Opiate and Nicotine Addiction: Involvement of cAMP Response Element Binding Protein (CREB)

1. Opiate and Nicotine Addiction: Involvement of cAMP Response Element Binding Protein (CREB) Matt Wolfe E-mail: mdw204@psu.edu

2. Addiction is a Disease? • Addiction = compulsive drug craving and administration despite horrendous adverse consequences. • All addictive drugs seem to follow the “final common pathway” model. This states that, despite different molecular targets, all result in an increased release and dysregulation of synaptic dopamine. • Ventral tegmental area and the nucleus accumbens • Los Angeles County Jail and New York City Rikers Island Prison.

3. Common Terms Associated with Drug Use • Tolerance: The need for an increasing dose of opiate to achieve the same effect. • Sensitization: An increasing effect achieved in response to a constant dose of opiate. • Dependence: Altered physiological state produced by repeated drug administration  Cessation leads to a withdrawal syndrome.

4. CREB • Transcription factor • cAMP stimulates its activation domain • Phosphorylated CREB protein activates transcription by binding to the CRE which is near the genes induced by cAMP. • Similar to signal transducers and activators of transcription (STAT) protein

5. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. By: Carrie L. Walters and Julie A blendyThe Journal of Neuroscience (2001) • Examined the role of final common mediators, such as CREB in the addiction process • Physical dependences alters signal transduction • G-proteins, adenylate cyclase, protein kinase A and its target CREB • CREB may affect positive and negative reinforcing properties of drugs • CREB is critical for the manifestation of the physical signs of opiate withdrawal, but its role is not known

7. The Experiment • In both the locus coeruleus and nucleus accumbens, the cAMP pathway was upregulated after chronic morphine • To investigate the role of CREB behavior in drug seeking and reinstatement, the authors examined the sensitization to the locomotor effects induced by repeated cocaine administration in CREB mutant mice. • Mutants have decreased CREB binding

8. Conditioned place preference • Animals subcutaneously implanted with one morphine pellet to induce dependence • Preconditioning phase: Placed in one side of box and allowed to roam freely, determine side biases of the mice • Conditioning Phase: 8 days, one group received saline on both sides of box, other group received morphine on one side and saline on opposite • Testing Phase: Test day, all animals receive saline injections and allowed to roam freely on both sides of box. Time spent on each side recorded.

9. Results • Mutant mice do not exhibit morphine-conditioned place preference • Wild-type mice administered morphine prefer the side paired with morphine • * p < 0.05 from saline group

10. Conclusion • CREB deficient mice do not respond to the reinforcing properties of morphine in a conditioned place preference paradigm. • Maybe a possible genetic link • Also, the rewarding and aversive properties of drugs of abuse (morphine) can be separated genetically

11. But, opioids aren’t the only addictive drugs… • Tobacco • Each year 1 million people attempt to quit • Only 15% do so for a full year • Genetic vs. Development factors • Twin Studies • CDC 2001 – smoking is the single greatest cause of preventable death in the U.S.

12. In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57B1/6J miceBy: Brunzell, D.H., Russell, D.S., and Picciotto, M. R.Journal of Neurochemistry (2003) • CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity increases drug reinforcment. • Also, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during withdrawal.

13. Experiment • Acute Study: Mice given either 200g/mL nicotine in 2% saccharin or saccharin alone, drank within two minutes, brains harvested 1.3 hours later • Chronic Treatment and Withdrawal Study: Mice given similar doses for 28-30 days, brains harvested • Withdrawal group: Nicotine solution replaced with a 2% saccharin solution 24 hours prior to decapitation

14. Results • Nucleus Accumbens (NAC): acute nicotine exposure increased CREB levels significantly • Chronic nicotine also resulted in an increase in total CREB, but also a decrease in pCREB • Levels of CREB were still elevated following 24 hours of withdrawal • Decrease in ratio of pCREB/CREB in the NAC following chronic nicotine exposure is consistent with studies that have shown that this decrease contributes to drug reinforcement.

16. Conclusions: • Increased CREB activity counteracts drug reinforcement • CREB may be dependent on ERK activation • Further studies needed to define the specific roles of ERK and CREB activation in behaviors surrounding nicotine addiction

17. Importance • Need to understand the mechanisms of addiction to provide better treatment and maintenance of a healthy lifestyle • Why is drug abuse considered more of a crime than an illness?

18. References • Google Images: Keith Richards Accessed April 1, 2003 • Brunzell, D.H., Russell, D.S., and Picciotto, M. R. (2003) In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57B1/6J mice.Journal of Neurochemistry, 84, 1431-1441. • Halpern, J.H. (2002) Addiction is a disease. Psychiatric Times, XIX, issue 10. • Walters, C.L., and Blendy, J.A. (2001) Different requirements for cAMP response element binding protein in postitive and negative reinforcing properties of drugs of abuse. The Journal of Neuroscience, 23, 9438-9444. • Becker, W. M., Kleinsmith, L.J., and Hardin, J. The World of the Cell—4th ed. Addison Wesley Longman, Inc., 2000.