petrov, R.R., L. Knight, S.R. Chen, J. Wager-Miller, S.W. McDaniel, F. Diaz, F. Barth, H.L. Pan, K. Mackie, C.N. Cavasotto, and P. Diaz, Mastering tricyclic ring systems for desirable functional cannabinoid activity. Eur J Med Chem, 2013. 69: p. 881-907.

Chen, D.H., A. Naydenov, J.L. Blankman, H.C. Mefford, M. Davis, Y. Sul, A.S. Barloon, E. Bonkowski, J. Wolff, M. Matsushita, C. Smith, B.F. Cravatt, K. Mackie, W.H. Raskind, N. Stella, and T.D. Bird, Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. Hum Mutat, 2013. 34(12): p. 1672-8.

Jain, T., J. Wager-Miller, K. Mackie, and A. Straiker, Diacylglycerol lipasealpha (DAGLalpha) and DAGLbeta cooperatively regulate the production of 2-arachidonoyl glycerol in autaptic hippocampal neurons. Mol Pharmacol, 2013. 84(2): p. 296-302.

Cristino, L., G. Busetto, R. Imperatore, I. Ferrandino, L. Palomba, C. Silvestri, S. Petrosino, P. Orlando, M. Bentivoglio, K. Mackie, and V. Di Marzo, Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci U S A, 2013. 110(24): p. E2229-38.

Straiker, A., K.T. Min, and K. Mackie, Fmr1 deletion enhances and ultimately desensitizes CB(1) signaling in autaptic hippocampal neurons. Neurobiol Dis, 2013. 56: p. 1-5.

Shonesy, B.C., X. Wang, K.L. Rose, T.S. Ramikie, V.S. Cavener, T. Rentz, A.J. Baucum, 2nd, N. Jalan-Sakrikar, K. Mackie, D.G. Winder, S. Patel, and R.J. Colbran, CaMKII regulates diacylglycerol lipase-alpha and striatal endocannabinoid signaling. Nat Neurosci, 2013. 16(4): p. 456-63.

Keimpema, E., G. Tortoriello, A. Alpar, S. Capsoni, I. Arisi, D. Calvigioni, S.S. Hu, A. Cattaneo, P. Doherty, K. Mackie, and T. Harkany, Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci U S A, 2013. 110(5): p. 1935-40.

Atwood, B.K., A. Straiker, and K. Mackie, CB(2) cannabinoid receptors inhibit synaptic transmission when expressed in cultured autaptic neurons. Neuropharmacology, 2012. 63(4): p. 514-23.

Atwood, B.K., A. Straiker, and K. Mackie, CB(2): therapeutic target-in-waiting. Prog Neuropsychopharmacol Biol Psychiatry, 2012. 38(1): p. 16-20.

Atwood, B.K., J. Wager-Miller, C. Haskins, A. Straiker, and K. Mackie, Functional selectivity in CB(2) cannabinoid receptor signaling and regulation: implications for the therapeutic potential of CB(2) ligands. Mol Pharmacol, 2012. 81(2): p. 250-63.

Straiker, A., J. Wager-Miller, J. Hutchens, and K. Mackie, Differential signalling in human cannabinoid CB1 receptors and their splice variants in autaptic hippocampal neurones. Br J Pharmacol, 2012. 165(8): p. 2660-71.

Straiker, A., J. Wager-Miller, and K. Mackie, The CB1 cannabinoid receptor C-terminus regulates receptor desensitization in autaptic hippocampal neurones. Br J Pharmacol, 2012. 165(8): p. 2652-9.

Ho, Y.C., H.J. Lee, L.W. Tung, Y.Y. Liao, S.Y. Fu, S.F. Teng, H.T. Liao, K. Mackie, and L.C. Chiou, Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci, 2011. 31(41): p. 14600-10.

Straiker, A., J. Wager-Miller, S.S. Hu, J.L. Blankman, B.F. Cravatt, and K. Mackie, COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation. Br J Pharmacol, 2011. 164(6): p. 1672-83.

Atwood, B.K., D. Lee, A. Straiker, T.S. Widlanski, and K. Mackie, CP47,497-C8 and JWH073, commonly found in 'Spice' herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists. Eur J Pharmacol, 2011. 659(2-3): p. 139-45.

Wu, C.S., J. Zhu, J. Wager-Miller, S. Wang, D. O'Leary, K. Monory, B. Lutz, K. Mackie, and H.C. Lu, Requirement of cannabinoid CB(1) receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections. Eur J Neurosci, 2010. 32(5): p. 693-706.

Marrs, W.R., J.L. Blankman, E.A. Horne, A. Thomazeau, Y.H. Lin, J. Coy, A.L. Bodor, G.G. Muccioli, S.S. Hu, G. Woodruff, S. Fung, M. Lafourcade, J.P. Alexander, J.Z. Long, W. Li, C. Xu, T. Moller, K. Mackie, O.J. Manzoni, B.F. Cravatt, and N. Stella, The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci, 2010. 13(8): p. 951-7.

Atwood, B.K. and K. Mackie, CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol, 2010. 160(3): p. 467-79.

Atwood, B.K., J. Huffman, A. Straiker, and K. Mackie, JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol, 2010. 160(3): p. 585-93.

Straiker, A., S.S. Hu, J.Z. Long, A. Arnold, J. Wager-Miller, B.F. Cravatt, and K. Mackie, Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons. Mol Pharmacol, 2009. 76(6): p. 1220-7.

Straiker, A. and K. Mackie, Cannabinoid signaling in inhibitory autaptic hippocampal neurons. Neuroscience, 2009. 163(1): p. 190-201.

Kellogg, R., K. Mackie, and A. Straiker, Cannabinoid CB1 receptor-dependent long-term depression in autaptic excitatory neurons. J Neurophysiol, 2009. 102(2): p. 1160-71.

Daigle, T.L., M.L. Kwok, and K. Mackie, Regulation of CB1 cannabinoid receptor internalization by a promiscuous phosphorylation-dependent mechanism. J Neurochem, 2008. 106(1): p. 70-82.

Lauckner, J.E., J.B. Jensen, H.Y. Chen, H.C. Lu, B. Hille, and K. Mackie, GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A, 2008. 105(7): p. 2699-704.

Daigle, T.L., C.S. Kearn, and K. Mackie, Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling. Neuropharmacology, 2008. 54(1): p. 36-44.