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

Matt WolfeMatt WolfeE-mail: mdw204@psu.eduE-mail: mdw204@psu.edu

Addiction is a Disease? Addiction is a Disease? Addiction = compulsive drug craving and administration Addiction = compulsive drug craving and administration

despite horrendous adverse consequences. despite horrendous adverse consequences.

All addictive drugs seem to follow the “final common All addictive drugs seem to follow the “final common pathway” model. This states that, despite different pathway” model. This states that, despite different molecular targets, all result in an increased release and molecular targets, all result in an increased release and dysregulation of synaptic dopamine. dysregulation of synaptic dopamine. – Ventral tegmental area and the nucleus accumbensVentral tegmental area and the nucleus accumbens

Los Angeles County Jail and New York City Rikers Island Los Angeles County Jail and New York City Rikers Island Prison. Prison.

Common Terms Associated with Drug UseCommon Terms Associated with Drug Use

Tolerance:Tolerance: The need for an The need for an increasing dose of opiate to increasing dose of opiate to achieve the same effect.achieve the same effect.

Sensitization:Sensitization: An increasing An increasing effect achieved in response to a effect achieved in response to a constant dose of opiate.constant dose of opiate.

Dependence:Dependence: Altered Altered physiological state produced by physiological state produced by repeated drug administration repeated drug administration Cessation leads to a withdrawal Cessation leads to a withdrawal syndrome. syndrome.

CREBCREB Transcription factorTranscription factor

– cAMP stimulates its activation cAMP stimulates its activation domaindomain

Phosphorylated CREB protein Phosphorylated CREB protein activates transcription by activates transcription by binding to the CRE which is binding to the CRE which is near the genes induced by near the genes induced by cAMP. cAMP.

Similar to signal transducers Similar to signal transducers and activators of transcription and activators of transcription (STAT) protein(STAT) protein

Different requirements for cAMP response element binding Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of protein in positive and negative reinforcing properties of

drugs of abuse. drugs of abuse. By: Carrie L. Walters and Julie A blendyBy: Carrie L. Walters and Julie A blendy

The Journal of Neuroscience (2001)The Journal of Neuroscience (2001)

Examined the role of final common mediators, such as Examined the role of final common mediators, such as CREB in the addiction processCREB in the addiction process

Physical dependences alters signal transductionPhysical dependences alters signal transduction– G-proteins, adenylate cyclase, protein kinase A and its target G-proteins, adenylate cyclase, protein kinase A and its target

CREBCREB CREB may affect positive and negative reinforcing CREB may affect positive and negative reinforcing

properties of drugsproperties of drugs CREB is critical for the manifestation of the physical signs CREB is critical for the manifestation of the physical signs

of opiate withdrawal, but its role is not knownof opiate withdrawal, but its role is not known

The ExperimentThe Experiment In both the locus coeruleus and nucleus accumbens, the In both the locus coeruleus and nucleus accumbens, the

cAMP pathway was upregulated after chronic morphinecAMP pathway was upregulated after chronic morphine

To investigate the role of CREB behavior in drug seeking To investigate the role of CREB behavior in drug seeking and reinstatement, the authors examined the sensitization and reinstatement, the authors examined the sensitization to the locomotor effects induced by repeated cocaine to the locomotor effects induced by repeated cocaine administration in CREBadministration in CREB mutant mice. mutant mice.

Mutants have decreased CREB bindingMutants have decreased CREB binding

Conditioned place preferenceConditioned place preference Animals subcutaneously implanted with one morphine Animals subcutaneously implanted with one morphine

pellet to induce dependencepellet to induce dependence Preconditioning phase:Preconditioning phase: Placed in one side of box and Placed in one side of box and

allowed to roam freely, determine side biases of the miceallowed to roam freely, determine side biases of the mice Conditioning Phase:Conditioning Phase: 8 days, one group received saline 8 days, one group received saline

on both sides of box, other group received morphine on on both sides of box, other group received morphine on one side and saline on opposite one side and saline on opposite

Testing Phase:Testing Phase: Test day, all animals receive saline Test day, all animals receive saline injections and allowed to roam freely on both sides of box. injections and allowed to roam freely on both sides of box. Time spent on each side recorded. Time spent on each side recorded.

ResultsResults Mutant mice do not Mutant mice do not

exhibit morphine-exhibit morphine-conditioned place conditioned place preferencepreference

Wild-type mice Wild-type mice administered morphine administered morphine prefer the side paired with prefer the side paired with morphinemorphine

* p < 0.05 from saline * p < 0.05 from saline groupgroup

ConclusionConclusion

CREB deficient mice do not respond to the CREB deficient mice do not respond to the reinforcing properties of morphine in a reinforcing properties of morphine in a conditioned place preference paradigm. conditioned place preference paradigm.

Maybe a possible genetic linkMaybe a possible genetic link Also, the rewarding and aversive properties Also, the rewarding and aversive properties

of drugs of abuse (morphine) can be of drugs of abuse (morphine) can be separated geneticallyseparated genetically

But, opioids aren’t the only But, opioids aren’t the only addictive drugs…addictive drugs…

TobaccoTobacco Each year 1 million people attempt to quitEach year 1 million people attempt to quit Only 15% do so for a full yearOnly 15% do so for a full year Genetic vs. Development factorsGenetic vs. Development factors Twin StudiesTwin Studies CDC 2001 – smoking is the single greatest CDC 2001 – smoking is the single greatest

cause of preventable death in the U.S. cause of preventable death in the U.S.

In vivo nicotine treatment regulates mesocorticolimbic CREB In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57B1/6J miceand ERK signaling in C57B1/6J mice

By: Brunzell, D.H., Russell, D.S., and Picciotto, M. R.By: Brunzell, D.H., Russell, D.S., and Picciotto, M. R.Journal of Neurochemistry (2003)Journal of Neurochemistry (2003)

CREB phosphorylation was reduced in the nucleus CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity previous reports that decreased accumbens CREB activity increases drug reinforcment. increases drug reinforcment.

Also, CREB phosphorylation was increased in the Also, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during withdrawal. in the ventral tegmental area during withdrawal.

ExperimentExperiment

Acute Study: Mice given either 200Acute Study: Mice given either 200g/mL g/mL nicotine in 2% saccharin or saccharin alone, drank nicotine in 2% saccharin or saccharin alone, drank within two minutes, brains harvested 1.3 hours within two minutes, brains harvested 1.3 hours laterlater

Chronic Treatment and Withdrawal Study: Mice Chronic Treatment and Withdrawal Study: Mice given similar doses for 28-30 days, brains given similar doses for 28-30 days, brains harvestedharvested– Withdrawal group: Nicotine solution replaced with a 2% Withdrawal group: Nicotine solution replaced with a 2%

saccharin solution 24 hours prior to decapitationsaccharin solution 24 hours prior to decapitation

ResultsResults Nucleus Accumbens (NAC): acute nicotine exposure Nucleus Accumbens (NAC): acute nicotine exposure

increased CREB levels significantlyincreased CREB levels significantly– Chronic nicotine also resulted in an increase in total Chronic nicotine also resulted in an increase in total

CREB, but also a decrease in pCREBCREB, but also a decrease in pCREB– Levels of CREB were still elevated following 24 hours Levels of CREB were still elevated following 24 hours

of withdrawalof withdrawal

Decrease in ratio of pCREB/CREB in the NAC following Decrease in ratio of pCREB/CREB in the NAC following chronic nicotine exposure is consistent with studies that chronic nicotine exposure is consistent with studies that have shown that this decrease contributes to drug have shown that this decrease contributes to drug reinforcement. reinforcement.

Conclusions:Conclusions: Increased CREB activity Increased CREB activity

counteracts drug reinforcementcounteracts drug reinforcement CREB may be dependent on CREB may be dependent on

ERK activationERK activation Further studies needed to define Further studies needed to define

the specific roles of ERK and the specific roles of ERK and CREB activation in behaviors CREB activation in behaviors surrounding nicotine addictionsurrounding nicotine addiction

ImportanceImportance

Need to understand the mechanisms of Need to understand the mechanisms of addiction to provide better treatment and addiction to provide better treatment and maintenance of a healthy lifestylemaintenance of a healthy lifestyle

Why is drug abuse considered more of a Why is drug abuse considered more of a crime than an illness? crime than an illness?

ReferencesReferences Google Images: Google Images: Keith RichardsKeith Richards Accessed April 1, 2003 Accessed April 1, 2003 Brunzell, D.H., Russell, D.S., and Picciotto, M. R. (2003) In vivo Brunzell, D.H., Russell, D.S., and Picciotto, M. R. (2003) In vivo

nicotine treatment regulates mesocorticolimbic CREB and ERK nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57B1/6J mice.signaling in C57B1/6J mice.Journal of Neurochemistry, 84, 1431-1441. Journal of Neurochemistry, 84, 1431-1441.

Halpern, J.H. (2002) Addiction is a disease. Psychiatric Times, XIX, Halpern, J.H. (2002) Addiction is a disease. Psychiatric Times, XIX, issue 10. issue 10.

Walters, C.L., and Blendy, J.A. (2001) Different requirements for Walters, C.L., and Blendy, J.A. (2001) Different requirements for cAMP response element binding protein in postitive and negative cAMP response element binding protein in postitive and negative reinforcing properties of drugs of abuse. reinforcing properties of drugs of abuse. The Journal of The Journal of NeuroscienceNeuroscience, 23, 9438-9444. , 23, 9438-9444.

Becker, W. M., Kleinsmith, L.J., and Hardin, J. Becker, W. M., Kleinsmith, L.J., and Hardin, J. The World of the CellThe World of the Cell—4—4thth ed ed. Addison Wesley Longman, Inc., 2000. . Addison Wesley Longman, Inc., 2000.