Ryan M. Drenan

Adjunct Professor of Medicinal Chemistry and Molecular Pharmacology, Associate Professor of Pharmacology, Northwestern University
Specialization: Neurobiology, Molecular Pharmacology


Research Faculty - California Institute of Technology, 2010-2011
Postdoc - California Institute of Technology, 2006-2010
Ph.D. - Washington University, 2006
B.S. - University of California San Diego, 2000


Molecular Pharmacology and Neurobiology of Nicotinic Acetylcholine Receptors

My laboratory utilizes an interdisciplinary approach to study the molecular biology, neurobiology, and in vivo action of neuronal nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of ligand-gated, cation-selective channels. Cholinergic neurotransmission is essential for cognitive processes such as arousal and sensitization to incoming stimuli, and is manipulated in smokers by the action of nicotine. By leading to diseases such as emphysema, lung cancer, and heart disease, nicotine addiction claims over 400,000 lives per year in the U.S.  Although nAChRs have been intensively studied for decades, little is known about the properties of specific nicotinic receptor subtypes or their function in the central nervous system. The goal of our research is to better understand these proteins, the neurons that express them, and the circuits they govern.  Our work, which employs mouse models, seeks to study nAChRs in their native subunit arrangement and in their native cell types in the brain.  Work in the lab is dedicated to the following projects:

A.  Mechanisms of nicotine reward in the dopamine pathway

Activation of the dopamine reward pathway is a common feature of all drugs of abuse, including nicotine.  This pathway, which includes dopamine neurons in the ventral tegmental area (VTA) and their terminals in the nucleus accumbens (NAc), expresses high levels of nAChRs.  Nicotine from tobacco products potently stimulates this pathway through nAChRs, setting up enduring changes in dopamine neuron excitability and dopamine release that is thought to underlie nicotine reward.  We are interested in identifying the complex nAChR subtypes on dopamine neurons that are most important for the rewarding response to nicotine, and have made several contributions to this problem.  We are also interested in understanding how exposure to rewarding nicotine concentrations alters glutamatergic transmission within the dopamine pathway.  We use genetically-modified mice to isolate and amplify the action of specific nAChR subtypes within this pathway, followed by functional analysis of these nAChRs using brain slice patch clamp electrophysiology, neurochemical approaches, and conditioned place preference reward assays.

B.  Identification of nAChRs important for nicotine aversion and withdrawal

It has recently been appreciated that intake of nicotine depends not only on its rewarding properties, but also on its aversive characteristics at high concentrations.  The medial habenula (MHb) is a small but important epithalamic structure that expresses huge amounts of nAChRs and has been shown recently to be critical for nicotine aversion signals and nicotine withdrawal behavior.  Projections of the MHb to the interpeduncular nucleus (IPN) also play a role in aversion/withdrawal.  Identifying which nAChRs and which neurons within this pathway are important for nicotine withdrawal is a major priority and could lead to new smoking cessation strategies and/or therapeutics.  In the lab, we expose mice to chronic nicotine and use several tools and techniques to study nicotine withdrawal, including brain slice patch clamp electrophysiology, quantification of nAChR expression using knockin mice expressing GFP-fused nAChR subunits, c-Fos induction immunohistochemistry, and behavioral measurements.

C. Identification and characterization of nAChRs involved in alcohol dependence

Smoking and alcohol consumption are highly co-morbid: smokers are more likely to drink significant amounts of alcohol than non-smokers, and alcoholics smoke more cigarettes than non-alcoholics.  Recent evidence indicates that alcohol may directly or indirectly target nAChRs in various brain pathways to enhance the rewarding properties of nicotine.  We are interested in identifying molecular, cellular, and circuit mechanisms involved in the co-morbidity between nicotine intake and alcohol consumption.  Toward this end, we study several mouse models, including 1) mice engineered to express hypersensitive nAChRs within the dopamine reward pathway, and 2) mice selectively bred to exhibit either high or low alcohol preference (in collaboration with Dr. Julia Chester, Psychological Sciences).  Techniques employed include patch clamp electrophysiology, immunohistochemistry (c-Fos), and several behavioral approaches (conditioned place preference, pre-pulse inhibition of startle, somatic and affective withdrawal testing, etc.).

Lab Members

Matthew Carl Arvin (Graduate Student)

Representative Publications

*corresponding author

Shih, P.Y., McIntosh, J.M., and *Drenan, R.M. (2015) Nicotine dependence reveals distinct responses from neurons and their resident nicotinic receptors in medial habenula. Mol. Pharmacol. 88: 1035-1044. <<download paper here>>

Berry, J.B., Engle, S.E., McIntosh, J.M., and *Drenan, R.M. (2015) α6-containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity. Neuroscience 304: 161-175. <<download paper here>>

Wieskopf, J.S., Mathur, J., Limapichat, W., Post, M.R., Al-Qazzaz, M., Sorge, R.E., Martin, L.J., Zaykin, D.V., Smith, S.B., Freitas, K., Austin, J-S., Dai, F., Zhang, J., Marcovitz, J., Tuttle, A.H., Slepian, P.M., Clarke, S., Drenan, R.M.Janes, J., Al Sharari, S., Segall, S.K., Aasvang, E.K., Lai, W., Bittner, R., Richards, C.I., Slade, G.D., Kehlet, H., Walker, J., Maskos, U., Changeux, J-P., Devor, M., Maixner, W., Diatchenko, L., Belfer, I., Dougherty, D.A., Su, A.I., Lummis, S.C.R., Damaj, M.I., Lester, H.A., Patapoutian, A., and Mogil, J.S. (2015) The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci. Transl. Med. 7(287): 287ra72. <<download paper here>>

Bordia, T., McGregor, M., McIntosh, J.M., Drenan, R.M., and Quik, M. (2015) Evidence for a role for α6* nAChRs in L-dopa-induced dyskinesias using parkinsonian α6* nAChR gain-of-function mice. Neuroscience 295:187-197. <<download paper here>>

Engle, S.E., McIntosh, J.M., and *Drenan, R.M. (2014) Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via α6-containing nicotinic receptors. Neuropharmacology 91: 13-22. <<download paper here>>

Shih, P.Y., Engle, S.E., Oh, G., Deshpande, P., Puskar, N.L., Lester, H.A., and *Drenan, R.M. (2014) Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. J. Neurosci. 34(29): 9789-802. <<download paper here>>

Wang, Y., Lee, J.-W., Oh, G., Grady, S.R., McIntosh, J.M., Brunzell, D.H., Cannon, J.R., and *Drenan, R.M(2013) Enhanced synethesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs. J. Neurochem. 129(2): 315-27. <<download paper here>>

Henderson, B.J., Srinivasan, R., Nichols, W.A., Dilworth, C.N., Gutierrez, D.F., Mackey, E.D.W., McKinney, S., Drenan, R.M., Richards, C.I., and Lester, H.A. (2013) Nicotine exploits a COPI-mediated process for chaperone-mediated upregulation of its receptors. J. Gen. Physiol. 143(1): 51-66. <<download paper here>>

Engle, S.E., Shih, P.Y., McIntosh, J.M., and *Drenan, R.M. (2013) α4α6β2* nAChR activation on VTA DA neurons is sufficient to stimulate a depolarizing conductance and enhance surface AMPA receptor function. Mol. Pharmacol. 84(3): 393-406. <<download paper here>>

Powers, M.S., Broderick, H.J., *Drenan, R.M., and *Chester, J.A. (2013) Nicotinic acetylcholine receptors containing α6 subunits are involved in alcohol reward behaviors. Genes, Brain, and Behavior 12(5):543-553. <<download paper here>>

*Drenan, R.M., and Lester, H.A. (2012) Neurobiology of the cholinergic system and nicotine probed with mice expressing gain-of-function nAChR subunits. Pharmacological Reviews 64(4): 869-79. <<download paper here>>

Engle, S.E., Broderick, H.J., and *Drenan, R.M. (2012) Local application of drugs to study nicotinic acetylcholine receptor function in mouse brain slices. J. Vis. Exp. (68), e50034, DOI: 10.3791/50034 <<watch video here>> <<download paper here>>

Mackey, E.D.W., Engle, S.E., Kim, M., O’Neill, H.C., Wageman, C.R., Patzlaff, N.E., Wang, Y., Grady, S.R., McIntosh, J.M., Marks, M.J., Lester, H.A., and *Drenan, R.M. (2012) α6* nicotinic acetylcholine receptor expression and function in a visual salience circuit. J. Neurosci. 32(30): 10226-10237. <<download paper here>>

Cohen, B.N., Mackey, E.D.W., Grady, S.R., McKinney, S., Patzlaff, N.E., Wageman, C.R., McIntosh, J.M., Marks, M.J., Lester, H.A., and *Drenan, R.M. (2012) Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior. Neuroscience 200: 31-41. <<download paper here>>

Xiao, C., Srinivasan, R., Drenan, R.M., Mackey, E.D., McIntosh, J.M., and Lester, H.A. (2011) Characterizing functional α6β2 nicotinic acetylcholine receptors in vitro: Mutant β2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. Biochemical Pharmacology 82(8): 852-61. <<download paper here>>

Gunapala, K.M., Chang, D., Hsu, C.T., Manaye, K., Drenan, R.M., Switzer, R.C., and Steele, A.D. (2010) Striatal pathology underlies prion infection-mediated hyperactivity in mice.  Prion 4(4): 1-14. <<download paper here>>

Drenan, R.M., Grady, S.R., Steele, A.D., McKinney, S., Patzlaff, N.E., McIntosh, J.M., Marks, M.J., Miwa, J., and Lester, H.A. (2010) Cholinergic modulation of locomotion and striatal dopamine release is mediated by a6a4* nicotinic acetylcholine receptors.  J. Neurosci. 30(29): 9877-9889. <<download paper here>>

Grady, S.R., Drenan, R.M., Breining, S.R., Yohannes, D., Wageman, C.R., Fedorov, N.B., McKinney, S., Whiteaker, P., Bencherif, M., Lester, H.A., and Marks, M.J. (2010) Structural differences determine the relative selectivity of nicotinic compounds for native a4b2*, a6b2*, a3b4*, and a7 nicotinic acetylcholine receptors.  Neuropharmacology 58(7): 1054-66. <<download paper here>>

Drenan, R.M., Grady, S.R., Whiteaker, P., McClure-Begley, T., McKinney, S., Miwa, J., Bupp, S., Heintz, N., McIntosh, J.M., Bencherif, M., Marks, M.J., and Lester, H.A. (2008) In vivo activation of midbrain dopamine neurons via sensitized, high-affinity a6* nicotinic acetylcholine receptors.  Neuron 60(1): 123-136.  **Previewed in Neuron 60(1): 4-6 (2008)<<download paper here>>

Drenan, R.M., Nashmi, R., Imoukhuede, P., Just, H., McKinney, S.L., and Lester, H.A. (2008) Subcellular trafficking, pentameric assembly and subunit stoichiometry of neuronal nicotinic ACh receptors containing fluorescently-labeled a6 and b3 subunits.  Mol. Pharmacol. 73(1): 27-41. <<download paper here>>

Osei-owusu, P., Sun, X., Drenan, R.M., Steinberg, T.H., Blumer, K.J. (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J. Biol. Chem. 282(43): 31656-65. <<download paper here>>

Drenan, R.M., Doupnik, C.A., Jayaraman, M., Buchwalter, A.L., Kaltenbronn, K.M., Huettner, J.E., Linder, M.E., and Blumer, K.J. (2006) R7BP augments the function of RGS7/Gb5 complexes by a plasma-membrane targeting mechanism. J. Biol. Chem., 281(38): 28222-31. <<download paper here>>

Drenan, R.M., Doupnik, C.A., Boyle, M.P., Muglia, L.J., Huettner, J.E., Linder, M.E., and Blumer K.J. (2005) Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. J. Cell Biol. 169(4): 623-33.  **Featured in Science STKE 294: 38 (2005). <<download paper here>>

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