Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in

1. Jacob P. Waletzky Memorial Lecture Experience-Dependent Alterations in the Function of Brain Reward Systems: The Role of CREB William A. Carlezon, Jr., Ph.D. Behavioral Genetics Laboratory Department of Psychiatry Harvard Medical School McLean Hospital

2. Addiction and Depressive Disorders • High rates of co-morbidity in both men and women (Kessler et al., 1997). • Causal relationships can be difficult to establish. • Addictive behaviors and depressive disorders have common triggers (e.g., stress). • Studies of addiction may give us insights on depressive disorders, and vice-versa.

3. Working Hypothesis Addiction and Depressive Disorders Involve Brain Reward Systems

4. Happy Hopeless Grumpy Listless Sad Worried Mood in Rodents?

5. Mood in Rodents? Happy Hopeless Grumpy Reward Despair Dysphoria Listless Sad Worried Anhedonia Hypoactivity Anxiety

6. Mood in Rodents • reward (feelings of pleasure) • anhedonia (reduced ability to experience rewarding things as rewarding) • dysphoria (feelings of discomfort) • despair (feelings of giving up) • anxiety (feelings of apprehension, fear) • hypoactivity (less active than normal)

7. Overview 1. CREB 2. Functional role of CREB in the NAc 3. CREB and dynorphin 4. Kappa antagonists and agonists

8. Overview 1. CREB 2. Functional role of CREB in the NAc 3. CREB and dynorphin 4. Kappa antagonists and agonists

9. CREB (cAMP Response Element Binding Protein)

10. Addictive Drugs Regulate CREB in the NAc CREB phosphorylation Turgeon et al., 1997

11. Drug Regulation of CREB Are there behavioral correlates of CREB activity in the NAc? • Drug tolerance? • Drug sensitization?

12. Elevation of CREB with Engineered Viruses CREB VTA NAc

13. Elevation of CREB with Engineered Viruses CREB VTA NAc

14. Blockade of CREB Function By Overexpression of mCREB with Engineered Viruses mCREB VTA NAc

15. a HSV-1 packaging site pBR 322 Amp SV-40 polyadenylation site Col E1 ori pHSV PrpUC oris IE 4/5 Promoter HSV-1 c Region cDNA (e.g. CREB, mCREB, LacZ) (Neve Lab)

16. Gene Transfer Using Viral Vectors Increased Protein Expression Minimal Damage

17. Overview 1. CREB 2. Functional role of CREB in the NAc 3. CREB and dynorphin 4. Kappa antagonists and agonists

18. Measurement of Drug Reward (and Aversion)

19. Anhedonia Dysphoria Effect of CREB Over Cocaine Doses Change in Time Spent in Drug Side (sec) Carlezon et al., 1998

20. Intracranial Self-Stimulation (ICSS) in mCREB transgenic mice

21. Aversive/Prodepressants (drug withdrawal, lithium, neuroleptics) Drugs of Abuse (amphetamine, cocaine, opiates, PCP, nicotine) ICSS Thresholds 100%

22. Intracranial Self-Stimulation (ICSS) in mCREB transgenic mice

23. Forced Swim Test (FST) Immobile Swimming

24. Elevated CREB Increases Immobility in the FST Latency to Immobility Locomotor Activity Time (sec) Beam Breaks (1 hr) CREB-On = More Depressive-like Signs CREB-Off = Fewer Depressive-like Signs

25. Forced Swim Test (FST) Immobile Swimming

26. Forced Swimming Activates CREB in the NAc Induction (swim / no swim) CREB in the NAc normally plays a role in reacting to stress Pliakas et al., 2001

27. Biology & Behavior CREB In NAc Drugs Stress Depressive Behavior CREB Target Genes

28. CREB (cAMP Response Element Binding Protein)

29. Overview 1. CREB 2. Functional role of CREB in the NAc 3. CREB and dynorphin 4. Kappa antagonists and agonists

30. Dynorphin • It is a kappa opioid receptor ligand (Chavkin et al., 1982) • It has CRE sites in its promoter (Douglass et al., 1994) • It is regulated by drugs of abuse (Hurd and Herkenham, 1993; Daunais et al., 1993; Cole et al., 1995) • Kappa agonists are aversive in people (Pfeiffer et al., 1986) • Kappa agonists are aversive rats (Bals-Kubik et al., 1993)

31. CREB Increases Dynorphin mRNA in the NAc CREB-On = More Dynorphin CREB-Off = Less Dynorphin Carlezon et al., 1998

32. Stress Increases Dynorphin mRNA in the NAc Stress = More Dynorphin Chartoff et al., unpublished

33. Biology & Behavior Drugs Stress CREB In NAc Depressive Behaviors

34. Biology & Behavior Drugs Stress CREB In NAc Depressive Behaviors dynorphin Clinical Implications

35. Overview 1. CREB 2. Functional role of CREB in the NAc 3. CREB and dynorphin 4. Kappa antagonists and agonists

36. U-69593 (kappa agonist) increases immobility and decreases swimming Mague et al., 2003

37. ANTI (IP) decreases immobility and increases climbing *ANTI: 5’-acetamidinoethylnaltrindole Mague et al., 2003

38. Proposed Circuitry Carlezon et al., 2000

39. Proposed Circuitry X X Carlezon et al., 2000

40. Proposed Circuitry X X Carlezon et al., 2000

41. Kappa-selective agonist O O O O O O O O Salvinorin A (kappa agonist) (Roth et al., 2002 )

42. Salvinorin A Microdialysis (NAc) (Carlezon et al., 2005)

43. Abuse Liability of Kappa Antagonists?

44. Effect of kappa ligands on ICSS

45. Effect of kappa ligands on ICSS

46. Effect of kappa ligands on ICSS

47. Effect of kappa ligands on ICSS

48. Medicinal Chemistry Program O Furan-ring derivatives O C2 derivatives O Lactone-ring derivatives O O O O O C4 derivatives Salvinorin A (kappa agonist)

49. Does CREB in the NAc Regulate Mood? Carlezon & Konradi, 2004

50. Acknowledgements Carlezon Lab Andrea Pliakas Andreas Arvanitogiannis Rebecca Ralph-Williams Sonia Guediche Steve Mague Brian Gilliss Elena Chartoff Hilarie Tomasiewicz Mark Todtenkopf Edward Meloni Alexandra Jackson Jacqueline Marcus Maria Papadopoulou Jennifer DiNieri Katie Famous Andrew Smith Jessica Pohlman Aram Parsegian Melissa Stoos Lyle Gerety Tracie Paine Dost Ongur Allison Knoll Matthew Barhight Antonia Dow McLean Labs Bruce Cohen, Christine Konradi Rachael Neve, Susan Andersen Funding Sources NIDA, NIMH, NARSAD