CrossTalk Between Cannabinoid and Opioid Systems

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Cross-Talk Between Cannabinoid and Opioid Systems

• Steven R. Goldberg, Ph.D.

Preclinical Pharmacology Section Behavioral
Neuroscience Research Branch Intramural Research
Program National Institute on Drug Abuse National
Institutes of Health, DHHS Baltimore, Maryland,
USA
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Cross-Talk Between Cannabinoid and Opioid Systems

• There is increasing experimental evidence from
  animal studies for reciprocal functional
  interactions between endogenous brain cannabinoid
  and opioid systems in the regulation of many
  physiological and behavioral processes
• Major bi-directional interactions have been found
  between cannabinoid and opioid systems in drug
  reinforcement/reward processes

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Recent Research at NIDA on Opioid-Cannabinoid
Interactions

• Reinforcement of drug-taking and drug-seeking
  behavior by THC and its modulation by opioid
  agonists and antagonists
• Modulation of subjective responses to THC by
  opioid agonists and antagonists, as measured by a
  drug-discrimination procedure
• THC induced changes in extracellular levels of
  endogenous opioids in brain areas associated with
  reinforcing effects of cannabinoids and opioids

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Fixed-Ratio Schedule of Intravenous THC Injection
in Squirrel Monkeys

• During daily one-hour sessions, every 10th lever
  press by the monkey produced an intravenous
  injection of 4 µg/kg of THC followed by a
  60-second timeout
• When responding was stable, vehicle and different
  doses of THC were studied by substitution for 5
  consecutive sessions

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THC self-administration in drug-naïve squirrel
monkeys(means S.E.M. n 3)
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Fixed-Ratio Schedule of Anandamide Injection in
Squirrel Monkeys

• Previous studies suggest that endogenous
  cannabinoid systems play a role in brain
  reward/reinforcement processes
• We have studied the effectiveness of the
  endogenous cannabinoid anandamide as a reinforcer
  of intravenous drug-taking behavior in squirrel
  monkeys

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Self-administration of the endogenous cannabinoid
anandamide in squirrel monkeys (means S.E.M.
n 4)
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SUMMARY I

• Our studies provide the first clear
  demonstrations that THC, the main psychoactive
  ingredient in marijuana, and anandamide, an
  endogenous cannabinoid, can serve as effective
  reinforcers of drug-taking behavior
• These findings provide direct evidence for
  involvement of endogenous cannabinoid systems in
  brain reward processes

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Opioid-Cannabinoid InteractionsModulation of
the reinforcing effects of THC in squirrel monkeys
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Fixed-Ratio Schedule of THC or cocaine
InjectionOpioid Antagonist Pretreatment (n 4)
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Fixed-Ratio Schedule of THC InjectionOpioid
Antagonist Pretreatment (n 4)
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Second-Order Schedule of Intravenous THC
Injection in Squirrel Monkeys

• Provides a measure of drug-seeking behavior in
  the absence of the direct pharmacological effects
  of the drug
• Every 10th lever press produces a brief 2-second
  flash of a light (a 10-response fixed-ratio
  schedule FR 10)
• The first 10-response fixed-ratio completed after
  a 30-minute interval of time elapses produces
  both the light and an intravenous injection of
  THC and ends the daily session

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Second-Order Schedule of THC Injection (n 5)
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Second-Order Schedule of THC Injection
Cannabinoid CB1 antagonist treatment (n 4)
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Second-Order Schedule of THC InjectionOpioid
Antagonist Pretreatment (n 3)
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Reinstatement of Extinguished THC-Seeking
Behavior
N 4
N 3
N 3
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SUMMARY II

• THCs reinforcing effects under both fixed-ratio
  and second-order schedules are reduced by
  treatment with an opioid antagonist
• Extinguished THC-seeking behavior can be
  reinstated by a pre-session priming injection of
  the opioid agonist morphine

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Opioid-Cannabinoid InteractionsModulation of
the subjective response to THC in rats

• The ability of drugs of abuse such as cannabis to
  produce effects that can be clearly discriminated
  is central to reinforcement of drug-taking
  behavior
• Drug-discrimination procedures provide subjective
  reports of the degree to which effects of
  administered doses of test compounds are like or
  unlike those of a training dose of THC
  previously received

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Drug Discrimination in Rats

• Two-lever choice schedule of food delivery
• Rats learn to press one lever for food on days
  they receive a pre-session injection of 3 mg/kg
  THC and the other lever on days they receive a
  pre-session injection of vehicle

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Morphine potentiates and naloxone reduces THC
discrimination
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Injection of the mu1 selective opioid antagonist
naloxonazine directly into the VTA prevents both
THC- and heroin-induced dopamine elevations in
the shell of the nucleus accumbens
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ß-Endorphin Levels in the VTA and Nucleus
Accumbens Shell After i.p. Injection of THC

• Rats implanted unilaterally with microdialysis
  probes attached to fluid swivels for free
  movement
• 24 hours later, microdialysis samples taken at
  30-min intervals for 3 hours before and after
  i.p. injection of 3 mg/kg THC (the training dose
  in discrimination studies)

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THC increases extracellular levels of ß-endorphin
in the nucleus accumbens shell and in the VTA
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Direct injection of ß-Endorphin Into the VTA or
Nucleus Accumbens Shell

• Rats were implanted bilaterally with guide
  cannulae in the VTA or in the shell of the
  nucleus accumbens
• Micro injections of different doses of
  beta-endorphin were given alone or 15 min before
  i.p. injection of a low threshold dose of THC

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Direct injection of ß-endorphin into the VTA
dose-dependently potentiates THC discrimination
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Direct injection of ß-endorphin into the nucleus
accumbens shell does not potentiate THC
discrimination
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SUMMARY III

• These results suggest that the subjective
  response to THC, a behavioral effect critically
  related to its abuse liability, is regulated by
  THC-induced elevations in extracellular levels of
  beta-endorphin in the VTA
• Augmented levels of ß-endorphins in the VTA are
  probably responsible for THC-induced dopamine
  elevations in the shell of the nucleus accumbens

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Opioid-Cannabinoid Interactions Are
BidirectionalThe reinforcing effects of opioids
can be modulated by cannabinoid agonist or
antagonist treatment
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THC potentiates and SR-141716 reduces the
reinforcing efficacy of Heroin under a
progressive-ratio schedule of intravenous drug
injection
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SUMMARY IV

• These results suggest that the endocannabinoid
  system is involved in the reinforcing effects of
  heroin
• It is possible that heroin self-injections
  increase levels of endogenous cannabinoids in
  brain areas involved in reward processes, in a
  fashion similar to that demonstrated for THC and
  ß-endorphin

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CONCLUSIONS

• THCs reinforcing and subjective effects are
  reduced by an opioid antagonist and reinstated or
  potentiated by an opioid agonist
• THC increases extracellular levels of ß-endorphin
  in the VTA and the shell of the nucleus accumbens
• Beta-endorphin injected directly into the VTA,
  but not the nucleus accumbens shell, potentiates
  the discrimination of low doses of THC and this
  is reversed by naloxone
• Augmented levels of ß-endorphins in the VTA may
  be responsible for previous findings by others of
  THC-induced dopamine elevations in the nucleus
  accumbens
• These studies provide a novel mechanism that
  could explain a wide range of observed
  opioid-cannabinoid interactions, including the
  alterations in the reinforcing effects of
  cannabinoids by opioid agonists and antagonists I
  reviewed today

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Acknowledgements

• Marcello Solinas, Ph.D.
• Zuzana Justinova, M.D.
• Gianluigi Tanda, Ph.D.
• Patrik Munzar, M.D.
• Abraham Zangen, Ph.D.
• Godfrey H. Redhi

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Intracranial Self-Administration of THCinto the
VTA or Nucleus Accumbens Shell

• Each rat implanted unilaterally with a 26-gauge
  cannula directed at either the posterior VTA,
  1.5mm dorsal to the posterior VTA, the anterior
  VTA, the accumbens shell or the accumbens core.
• Rats given access to two levers each press on
  one active lever produced a microinjection
  while presses on other inactive lever did not.
• Rats learned to press the active lever regularly
  within the first 3-hour session, without
  shaping or priming.
• Self-administration behavior extinguished when
  vehicle was substituted for THC and was
  reinstated when THC was again available.
• Zangen A, Solinas M, Ikemoto S, Goldberg SR, Wise
  RA

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Intracranial self-administration of THC into the
VTA and into the nucleus accumbens
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Abuse-Related Interactions Between Cannabinoid
and Opioid Systems

• Opioid antagonists can precipitate withdrawal
  signs in THC dependent animals
• The cannabinoid antagonist SR-141716A can
  precipitate withdrawal signs in opiate dependent
  animals
• Opioid antagonists block THC induced dopamine
  elevations in the nucleus accumbens
• Opioid antagonists block the effects of THC on
  intracranial self-stimulation
• Mu-receptor deficient mice do not develop
  THC-induced conditioned place preferences