1. Exercise as an Intervention and Prevention Strategy for Nicotine Use in Adolescents Darlene H. Brunzell, Ph.D. Associate Professor of Pharmacology and Toxicology Virginia Commonwealth University Wendy Lynch, Ph.D. Associate Professor of Psychiatry University of Virginia

2. Why Study Exercise as a Cessation Strategy During Adolescence? nA healthy option to pharmacological therapies that may affect development of the adolescent brain nNicotine and exercise regulate similar hormones and signaling pathways suggesting an overlap of these two systems nPotential secondary benefit to prevent obesity, the second leading preventable cause of death

3. Why Study Sex Differences in Nicotine Use During Adolescence? nAdolescent males and females are different nMost individuals initiate smoking during their teens nThe hormone transition phase during adolescence may provide insight into biological basis of sex differences in smoking behavior observed in adults

4. Rat Nicotine Self Administration as a Model for Adolescent Smoking Like humans smokers, rats voluntarily self administer nicotine Similar to smoking, i.v. administration of nicotine provides fast delivery of the drug to the brain Rodents have similar circulating hormones, brain areas, and neurotransmitters thought to control smoking in humans

5. Behavioral Studies

6. Nicotine Use Nicotine Abstinence ExerciseNicotine Seeking ? Males?Females? Females > Males NIC versus SAL Wheel versus Sedentary Extinction

7. Nicotine-Seeking: Results Males: Exercise attenuates nicotine-seeking during extinction Females: Low levels of nicotine-seeking under both unlocked and locked wheel conditions. Wheel running prevents nicotine seeking? Sanchez et al. 2014 Psychopharmacology

8. Wheel running prevents nicotine seeking Sanchez et al. 2014 Psychopharmacology Males: Exercise attenuates nicotine-seeking during extinction Females: Low levels of nicotine-seeking under both unlocked and locked wheel conditions. Wheel access attenuates nicotine-seeking in females

9. Age (Postnatal Day) Adolescent females rats were more active than males during wheel access PND 45-56 Exercise Wheel 2 hr/day 123456789 10 Number of wheel rotations 0 2000 4000 6000 8000 10000 12345678910 Female NIC Male NIC Female SAL Male SAL 5  g/kg10  g/kg

10. …but exercise-dependent decreases in nicotine seeking were not individually correlated with level of exercise PND 57 Extinction of Nicotine SA Wheel Rotations Number of Lever Presses 0 50 100 150 200 05000100001500020000 r = 0.18 r = 0.01 Female NIC Male NIC

11. A little exercise can go a long way 30 minutes of structured exercises 3 to 4 times a week can improve health and promote weight loss. Those who include exercise in their daily routine not only lose weight quicker but are more likely to keep the weight off.

12. Mechanistic Studies

13. Cytokines, Neurotransmitters, Growth Factors and Second Messengers Regulated by Nicotine and Exercise Species Neurochemical Agent Mediated by Exercise Associated with Nicotine Use/Dependence Human Cytokines TNF- , IL6 IL2, IL6, Growth Factors BDNFTrk2 (BDNF) receptors Neurotransmitters DopamineDopamine, Glutamate transporter Second Messengers ERK (skeletal muscle)ERK (epithelial lung cells) Rodent Cytokines TNF- , IL1 , IL6TNF- , IL1, IL10, IL12 Growth Factors BDNF, NGF, VGFBDNF, FGF2 Neurotransmitters Dopamine, GlutamateDopamine Second Messengers ERK, CREB

14. Mesocorticolimbic Dopamine Pathway Supports the Reinforcing Effects of Nicotine Nucleus Accumbens (NA) Prefrontal Cortex (PFC) Ventral Tegmental Area (VTA)

15. What are the changes in intracellular signaling that support nicotine-associated neural plasticity Nucleus Accumbens (NA) Prefrontal Cortex (PFC) Ventral Tegmental Area (VTA)

16. Exercise and nicotine affect neurotransmitters and neurotrophins that converge on the Extracellular Regulated Kinase (ERK1/2) signaling pathway Brunzell, Drug Abuse Handbook, 2007 BDNF Dopamine CREB

17. Brunzell, Drug Abuse Handbook, 2007 U0126 Is ERK activation necessary for nicotine-associated changes in Signaling and Behavior?

18. Nicotine Use Nicotine Abstinence NIC versus SAL Wheel versus Sedentary Extinction

19. Does ERK 1/2 in the NAc shell regulate nicotine use following protracted abstinence?

20. 20 Modified from Korhonen et al, Tobacco Induced Disease 2005 Pre-Abstinence Post Nicotine-Abstinence Modified from Bedi et al, Biological Psychiatry 2011

21. ERK? BDNF?

22. Exercise as a prevention strategy for nicotine use ExerciseNicotine Use ? Males? NIC versus SALWheel versus Sedentary

23. Acquisition: Experimental Design Exercise: unlocked running Sedentary: (1) locked wheel access (2) no wheel access Acquisition: Experimental Design 22 PND 28 30 45 Acclimation Surgery Exercise: 2-hr/day prior to self-administration Acquisition testing: FR-1schedule, 21-hr/day

24. Acquisition: Results A locked wheel does not affect acquisition Sanchez et al, 2015 Drug and Alcohol Dependence

25. Exercise significantly reduced nicotine reinforcement in male rats A locked wheel does not affect acquisition Exercise robustly decreases acquisition Sanchez et al, 2015 Drug and Alcohol Dependence

26. Exercise reduced motivation to self-administer nicotine Exercise had robust and persistent effects on motivation for nicotine Higher levels of exercise were associated with greater decreases in motivation for nicotine Sanchez et al, 2015 Drug and Alcohol Dependence

27. Does Exercise During Adolescence Protect Against Tobacco Use? Exercise is an effective intervention and prevention strategy to reduce nicotine use during adolescence Exercise and nicotine regulate ERK in the brain areas that support tobacco dependence

28. Acknowledgements Brunzell Lab Karen Boschen Yun Ding Jennifer Lee Lauren Thompson Lynch Lab Florence Breslin Vivian Hofler Victoria Sanchez Justin Polkis Edmund Acevedo Collaborators/Consultants Wendy Lynch