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Opiate and Nicotine Addiction:
Involvement of cAMP Response
Element Binding Protein (CREB)
Matt Wolfe
E-mail: [email protected]
Addiction is a Disease?
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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
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Los Angeles County Jail and New York City Rikers Island
Prison.
Common Terms Associated with Drug Use

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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.
CREB

Transcription factor
– cAMP stimulates its activation
domain

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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
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 blendy
The Journal of Neuroscience (2001)

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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

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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
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
Conditioned place preference
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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.
Results
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Mutant mice do not
exhibit morphineconditioned place
preference
Wild-type mice
administered morphine
prefer the side paired with
morphine
* p < 0.05 from saline
group
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

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.

In vivo nicotine treatment regulates mesocorticolimbic CREB
and ERK signaling in C57B1/6J mice
By: 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.
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
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.
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
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?
References
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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.