+ Team Members: Brian Barnett Valerie Cohen Taylor Hearn Emily Jones Reshma Kariyil Alice Kunin Sen Kwak Jessica Lee Brooke Lubinski Gautam Rao Ashley Zhan Research in Testing ADHD's Link to Impulsivity in Neuroscience Mentor: Matthew Roesch TEAM RITALIN

+ Introduction ADHD (Attention Deficit Hyperactivity Disorder) “In 30 years there has been a twentyfold increase in the consumption of drugs for attention-deficit disorder” (Sroufe, 2012) Limited research on the neurobiology of the disorder Diagnoses are made based on subjective, behavioral observations rather than reliable objective identifiers Frequent misdiagnoses and rising medical costs

+ Importance of Our Project No valid animal model of ADHD developed yet Women who smoke during pregnancy are three times as likely to have children diagnosed with ADHD (Linnet et al., 2005) Validating the fetal nicotine rat model to further study ADHD Research valuable to scientists, psychiatrists, pharmacists, drug companies, patients, and relatives of patients

+ Literature Review: Impulsivity Impulsivity Clinical characteristic of ADHD The ability to stop an ongoing or habitual movement Stop-Signal Task Performance is worse in humans with ADHD and in proposed animal models of ADHD (Bari et al., 2011)

+ Literature Review: Neurophysiology Dorsal Prelimbic Cortex (dPL) Previously associated with controlling impulsive behavior Pharmacology Dopamine & DAT Noradrenaline Monoamine oxidase Nicotine (Vertes, 2004)

+ Literature Review: Adderall 25% of all prescriptions written for ADHD (Sallee & Smirnoff, 2004) Composed of D-amphetamine and L-amphetamine Increases the amount of postsynaptic dopamine and noradrenaline Change in conformation and inhibition of dopamine transporter Inhibition of monoamine oxidases A and B

+ Literature Review: Fetal Nicotine Rats Face validity: increased stop-signal reaction time, decreased percent correct stop trials Construct validity: decreased firing in the dPL cortex following stop signal Predictive validity: altered dPL firing and stop-signal performance reversed by Adderall administration (Sontag, Tucha, Wlitza, & Lange, 2009)

+ Research Questions & Hypotheses How will neural firing in the dorsal prelimbic cortex and stop- signal task performance differ between control, fetal nicotine, and Adderall-administered rats? Will these neural differences be sufficient to validate the fetal nicotine rat as an animal model of ADHD? Hypothesis: Fetal nicotine rats will exhibit reduced neural firing in the dPL cortex and worsened stop-signal task performance as compared to the control group. Adderall administration will increase dPL activity and improve task performance in fetal nicotine rats.

+ Methodology: Variables Independent Variables Drug administration Stop-signal timing Dependent Variables Neural recording Task performance Rat behavior Control: Control rats + saline Experimental 1: Fetal Nicotine rats + saline Experimental 2: Fetal Nicotine rats + Adderall Variables Test Groups (Bari et al., 2011) (Schoenbaum, 2000)

+ Methodology: Procedure

+ Timeline Spring 2012 IACUC approval Apply for grants Build electrodes Summer 2012 Fetal Nicotine Pilot Study Fall 2012 Exp. Group 1 Control Group Junior Colloquia Spring 2013 Exp. Group 1 Exp. Group 2 Histology Studies Fall 2013 Data analysis Write Thesis paper Spring 2014 Complete Thesis paper Senior Thesis Conference

+ Anticipated Results & Scientific Impact Physiological & neurotransmitter pathway disruption in inhibiting impulsivity Repaired with Adderall Nicotine exposure as cause of ADHD Fetal nicotine rats as valid model of ADHD Applicable to humans

+ References Bari, A., Mar, A.C., Theobald, D.E., Elands, S.A., Oganya, K.C., Eagle, D.M. & Robbins, T.W. (2011) Prefrontal and monoaminergic contributions to stop-signal task performance in rats. Journal of Neuroscience, 31, Jensen, P.S., Kettle, L., Roper, M.T., Sloan, M.T., Dulcan, M.K., Hoven, C., Bird, H.R., Bauermiester, J.J., & Payne, J.D. (1999). Are stimulants overprescribed? treatment of ADHD in four U.S. communities. Journal of the American Academy of Child & Adolescent Psychiatry, 38, Linnet, K., Wisborg, K., Obel, C., Secher, N.J., Thomsen, P.H., Agerbo, E., & Henriksen, T.B. (2005) Smoking during pregnancy and the risk for hyperkinetic disorder in offspring. Pediatrics, 116(2), Sallee, F. R., & Smirnoff, A. V. (2004). Adderall XR: long acting stimulant for single daily dosing. Expert Review of Neurotherapeutics, 4(6), doi: / Schoenbaum, G. Olfactory Learning and the Neurophysiological Study of Rat Prefrontal Function. In: CRC Series: Methods and Frontiers in Neuroscience. Edited by S.A. Simon and M.A.L. Nicolelis, CRC Press, NY, Sontag, T. A., Tucha, O., Walitza, S., & Lange, K. W. (2010). Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review. ADHD Attention Deficit and Hyperactivity Disorders, 2(1), doi: /s x Sroufe, A. L. (2012, January 28). Ritalin Gone Wrong. The New York Times. Retrieved from term.html?_r=1&pagewanted=all term.html?_r=1&pagewanted=all Vertes, R. P. (2004). Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse DOI /syn

+ Questions?