Contact

Department

Cellular and Integrative Physiology

Lynette C. Daws, Ph.D.

Professor

Education

B.S. (Honors), Flinders University of South Australia, 1989
Ph.D., Flinders University of South Australia, 1994

Research

The broad area of my research is studying the function and regulation of biogenic amine transporters, including the classical serotonin, dopamine and norepinephrine transporters, as well as more recently identified transporters in brain, such as the organic cation transporters and plasma membrane monoamine transporter. Understanding how these transporters function is important in that they are pivotal in controlling the extracellular concentration of biogenic amines and hence, neurotransmission. Moreover, they are the primary site of action for numerous psychotherapeutic and addictive drugs.

One of my primary research interests relates to the serotonin transporter. In humans, a polymorphism of the gene encoding the serotonin transporter leads to its reduced expression. This polymorphism has been linked to a number of disorders including alcoholism and depression. Moreover, individuals with this polymorphism appear to respond differently to drug treatment. We are using mice with a genetically induced reduction in the density of the serotonin transporter (heterozygote serotonin transporter knockout mice, which express 50% fewer serotonin transporters than the “normal”, wild-type mouse) to investigate neuroadaptive changes associated with reduced expression of the transporter. We are further investigating the interaction that occurs between stress, serotonin transporter genotype and predisposition to depression and alcoholism, as well as resistance to commonly prescribed medications for these disorders.

Another major focus of our studies is the mechanism of MDMA (“Ecstasy”), para-methoxyamphetamine, amphetamine and cocaine at the dopamine and serotonin transporters. The acute and long term effects of these drugs on transporter function in vivo are being studied. In addition, we have more recently demonstrated that hormones, such as insulin, can influence the activity of biogenic amine transporters. Importantly, we have found that insulin status dictates responsiveness to certain drugs of abuse as well as antidepressants. Thus, it appears that insulin can profoundly affect reward and mood circuitry in brain. We are currently investigating the mechanism through which this occurs. These data have important implications for understanding the high-comorbidity of depression, eating disorders and drug abuse as well as food “addictions,” which may lead to obesity.

On a more fundamental level, we are interested in studying how biogenic amine transporters are regulated by receptors. We are currently investigating the role of the 5-HT1B autoreceptor, alpha-adrenoceptors, adenosine receptors and interleukin1-b receptors in regulating activity of the serotonin transporter and of the D2 autoreceptor in regulating activity of the dopamine transporter.

We implement several state-of-the-art techniques including in vivo high-speed chronoamperometry as well as a variety of neurochemical, molecular and behavioral approaches. Dr. Daws’ research group comprises Georgianna Gould (Associate Professor/Research); W. Anthony Owens (Research Scientist), Melissa Vitela (Senior Research Associate), Myrna Herrera-Rosales (Research Associate), Mohamed Basiouny (Research Assistant), Christina George (Research Assistant), Melodi Bowman (graduate student), Valentina Garbarino (graduate student), T. Lee Gilman (post-doctoral fellow), and Audrey Hager (post-doctoral fellow).

Key Words: Serotonin Transporter; Dopamine Transporter; Norepinephrine Transporter, Organic Cation Transporters, Depression; Stress; Drug Abuse; Eating Disorders; In Vivo Chronoamperometry

Lab Members

Graduate Student
Postdoctoral Fellow
Associate Professor – Research
Postdoctoral Fellow
 Myrna Herrera-Rosales
Research Associate
 W. Anthony Owens
Research Scientist
 Melissa Vitela
Research Associate – Senior

Publications

Gasser, P.J., Daws, L.C. (2017) Extending the family: Roles for uptake2 transporters in regulation of monoaminergic signaling. Chemical Neuroanatomy ePub ahead of print, 2017 Oct;83-84:107-108. doi: 10.1016/j.jchemneu.2017.07.009. Epub 2017 Jul 28. No abstract available.

Krause-Heuer, A.M.,† Fraser-Spears, R.†, Dobrowolski, J., Ashford, M.E.,  Wyatt, N.A., Roberts, M.P., Gould, G.G., Cheah, W-C., Ng, C., Bhadbhade, M., Zhang, B., Greguric, I., Wheate, N.J., Kumar, N., Koek, W., Callaghan, P.D., Daws, L.C*., Fraser, B.H.* (2017) Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22. European Journal of Medicinal Chemistry 137:476-487. * co-corresponding authors, contributed equally;  co-first authors

Mitchell, N.C., Bowman, M.A., Gould, G.G., Koek, W., Daws, L.C. (2017) Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice. Journal of Pharmacology and Experimental Therapeutics 360(1):84-94.

Koek, W.,  Sandoval, T.L., Daws, L.C.  (in press) Effects of the antidepressants desipramine and fluvoxamine on latency to immobility and duration of immobility in the forced swim test in adult male C57BL/6J mice.  Behavioural Pharmacology

Sung, U., Savchenko V., Binda F., Owens, W.A., Daws, L.C. (2017)  Ca2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca2+ calmodulin kinases.  Special Issue: Neurotransmitter Transporters in Health and Disease; Journal of Chemical Neuroanatomy, Epub ahead of print.  Journal Cover

Samboa, D., Lin, M., Owens, W.A., Richardson, B., Jagnarine, D.A., Madhur, S., Alonge, T., Ali, M., Katz, J., Febo, M., Henry, K., Bruijnzeel, A.W., Daws, L.C., Khoshbouei, K. (in press) Sigma-1 receptor regulation of dopamine neurotransmission: beyond the surface membrane.  Nature Communications

Koek, W., Mitchell, N.C., Daws, L.C. (in press) Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram’s anxiogenic effects in the novelty-induced hypophagia (NIH) test in mice?  Behavioural Pharmacology Oct 13. doi: 10.1097/FBP.0000000000000345. [Epub ahead of print]

Mitchell, N.C., Owens, W.A.,Vitela, M., Gould, G., Koek, W.,Daws, L.C. (2016) Ontogeny of SERT expression and antidepressant-like response to escitalopram in wild-type and SERT mutant mice. Journal of Pharmacology and Experimental Therapeutics 358(2):271-281.

Mitchell, N.C., Koek, W., Daws, L.C. (2015)  Antidepressant-like effects and basal immobility depend on age and serotonin transporter genotype.  Genes, Brain and Behavior 14(7):543-549

Zhang, W.Q., Smolik, C.M., Barba-Escobedo, P.A., Gamez. M., Sanchez, J.J., Javors, M.A., Daws, L.C., Gould, G.G. (2015) Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three iInbred mouse strains. Neuropharmacology Mar;90:1-8. doi: 10.1016/j.neuropharm.2014.10.024. Epub 2014 Nov 4.

Baladi, M.G., Daws, L.C., France, C.P. (2015)  The impact of eating high fat chow on sensitivity to the locomotor stimulating effects of cocaine and on dopamine clearance in adolescent and adult male rats.  International Journal of Neuropsychopharmacology Mar 24; 18(7):pyv024. doi: 10.1093/ijnp/pyv024.

Montañez, S., Munn, J.L., Owens, W.A., Horton, R.E., Daws, L.C.  (2014)  5-HT1B receptor modulation of the serotonin transporter in vivo: Studies using KO mice.  Neurochemistry International, (Special Issue: The Brain in Flux) 73:127-131.

Lamb, R.J., Pinkston, J.W., Daws, L.C. (2014) Ethanol effects on multiple fixed-interval, fixed-ratio responding in mice with deletions of the serotonin transporter gene.  Behavioral Pharmacology 25(1):92-95

Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, Vitela M, Gould GG, Koek W, Daws LC. J Neurosci. 2013 Jun 19;33(25):10534-43. doi: 10.1523/JNEUROSCI.5687-11.2013. PMID: 23785165 [PubMed – indexed for MEDLINE]

Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release. Rickhag M, Owens WA, Winkler MT, Strandfelt KN, Rathje M, Sørensen G, Andresen B, Madsen KL, Jørgensen TN, Wörthwein G, Woldbye DP, Sitte H, Daws LC, Gether U.J Biol Chem. 2013 Jul 24. [Epub ahead of print] PMID:23884410[PubMed – as supplied by publisher]

Ethanol Self-Administration in Serotonin Transporter Knockout Mice: Unconstrained Demand & Elasticity. Lamb RJ, Daws LC. Genes Brain Behav. 2013 Aug 8. doi: 10.1111/gbb.12068. [Epub ahead of print] PMID: 23927813[PubMed – as supplied by publisher]

Lamb, R.J., Daws, L.C. (2013) Ethanol self-administration in serotonin knockout mice: Unconstrained demand and elasticity. Genes, Brain and Behavior 12(7):741-747.

Mitchell, N.C., Gould, G.G., Smolik, C.M., Koek, W., Daws, L.C. (2013) Antidepressant-like drug effects in juvenile and adolescent mice in the tail suspension test: Relationship with hippocampal serotonin and norepinephrine transporter expression and function. Frontiers in Pharmacology (Neuropharmacology), Special Issue: New frontiers in the neuropsychopharmacology of mental illness. [Epub ahead of print] Oct 28;4:131. doi: 10.3389/fphar.2013.00131. eCollection 2013.

Rickhag, M., Owens, W.A., Winkler M-T.,  Nørgaard-Strandfelt, K., Andresen, B., Sørenesn, G., Madsen, K.L., Wörtwein, G., Woldbye, D., Sitte, H.H., Daws, L.C., Gether, U. (2013) Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release.  Journal of Biological Chemistry 288(38):27534-27544.  *selected as “Paper of the Week”.

Revisiting serotonin reuptake inhibitors and the therapeutic potential of “uptake-2” in psychiatric disorders. Daws LC, Koek W, Mitchell NC. ACS Chem Neurosci. 2013 Jan 16;4(1):16-21. doi: 10.1021/cn3001872. PMID:23336039[PubMed – indexed for MEDLINE]

Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, Vitela M, Gould GG, Koek W, Daws LC. J Neurosci. 2013 Jun 19;33(25):10534-43. doi: 10.1523/JNEUROSCI.5687-11.2013. PMID: 23785165[PubMed – indexed for MEDLINE]

What’s old is new. Andrews AM, Daws LC. ACS Chem Neurosci. 2013 Jan 16;4(1):1-2. doi: 10.1021/cn300229z. No abstract available. PMID: 23336035 [PubMed – indexed for MEDLINE]

Revisiting serotonin reuptake inhibitors and the therapeutic potential of “uptake-2” in psychiatric disorders. Daws LC, Koek W, Mitchell NC. ACS Chem Neurosci. 2013 Jan 16;4(1):16-21. doi: 10.1021/cn3001872. PMID: 23336039 [PubMed – indexed for MEDLINE]

Inhibition of dopamine transporter activity by G protein βγ subunits.Garcia-Olivares J, Torres-Salazar D, Owens WA, Baust T, Siderovski DP, Amara SG, Zhu J, Daws LC, Torres GE. PLoS One. 2013;8(3):e59788. doi: 10.1371/journal.pone.0059788. Epub 2013 Mar 26. PMID: 23555781 [PubMed – in process]

Owens WA, Williams JM, Saunders C, Avison MJ, Galli A, Daws LCRescue of Dopamine Transporter Function in Hypoinsulinemic Rats by a D2 Receptor-ERK-Dependent Mechanism. J Neurosci. 2012 Feb 22;32(8):2637-47

You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists. Baladi MG, Daws LC, France CP. Neuropharmacology. 2012 Jul;63(1):76-86. doi: 10.1016/j.neuropharm.2012.02.005. Epub 2012 Feb 23. Review.PMID: 22710441 [PubMed – indexed for MEDLINE]

Gould G.G., Hensler, J.G., Burke, T.F., Benno, R., Onaivi, E.S. and Daws, L.C. (2011) Density and Function of Central Serotonin (5-HT) Transporters, 5-HT1A and 5-HT2A Receptors, and Effects of their Targeting on BTBR T+tf/J Mouse Social Behavior. Journal of Neurochemistry 116(2):291-303.

Niswender, K., Daws, L.C., Avison, M.J. and Galli, A. (2011) Insulin regulation of monoamine signaling: Pathway to obesity. Neuropsychopharmacology 36:359-360.

Thompson, B.J., Jessen, T., Henry, L.K., Field, J.R., Gamble, K.L., Gresch, P.J., Carneiro, A.M., Horton, R.E., Chisnell, P.J., McMahon, D.G., Daws, L.C. and Blakely, R.D. (2011) Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.Proceedings of the National Academy of Science 108(9):3785-3790

Daws, L.C., Avison, M.J., Robertson, S.D., Niswender, K., Galli, A. and Saunders, C. (2011) Insulin signaling and addiction. Neuropharmacology (Special issue on “Synaptic Plasticity and Addiction”) 61(7):1123-1128.

Daws, L.C. and Gould, G.G. (2011) Ontogeny and regulation of the serotonin transporter: Providing insights into human disorders. Pharmacology and Therapeutics 131(1):61-79.

Siuta, M., Robertson, S., Kocalis, H., Saunders, C., Gresch, P., Khatri, V., Shiota, C., Kennedy, J.P., Lindsley, C., Daws, L.C., Polley, D., Veenstra-Vanderweele, J., Stanwood, G., Magnuson, M., Niswender, K. and Galli, A. (2010) Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal Rictor null mice. Public Library of Science Biology 8(6):e1000393.

Robertson, S.D., Matthies, H.J.G., Owens, W.A., Sathananthan, V., Bibus, N.S., Kennedy, J.P., Lindsley, C.W., Daws, L.C.* and Galli, A.* (2010) Insulin signaling regulation of norepinephrine transporter (NET) surface availability and function, reveals Akt as a novel and potent regulator of the transporter. Journal of Neuroscience 30(34):11305-11316. * contributed equally, co-corresponding authors **Comment in “Letters to the Editor” Lang, U.E., Hortnagl, H., Lang, F. Modulation of norepinephrine brain concentrations through phosphoinositide 3-kinase siganling. Journal of Neuroscience Sept 22, 2011

Zhu, C-B., Lindler, K.M., Owens, W.A., Daws, L.C., Blakely, R.D. and Hewlett, W.A. (2010) IL-1R activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35(13):2510-2520.

Baganz, N.L., Horton, R.E., Martin, K.P., Holmes, A. and Daws, L.C. (2010) Repeated swim impairs serotonin clearance via a corticosterone-sensitive mechanism: Organic cation transporter 3, the smoking gun. Journal of Neuroscience 30(45): 15185-15195.

France CP, Li JX, Owens WA, Koek W, Toney GM, Daws LC. Reduced effectiveness of escitalopram in the forced swimming test is associated with increased serotonin clearance rate in food-restricted rats.Int J Neuropsychopharmacol. 2009 Jul;12(6):731-6.

Sevak RJ, Koek W, Daws LC, Owens WA, Galli A, France CP. Behavioral effects of amphetamine in streptozotocin-treated rats. Eur J Pharmacol. 2008 Feb 26;581(1-2):105-12.

Sevak RJ, Koek W, Owens WA, Galli A, Daws LC, France CP. Feeding conditions differentially affect the neurochemical and behavioral effects of dopaminergic drugs in male rats. Eur J Pharmacol. 2008 Sep 11;592(1-3):109-15.

Baganz NL, Horton RE, Calderon AS, Owens WA, Munn JL, Watts LT, Koldzic-Zivanovic N, Jeske NA, Koek W, Toney GM, Daws LC. Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18976-81.

Sevak RJ, Owens WA, Koek W, Galli A, Daws LC, France CP. Evidence for D2 receptor mediation of amphetamine-induced normalization of locomotion and dopamine transporter function in hypoinsulinemic rats. J Neurochem. 2007 Apr;101(1):151-9.

Price DA, Owens WA, Gould GG, Frazer A, Roberts JL, Daws LC, Giuffrida A. CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem. 2007 Apr;101(2):389-96.

Wiedholz L, Owens WA, Horton RE, Feyder M, Hefner KM, Sprengel R, Daws LC, Holmes A.Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors. Mol Psychiatry. 2007 Aug 7.

Williams JM, Owens WA, Turner GH, Saunders C, Dipace C, Blakely RD, France CP, Gore J.C., Daws LC, Avison MJ, Galli A. Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine. PLoS Biol. 2007 Oct 16;5(10):2369-78.

Daws, L.C., Montañez, S., Munn, J.L., Owens, W.A., Baganz, N.L., Boyce-Rustay J.M., Millstein, R., Wiedholz, L.M., Murphy, D.L. and Holmes, A. Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci. 2006 Jun 14;26(24):6431-8.

Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U. Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron. 2006 Aug 17;51(4):417-29.

Boyce-Rustay JM, Wiedholz LM, Millstein RA, Carroll J, Murphy DL, Daws LC, Holmes A. Ethanol-related behaviors in serotonin transporter knockout mice. Alcohol Clin Exp Res. 2006 Dec;30(12):1957-65.

Daws, L.C. , Montañez, S., Owens, W.A., Gould G.G., Frazer, A., Toney, G.M. and Gerhardt, G.A. (2005) Transport mechanisms governing serotonin clearance in vivo revealed by high speed chronoamperometry. Journal of Neuroscience Methods – Special Issue, Studying monoamine transporters: Beyond hypermonoamineaemia. 143: 49-62.

Owens, W.A., Sevak, R., Galici, R., Chang, X., Javors, M.A., Galli, A., France, C.P. and Daws, L.C.Deficits in dopamine clearance and locomotion in hypoinsulinemic rats unmask novel modulation of dopamine transporters by amphetamine. J Neurochem. 2005 Sep;94(5):1402-10.

Ansah, T.A., Ramamoorthy, S., Montañez, S., Daws, L.C. and Blakely, R.D. (2003) Calcium-dependent inhibition of synaptosomal serotonin transport by the alpha 2-adrenergic receptor agonist UK14304Journal of Pharmacology and Experimental Therapeutics 305:956-965.

Montañez, S., Owens, W.A., Gould, G.G., Murphy, D.L. and Daws, L.C. (2003) Exaggerated effects of fluvoxamine in heterozygote serotonin transporter knockout mice. Journal of Neurochemistry 86:210-219.

Daws, L.C. , Callaghan, P.D., Morón, J., Kahlig, M.K., Shippenberg, T.S., Javitch, J.A. and Galli, A. (2002) Cocaine increases dopamine uptake and cell surface expression of dopamine transporters.Biochemical and Biophysical Research Communications 290(5):1545-1550.

Daws, L.C. , Irvine, R.J., Callaghan, P.D., Toop, N.P., White, J.M. and Bochner, F. (2000) Differential behavioral and neurochemical effects of para-methoxyamphetamine and 3,4- methylenedioxymethamphetamine in ratProgress in Neuro-Psychopharmacology and Biological Psychiatry 24(6): 955-977.

Daws, L.C ., Gould G.G., Teicher, S.D., Gerhardt, G.A. and Frazer, A. (2000) 5-HT 1B receptor-mediated regulation of serotonin clearance in rat hippocampus in vivoJournal of Neurochemistry75(5): 2113-2122.