The role of endogenous opioid peptides in cocaine reward

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The role of endogenous opioid peptides in cocaine
reward

• Kabirullah Lutfy, Ph.D.
• July 31, 2009

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Outline1. Cocaine addiction2. Brain reward
circuitry3. Endogenous Opioids4. Animal models
of reward Conditioned Place Preference (CPP) 5.
The role of endogenous opioid peptides in cocaine
reward
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Learning Objectives
The purpose of this talk is to

• introduce to you concepts such as, addiction, the
  brain reward circuitry, and the endogenous opioid
  system.

• familiarize you with animal models of
  reward/reinforcement.

• inform you about our research on the role of the
  endogenous opioid peptides in the rewarding
  actions of cocaine.

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Addiction
Addiction is a major health issue costing
addicts their jobs, personal relationships,
financial burdens, happiness and, in some cases,
their lives.
Line of cocaine in shape of death skull
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Addiction
Addiction is defined as a chronic relapsing brain
disorder that results from neuronal plastic
changes along numerous circuits, leading to
dysregulation of the hedonic homeostasis.
It also affects the decision making center.
The transition from drug use to compulsive drug
use/abuse involves conditioned learning.
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The mesolimbic reward circuitry
The mesolimbic dopaminergic neurons mediate the
rewarding action of natural and drug reward
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The endogenous opioid system has long been known
as a principal regulator of the mesolimbic
dopaminergic neurons (Belluzzi and Stein, 1977).
The endogenous opioid system Cocaine Addiction

• There is a growing body of evidence implicating
  the endogenous opioid system in the rewarding and
  addictive actions of cocaine.

• Opioid antagonists have been shown to reduce the
  motor stimulatory and rewarding actions of
  cocaine (Houdi et al., 1989), raising the
  possibility that endogenous opioid peptides play
  a functional role in the rewarding action of
  cocaine.

• However, it is not known which one of the opioid
  peptides is involved in the action of cocaine.

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consists of opioid peptides and their
corresponding receptors.Opioid peptide family
Precursor 1. beta-endorphin
proopiomelanocortin (POMC) 2. enkephalins
proenkephalin (pENK) 3. dynorphins
prodynorphin (pDYN) 4. endomorphins
unknown Opioid peptide family Opioid
receptor class 1. beta-endorphin mu opioid
receptors 2. enkephalins delta
opioid receptors 3. dynorphins
kappa opioid receptors 4. endomorphins mu
opioid receptors
The endogenous opioid system
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Hypothesis 1 beta-Endorphin plays a functional
role in the rewarding action of cocaine.

• Cocaine administration increases the level of
  beta-endorphin in the nucleus accumbens (Olive et
  al., 2001).

• Administration of opiates in the nucleus
  accumbens is rewarding (Kelsey et al., 1989,
  Wise, 1989).

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Materials Methods

• Subjects
• Male mice lacking one of the opioid peptides or
  mu opioid receptor and their respective wild-type
  littermates were used.
• Animal model of reward
• A single conditioning CPP paradigm was used to
  measure the rewarding action of acute cocaine (30
  mg/kg) or morphine (10 mg/kg).

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Materials Methods

• The CPP protocol that we used consisted of
• Preconditioning (day 1 D1)
• Conditioning (days 2 3)
• Saline/Cocaine or Cocaine/Saline
• Postconditioning (day 4 D4)

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Preconditioning Test
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Conditioning Phase
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Postconditioning Test
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Cocaine CPP in mice lacking beta-endorphin
(betaend-) wild-types (betaend)
Marquez et al., Psychopharmacology 197 443-448,
2008
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Morphine CPP in beta-endorphin deficient
(betaend-) wild-types (betaend)
Marquez et al., Psychopharmacology 197 443-448,
2008
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Cocaine CPP in mice lacking enkephalins (pENK-/-)
and wild-types (pENK/)
Marquez Lutfy, unpublished data
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Cocaine CPP in mice lacking dynorphins (pDYN-/-)
wild-types (pDYN/)
Marquez Lutfy, unpublished data
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Summary
1. Cocaine CPP was attenuated in beta-endorphin
deficient mice.
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Summary
1. Cocaine CPP was attenuated in beta-endorphin
deficient mice.
2. Morphine CPP was not affected in mice lacking
beta-endorphin.
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Summary
1. Cocaine CPP was attenuated in beta-endorphin
deficient mice.
2. Morphine CPP was not affected in mice lacking
beta-endorphin.
3. Cocaine CPP was not altered in mice lacking
enkephalins or dynorphins.
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Does the mu receptor mediate the regulatory
actions of endogenous beta-endorphin on cocaine
CPP?
Given that cocaine CPP was altered in
beta-endorphin deficient mice and beta-endorphin
is considered as an endogenous ligand of the mu
opioid receptor, we determined the rewarding
action of acute cocaine in mice lacking the mu
opioid receptors and their wild-type littermates.
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Morphine CPP in mice lacking mu opioid receptor
(MOR-/-) wild-types (MOR/)
Marquez Lutfy, unpublished data
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Cocaine CPP in mice lacking the mu opioid
receptor (MOR-/-) wild-types (MOR/)
Marquez Lutfy, unpublished data
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Summary
1. Cocaine CPP was not altered in mice lacking
the mu opioid receptor.
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Summary
1. Cocaine CPP was not altered in mice lacking
the mu opioid receptor.
2. Morphine CPP was abolished in mice lacking the
mu opioid receptor.
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Conclusion

• The endogenous opioid peptide beta-endorphin is
  selectively involved in the rewarding action of
  acute cocaine because cocaine-induced but not
  morphine-induced CPP was altered in mice lacking
  beta-endorphin.

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Conclusion

• The endogenous opioid peptide beta-endorphin is
  selectively involved in the rewarding action of
  acute cocaine because cocaine-induced but not
  morphine-induced CPP was altered in mice lacking
  beta-endorphin.

• Enkephalins and dynorphins may not play a
  functional role in the rewarding action of acute
  cocaine because cocaine CPP was not altered in
  mice lacking dynorphins or enkephalins.

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Conclusion

• The mu opioid receptor may not mediate the
  regulatory action of endogenous beta-endorphin on
  the rewarding action of acute cocaine because
  cocaine CPP was not altered in mice lacking the
  mu opioid receptor.

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Conclusion

• The mu opioid receptor may not mediate the
  regulatory action of endogenous beta-endorphin on
  the rewarding action of acute cocaine because
  cocaine CPP was not altered in mice lacking the
  mu opioid receptor.

• It is possible that the mu receptor knockout mice
  lack the subtype of the mu receptor mediating the
  actions of morphine but not that of
  beta-endorphin.

• Alternatively, it may be that endogenous
  beta-endorphin acts via a different receptor than
  mu receptor.

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Acknowledgments

• Paul Marquez
• Abdul Hamid
• Alex T. Nguyen
• Drupad Parikh
• Khanh Nguyen

Emelia Agazadeh Parastoo Darakhshanian Ibrahim
Dabaja Duc Le Dr. Friedman Dr. Nazarian NIDA R01
DA016682 R24 DA017298 (MIDARP) WesternU
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Thank you for your attention

• Any questions?