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Daniel McGehee, PhD University of Chicago Department of Anesthesia & Critical Care

Synaptic Mechanisms Underlying Nicotine-Induced Excitation of Brain Reward Areas. Daniel McGehee, PhD University of Chicago Department of Anesthesia & Critical Care Committee on Neurobiology Committee on Cell Physiology. Nicotiana tobacum. (North, Central, and South America)

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Daniel McGehee, PhD University of Chicago Department of Anesthesia & Critical Care

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  1. Synaptic Mechanisms Underlying Nicotine-Induced Excitation of Brain Reward Areas Daniel McGehee, PhD University of Chicago Department of Anesthesia & Critical Care Committee on Neurobiology Committee on Cell Physiology

  2. Nicotiana tobacum (North, Central, and South America) Active Component: Nicotine Leaves 0.5-9% nicotine dry weight 40-60 mg lethal in humans 430,000 deaths/ year in U.S. are from smoking related causes $150 billion in medical costs and lost productivity per year ~75% of adult smokers “want to quit” Only a few percent succeed.

  3. Predicted stoichiometry of neuronal nAChRs Subunits a7 a4b2 predominate in CNS Antagonists MLA*, aBGT b2 - DHbE All - MEC Agonists Choline b2 - epibatidine PCa/PNa ~20 ~1.5

  4. The Dopamine Reward System Horizontal slice preparation

  5. Where are the nAChRs that enhance DA release?

  6. Dopamine cells in the VTA express Ih -60 mV -120 mV 50 pA 250 ms

  7. Nicotine enhances excitatory inputs to VTA DA neurons +DNQX 1 mM nicotine EPSC amplitude (%) control 25 pA nicotine 10 ms Time (s) +MLA Control 1 mM nicotine 1 mM nicotine EPSCs / 5 sec 1 mM nicotine Time (s) Time (s)

  8. Presynaptic a7 nAChRs enhance glutamate release Nic

  9. Pairing of pre- and postsynaptic activity induces LTP in VTA Pairing protocol: 1 second post EPSC amplitude (%) pre Time (min)

  10. Pairing nicotine with post-synaptic activation induces LTP post pre 1 mM nicotine

  11. Presynaptic a7 nAChRs contribute to LTP induction in VTA nAChRs?

  12. MEC TTX nicotine IPSCs / 5 sec Nicotine increases spontaneousGABA transmission in the VTA

  13. GABA transmission is modified by non-a7 nAChRs

  14. Nicotine enhances and then depresses GABAergic synaptic transmission

  15. Low nicotine concentrations desensitize nAChRs on GABA neurons 1 mM nicotine 250 nM nicotine Effect of 1 mM nicotine (%) IPSCs per 5 sec * * Time (s) [nicotine] (nM)

  16. Timecourse of nicotine effects in the brain reward areas during smoking LTP Adapted from Henningfield et al 1993

  17. PPTg X

  18. Bupropion • An atypical antidepressant recently approved as a smoking cessation aid. • Mechanism of action is unknown. • Weak DAT inhibitor. • Broad-spectrum antagonist of nAChRs.

  19. Bupropion Blocks nAChRs on VTA DA Neurons

  20. Bupropion Blocks nAChR Modulation of Excitatory Input to VTA DA Neurons

  21. Bupropion Blocks nAChR Modulation of Inhibitory Input to VTA DA Neurons

  22. Bupropion Also Reduces the Basal Frequency of Spontaneous IPSCs

  23. Buproprion effects are not due to DAT inhibition

  24. Bupropion limits nAChR activity within brain reward pathways X X

  25. Age-Dependent Differences in Susceptibility Drug Abuse

  26. Adults Show Lower Sensitivity to Nicotine Than Young Rats EPSC Response to 1mM Nicotine IPSC Response to 1mM Nicotine 400 600 500 300 400 * Frequency (% Control) Frequency (% Control) 200 300 * 200 100 100 0 0 Adult Pup Adult Pup 70 120 60 100 50 80 40 Response Prevalence Response Prevalence 60 30 40 20 20 10 0 0 Adult Pup Adult Pup

  27. The McGehee Lab Huib Mansvelder Jonathan Genzen J. Russel Keath Edward Lin Lindy Nakamura Amiinah Kung Wendy Chan Dan Locks Hong Cheng Katrina Oppen Greg Sobolski Wil Van Cleve Dan McGehee Zara Fettig Mike Iacoviello Ben Chang Ben Cho Michelle Madonia Sonya Dave Funding from NIDA, NINDS and The Brain Research Foundation

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