Neurotransmitter and morphin dependency depend on:

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Neurobiology of
Reward Addiction
M. R. Zarrindast
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REWARD

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History

• James Olds (1954)
• Pleasure is a distinct neurobiological function
  that is linked to a complex reward
  reinforcement system
• Biochemical Biological studies

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Drug Reward

• Reward A response to a stimulus which causes
  pleasure natural reward (food, liquids, sex)
  as well as electrical stimulation and many drugs
• Reinforcement Continuing an action which has
  been shown reward previously

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Systems involves in biology of REWARD

• Serotonin in Hypothalamus
• Enkephalins (opioid peptide) in VTA Nucleus
  accumbens
• GABA in VTA Nucleus accumbens
• NE (Release of NE in Hyppocampus from neuronal
  fibers that originate in the LC)

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Importance of Reward

• Reinforcement (Reward) leads to more drug
  administration
• Which may lead to drug tolerance
• To gain the previous drug effect after tolerance
  induction, Higher doses of drug is needed which
  may cause dependence

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Dopaminergic System Is the final common
pathway
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Dopamine receptors

• D1 type (D1 D5) increase cAMP
• D2 type (D2, D3 D4) decrease cAMP

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Animal Models
(Based on Conditioning)

• Intracranial Self-stimulation
• Drug Self-administration
• Conditioning Place Preference

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Conditioned Place Preference (CPP)

• A paradigm for studying the brain reward system

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• CPP procedure
• The pairing of environmental stimuli (place)
  with
• a primary reward (drug)
• an acquired preference for those specific stimuli
  in the absence of the primary reward.

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• CPP is consisted of three phases
• 1- Pre-conditioning
• 2- Conditioning
• 3- Post-conditioning (testing)

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CPP Apparatus
B
A
C
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NO and Ventral tegmental area

• Acquisition
• L-arginine increased morphine- CPP
• L-NAME decreased morphine-CPP
• L-arginine response was decreased by L-NAME.
• L-arginine and L-NAME by themselves did not
  induce CPP
• Expression
• L-arginine and L-NAME decreased morphine-CPP
• L-arginine response was inhibited by L-NAME.
• Conclusion
• NO in ventral tegmental area may be involved in
  morphine-CPP

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NO and medial septum

• Acquisition
• L-arginine or L-NAME did not affect morphine-CPP.
  
• L-arginine and L-NAME did not induce alone CPP.
• Expression
• L-arginine but not L-NAME increased the
  expression of morphine-CPP.
• L-NAME did not affect L-arginine response.
• Conclusion
• No in the rat median septum may play a role in
  the morphine-CPP 

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No and Hippocampal CA1 region
Acquisition

1- L-arginine but not
L-NAME increased morphine-CPP
2-L-arginine response was
blocked by L-NAME
. 3- L-arginine or L-NAME by
itself did not induce CPP
Expression

1- L-arginine
but not L-NAME increased morphine-CPP
2-L-NAME blocked the
L-arginine response.
NO in the rat
hippocampal CA1 area may be involved in
morphine-CPP
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NO and Central amygdala
Acquisition
1-L-arginine,
but not L-NAME increased morphine-CPP
2- L-arginine response was
blocked by L-NAME
3- L-arginine and L-NAME by
themselves did not induce CPP
Expression
1-L-arginine but not L-NAME increased
morphine-CPP 2- this effect was blocked
by L-NAME
NO in the central
amygdala may have an influence on morphine-CPP




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NO and Nucleus accumbens

Acquisition 1-L-arginine increased morphine- CPP

2-L-NAME decreased morphine-CPP 3-L-arginine
response was decreased by L-NAME.
4-L-arginine and L-NAME by themselves did not
induce CPP Expression 1-L-arginine but not L-NAME
decreased morphine-CPP 2-L-arginine response
was inhibited by L-NAME. Conclusion NO in the
nucleus accumbens may be involved in morphine-CPP

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Dopamine and
central amygdala

• Acquisition
• SKF 38393 Quinpirole potentiated morphine-CPP.
• This response of SKF 38393 or Quinpirole was
  attenuated by SCH 23390 or Sulpiride.
• SCH 23390 or Sulpiride by itself reduced
  morphine-CPP.
• SKF 38393, Quinpirole, SCH 23390 or Sulpiride did
  not induce alone CPP.
• Expression
• SKF 38393 reduced morphine-CPP but The lower dose
  of quinpirole reduced morphine-CPP, but the high
  dose of quinpirole potentiated this expression.
• Sulpiride attenuated the quinpirole response.
• SCH 23390 or Sulpiride abolished morphine-CPP.
• Conclusion
• The central amygdala dopamine D1- D2-like
  receptors may play an active role in morphine
  reward.

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Cross-tolerance between morphine- and
nicotine-induced CPP

• Both morphine nicotine induce CPP
• Naloxone but not Mecamylamine induce CPA
  (Conditioned place aversion)
• The antagonists reverse the response of morphine
  and nicotine
• Conclusion
• There may be a cross-tolerance between the effect
  of two drugs

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Addiction
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Drug Dependence

• Psychological Dependence
• a psychological need to use a drug
• for example, to relieve negative emotions
• especially true for stress-relieving drugs
• Physical Dependence
• discomfort and distress that follow discontinued
  use of an addictive drug
• a physiological need for a drug to function w/in
  normal limits
• marked by unpleasant withdrawal symptoms
• Depends on drug-
• Stimulant withdrawal?CNS depression and lethargy
• Opiate withdrawal?severe flu-like symptoms

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Cellular MolecularAdaptations Underlying
OpiateTolerance Dependence
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Cellular Effects of Opioid Receptor Stimulation

• Reduced cAMP-mediated signal transduction
  (Adenylate cyclase inhibition)
• Decreased neurotransmitter release (ca channel
  inhibition)
• Decreased neuronal excitability (K channel
  stimulation )
• Overall inhibitory effect on the cell.

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Mechanism of action of opiates LC

• Combined presence of opiates and up-regulated
  cAMP pathway helps to restore LC neurons to
  normal firing rates
• Removal of opiate allows hyperactivation of
  neurons due to unopposed activity of cAMP
  signaling (cAMP overshoot)
• increased noradrenergic neurotransmission
• Thought to underlie physical withdrawal symptoms
• perspiration, tremors, increased heart rate
  blood pressure

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Locus Ceruleus (LC)

• Located in brainstem
• Major noradrenergic-containing neurons in brain
• Involved in control of autonomic function and
  attentional states
• More closely associated with the physical aspects
  of withdrawal

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Morphine Dependency depends on

• Individual
• Drug properties
• Drug doses
• Interval of administrations

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Naloxone-induced jumping

• Method
• 1-Mice were treated chronically with morphine
  (50,5075mg/Kg S.C.) 3 times daily, for 3 days.
• 2-The animals received naloxone (in the 4th day)
  showed jumping.
• 3-Number of jumps in 30 min indicate degree of
  physical dependence.

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Cholinergic system Morphine dependency
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Effect of Nicotine on Morphine-induced Dependence
in mice

• NE (hippocampus)
• Ach (cortex)
• DA (limbic,striatum)
• ENK synthesis and release
• Brain excitability
• Antinociception
• Antiduresis

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Continued

• NE, DA, 5HT, GLU
• Improve mood
• Stress and appetite
• Locomotion
• Reinforcing effects
• Thermoregulation

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Conclusion

• Nicotine decreases naloxone-induced jumping
• Mecamylamine increases naloxone-induced jumping
• The data indicates that nicotine may have
  cross-dependence with morphine

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Adenosine System and Morphine Dependence

• Adenosine is a brain neuromodulator
• Adenosine receptores (A1,A2 ,A3 ,A4)
• Effectsanalgesia, anticonvulsant, hypnotic,
  catalepsy

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Mechanism of A1 receptor

• Inhibition of adenylate cyclase and cAMP
• Opening of K channels
• Inhibit of Ca influx into neurones

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• A1 agonist increases while A1 antagonist
  decreases naloxone-induced jumping
• A2 agonist decreases naloxone-induced jumping but
  A2 antagonist has not any effect
• Conclusion
• Both A1 A2 naloxone-jumping in
  morphine-dependent mice

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GABA

• Inhibitory neurotransmitter
• in
• Central nervous system

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GABA synthesis
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GABA-A receptors

• GABA-A receptor activation results in increased
  Chloride influx
• Three binding sites are important on this complex
• 1. GABA site
• 2. Benzodiazepine site
• 3. Barbiturate site
• Sedation,anxiolytic, hypnotic, memory,
  anticonvulsant, muscular relaxation

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GABA-B receptors

• GABA-B----G-protein linked
• Highest conc. in the interpeduncular nuclie and
  the cerebellum
• Also inhibitory
• Muscle relaxation, antispasmodic
• Binding site for baclofen

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Functioning of GABA

• Relationship with dopamine in nigrostriatal
  system and mesolimbic system
• GABA inhibits dopamine neurons
• Role in movement, memory, anxiety, sleep

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GABA system and morphine dependence

• Both GABAA GABAB agonist decrease jumping while
  GABA antagonist increase jumping
• Conclusion
• Both GABAA GABAB receptors are involved in
  morphine withdrawal syndrome

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Imipramine and Expression of Morphine Dependency

• Imipramine increases naloxone-induced jumping
• Yohimbine decreases imipramine response
• Clonidine did not induced any effect

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Imipramine and Development of Morphine Dependency

• Imipramine increases naloxone-induced jumping
• Yohimbine increases imipramine response

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a2
-
Imipramine
NA
a1
a2
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Histamine Receptors

• Effect of H1 receptors is mediated by excitation
  of Ca
• Effect of H2 receptors is mediated by cAMP
• H3 receptors are at presynaptic sites and
  inhibite release of a variety of neurotransmitters

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Histamine and Morphine Dependency

• Histamine decreases naloxone-induced jumping
• Cimetidine (H2 antagonist) increases
  naloxone-induced jumping
• Pyrilamine (H1 antagonist) did not induced any
  response
• H2 antagonists antagonise the effects of
  histamine
• Conclusion
• H2 receptor mechanism may be involve in
  experssion of jumping

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Dopamine Mechanism and Morphine Dependency

• D2 receptor agonists (Quinpirole Apomorphine)
  decrease experssion of jumping
• D2 anagonist (sulpiride) decreases the agonist
  effect
• D1 mechanism has no influense on experssion of
  naloxone-induced jumping
• During the development, both D1 D2 stimulation
  decreases jumping
• Conclusion
• Dopamine mechanism may be involved in
  naloxone-induced jumping