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The Reward Pathway
    The Bottom Up System vs. The Top Down System
Nicotine, Alcohol, Opiates, Stimulants, Hallucinogens
   Psychopharmacology of Feeding, Hunger and Sex
   A natural high or drug induced high is mediated by the mesolimbic
    dopamine pathway which is sometimes referred to as the pleasure center of
    the brain, with dopamine as the pleasure neurotransmitter.
1. Ventral tegmental
area(VTA), (dopamine cell
bodies)

2. Nucleus
accumbens, (dopaminerg
ic axons project)


3. Amygdala, connects
with both the VTA and
the nucleus accumbens
Projections from :

1. orbitofrontal cortex(OFC)
   involved in regulating
   impulses,

2. ventromedial prefrontal
   cortex(VMPFC) involved in
   regulating emotions,

3. dorsolateral prefrontal
   cortex(DLPFC) involved in
   analyzing situations and
   regulating whether an
   action takes place.
The brain makes its own drugs:

   Endorphines and Enkephalins =     Morphine/Heroin
   Anandamide = Cannabis/marijuana
   Acetylcholine = Nicotine
   Dopamine = Cocaine/amphetamine
   The numerous psychotropic drugs of abuse
    that occur in nature mimic the brain’s own
    neurotransmitters.

   Directly stimulate the brain’s receptors in the
    reward system, causing dopamine release and
    a consequent “artificial high”.
Impulsive Cycle
      *Occasional substance use is
      an impulsive choice driven by
      positive reinforcement of the
      drug’s expected effect
      (pleasure and reward).

      *This “teaches” the brain to
      anticipate reward on
      subsequent exposure to the
      drug.

      *When the substance is
      taken, pleasure will be
      experienced again, usually
      followed by regret
Compulsive Cycle
*With repeated exposure to drug
neurobiological changes occur in
the brain, leading to
craving, reduced reward on drug
exposure and withdrawal during
abstinence(negative reinforcement).

*This leads to craving which is
released by drug ingestion.
   The rate of dopamine release in the nucleus accumbens
    determines how addictive a substance is.
   Two ways of dopamine release: Regular (Tonic) and Irregular (Phasic)
   Constant (tonic) dopamine release is not addictive.
   Bursts of dopamine (Phasic) release is addictive.
   Three mechanisms of action:
   Directly causes dopamine release in the nucleus accumbens by binding to
    α4β2 nicotinic postsynaptic receptors on dopamine neurons in the VTA
   Indirectly causes dopamine release by binding to the alpha 7 nicotinic
    receptors on the glutamatergic neurons.
   Disinhibits mesolimbic dopamine neurons by desensitizing α4β2 on GABA
    interneurons in the VTA.
   Varenicline is a nicotinic partial agonist (NPA) selective for the α4β2 nicotinic
    receptors located on dopamine neurons and GABA interneurons in the VTA
CHANTIX tablets contain varenicline (as the tartrate salt), which is a
partial agonist selective for α4β2 nicotinic acetylcholine receptor
subtypes.

 The recommended dose of CHANTIX is 1 mg twice daily
  following a 1week titration as follows:
Days 1 – 3:    0.5 mg once daily
Days 4 – 7:    0.5 mg twice daily
Day 8 - 1 mg twice daily
Patients should be treated with CHANTIX for 12 weeks.

Box Warning: Serious neuropsychiatric events including, but not
limited to, depression, suicidal ideation, suicide attempt, and
completed suicide have been reported in patients taking CHANTIX.
   In addition to enhancing GABA inhibition and reducing glutamate
    excitation, alcohol also enhances euphoric effects by releasing
    opiates and endocannabinoids, thereby mediating its “high”.
   Naltrexone is a mu opiate receptor antagonist
    Available in oral formulation and a once-monthly intramuscular injection
    (extended-release 380 mg every 4 weeks).

   Extended-release form requires less will power to refrain from drinking.
   With oral naltrexone, one must decide daily whether or not to continue the
    treatment.
   Acamprosate is a derivative of the amino acid taurine .
   It can be thought of as “artificial alcohol” because :

            -Reduces excitatory glutamate neurotransmission

           - Enhances GABA neurotransmission.

Acamprosate: dosage for alcohol dependence:

   The recommended dose of acamprosate for most people is 666 mg TID

   It is not approved for use in people who have not yet stopped drinking.

   Acamprosate should be used with an appropriate treatment program, including
    counseling and group sessions as necessary.

Adverse effects:
 Acamprosate is renally excreted, thus for people with moderate kidney
  problems, the recommended dose is acamprosate 333 mg TID. For people with
  severe kidney problems, the drug is not recommended.
   Opiate Neurons originate in the arcuate nucleus and project to both the
    ventral tegmental area(VTA), and to the nucleus accumbens. Opiate neurons
    release endogenous opiates such as enkephalin. Enkephalin increases
    dopamine in nucleus accumbens.
   Opiate drugs act on opiate receptors such as mu, delta, and kappa.
   Endogenous opiate- are peptides derived from precursor proteins called
    POMC (pro-opio-melano-cortin).
   They are proenkephalin and prodynorphin.
   Endorphins, enkephalins or dynorphin, which are then stored in opiate
    neurons.
   Sigma receptors are no longer considered opiate receptors.
Methadone is a full agonist at all
opioid receptors.

Buprenorphine is a partial agonist
µ-opioid receptors, partial
agonist at δ-opioid
receptors, and antagonist at the
κ-opioid receptors.
   Buprenorphine is much harder to abuse (partial agonist) so
    patients are allowed to take it home. Methadone can be
    abused, so patients need to travel to a clinic each day to
    take their medication.

   Withdrawal from Buprenorphine is generally less severe
    than Methadone.

   The risk of a fatal overdose on Buprenorphine is less than
    with Methadone.

   For people with heavy opiate habits and serious
    addiction, Buprenorphine cannot provide effective relief
    from withdrawal symptoms. Methadone works better for
    such individuals.
Buprenorphine is used for:
1. Treatment of opioid addiction in higher dosages (>2 mg),
2. Control moderate chronic pain in dosages ranging from 20–70 µg/hour.
Formulations:
   The abuse properties of stimulants stem from their ability to
    enhance dopamine release in the nucleus accumbens.
   The main mechanism of action of cocaine is to block reuptake
    of monoamines, principally dopamine(DA) but also
    norepinephrine(NE) and serotonin(5HT).
   There is also a local anesthetic action.
   Amphetamine and methamphetamine are both
    pseudosubstrates
   reverse transporters of dopamine (DAT)
   act as inhibitors of the vesicular monoamine
    transporter(VMAT).
Changes in dopamine neurons, include:
-long lasting depletions of dopamine levels
-axonal degeneration,
-a state that clinically and pathologically is called “burn-out”
Decrease in the release of
GABA from GABA-ergic
neurons causes DA neurons
to be disinhibited and their
firing rate increases (see
example single-unit
recording in red).

This results in more DA being
released in the nucleus
accumbens.
   Marijuana delivers its active ingredients, the cannabinoids to the brain’s own
    cannabinoid receptors, triggering dopamine release in the nucleus accumbens.
Receptors:
*CB1 receptor is found
primarily in the
brain, and mediates
the psychological
effects of THC.

*CB2 receptor is
associated with the
immune system
   Nonpsychotropic cannabinoids act as N-methyl-D-
    aspartate receptor blockers.

   Cannabidiol is a component of marijuana that does not
    activate cannabinoid receptors, but moderately inhibits the
    degradation of the endocannabinoid anandamide.

   Elevation of anandamide levels in cerebrospinal fluid is
    inversely correlated to psychotic symptoms.

   Enhanced anandamide signaling leads to a lower transition
    rate from initial prodromal states of schizophrenia into
    frank psychosis.

   Currently in Phase 2 clinical trials.
Club drugs such as
phencyclidine(PCP) and ketamine
are antagonists at N-methyl-D-
aspartate(NMDA) receptors and
thus cause NMDA
hypoactivity, which in turn leads
to disinhibition of dopamine
release.

Gamma hydroxybutirate(GHB) is
an agonist at GHB and GABA-B
receptors.

GHB is used in the treatment of
fibromyalgia.
The circuitry of hunger is
interconnected with the
circuitry of reward, however
food consumption is also
regulated by peripheral
signaling systems (leptin and
insulin).

Dopamine projections extend
to the mamilary nucleus
(MAM) of the
hypothalamus, an area
important for regulatory
control of eating

Projections from the MAM
nucleus extend to the nucleus
accumbens.
Dopamine activity in reward
circuitry is thought to play a
central role in sexual desire
and arousal.

Dopaminergic neurons also
project to the
hypothalamus, where they
may have input to the
regulation of sexual desire
and arousal via neurons in
the medial preoptic area
(MPOA) and the projection of
those neurons to the nucleus
accumbens.
Disorders of the reward system
Disorders of the reward system

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Disorders of the reward system

  • 1. The Reward Pathway The Bottom Up System vs. The Top Down System Nicotine, Alcohol, Opiates, Stimulants, Hallucinogens Psychopharmacology of Feeding, Hunger and Sex
  • 2. A natural high or drug induced high is mediated by the mesolimbic dopamine pathway which is sometimes referred to as the pleasure center of the brain, with dopamine as the pleasure neurotransmitter.
  • 3.
  • 4. 1. Ventral tegmental area(VTA), (dopamine cell bodies) 2. Nucleus accumbens, (dopaminerg ic axons project) 3. Amygdala, connects with both the VTA and the nucleus accumbens
  • 5. Projections from : 1. orbitofrontal cortex(OFC) involved in regulating impulses, 2. ventromedial prefrontal cortex(VMPFC) involved in regulating emotions, 3. dorsolateral prefrontal cortex(DLPFC) involved in analyzing situations and regulating whether an action takes place.
  • 6.
  • 7. The brain makes its own drugs:  Endorphines and Enkephalins = Morphine/Heroin  Anandamide = Cannabis/marijuana  Acetylcholine = Nicotine  Dopamine = Cocaine/amphetamine
  • 8. The numerous psychotropic drugs of abuse that occur in nature mimic the brain’s own neurotransmitters.  Directly stimulate the brain’s receptors in the reward system, causing dopamine release and a consequent “artificial high”.
  • 9. Impulsive Cycle *Occasional substance use is an impulsive choice driven by positive reinforcement of the drug’s expected effect (pleasure and reward). *This “teaches” the brain to anticipate reward on subsequent exposure to the drug. *When the substance is taken, pleasure will be experienced again, usually followed by regret Compulsive Cycle *With repeated exposure to drug neurobiological changes occur in the brain, leading to craving, reduced reward on drug exposure and withdrawal during abstinence(negative reinforcement). *This leads to craving which is released by drug ingestion.
  • 10. The rate of dopamine release in the nucleus accumbens determines how addictive a substance is.  Two ways of dopamine release: Regular (Tonic) and Irregular (Phasic)  Constant (tonic) dopamine release is not addictive.  Bursts of dopamine (Phasic) release is addictive.
  • 11.
  • 12.
  • 13.
  • 14.
  • 15. Three mechanisms of action:  Directly causes dopamine release in the nucleus accumbens by binding to α4β2 nicotinic postsynaptic receptors on dopamine neurons in the VTA  Indirectly causes dopamine release by binding to the alpha 7 nicotinic receptors on the glutamatergic neurons.  Disinhibits mesolimbic dopamine neurons by desensitizing α4β2 on GABA interneurons in the VTA.
  • 16. Varenicline is a nicotinic partial agonist (NPA) selective for the α4β2 nicotinic receptors located on dopamine neurons and GABA interneurons in the VTA
  • 17. CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.  The recommended dose of CHANTIX is 1 mg twice daily following a 1week titration as follows: Days 1 – 3: 0.5 mg once daily Days 4 – 7: 0.5 mg twice daily Day 8 - 1 mg twice daily Patients should be treated with CHANTIX for 12 weeks. Box Warning: Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking CHANTIX.
  • 18.
  • 19. In addition to enhancing GABA inhibition and reducing glutamate excitation, alcohol also enhances euphoric effects by releasing opiates and endocannabinoids, thereby mediating its “high”.
  • 20. Naltrexone is a mu opiate receptor antagonist  Available in oral formulation and a once-monthly intramuscular injection (extended-release 380 mg every 4 weeks).  Extended-release form requires less will power to refrain from drinking.  With oral naltrexone, one must decide daily whether or not to continue the treatment.
  • 21. Acamprosate is a derivative of the amino acid taurine .  It can be thought of as “artificial alcohol” because : -Reduces excitatory glutamate neurotransmission - Enhances GABA neurotransmission. Acamprosate: dosage for alcohol dependence:  The recommended dose of acamprosate for most people is 666 mg TID  It is not approved for use in people who have not yet stopped drinking.  Acamprosate should be used with an appropriate treatment program, including counseling and group sessions as necessary. Adverse effects:  Acamprosate is renally excreted, thus for people with moderate kidney problems, the recommended dose is acamprosate 333 mg TID. For people with severe kidney problems, the drug is not recommended.
  • 22.
  • 23. Opiate Neurons originate in the arcuate nucleus and project to both the ventral tegmental area(VTA), and to the nucleus accumbens. Opiate neurons release endogenous opiates such as enkephalin. Enkephalin increases dopamine in nucleus accumbens.
  • 24. Opiate drugs act on opiate receptors such as mu, delta, and kappa.  Endogenous opiate- are peptides derived from precursor proteins called POMC (pro-opio-melano-cortin).  They are proenkephalin and prodynorphin.  Endorphins, enkephalins or dynorphin, which are then stored in opiate neurons.  Sigma receptors are no longer considered opiate receptors.
  • 25. Methadone is a full agonist at all opioid receptors. Buprenorphine is a partial agonist µ-opioid receptors, partial agonist at δ-opioid receptors, and antagonist at the κ-opioid receptors.
  • 26. Buprenorphine is much harder to abuse (partial agonist) so patients are allowed to take it home. Methadone can be abused, so patients need to travel to a clinic each day to take their medication.  Withdrawal from Buprenorphine is generally less severe than Methadone.  The risk of a fatal overdose on Buprenorphine is less than with Methadone.  For people with heavy opiate habits and serious addiction, Buprenorphine cannot provide effective relief from withdrawal symptoms. Methadone works better for such individuals.
  • 27. Buprenorphine is used for: 1. Treatment of opioid addiction in higher dosages (>2 mg), 2. Control moderate chronic pain in dosages ranging from 20–70 µg/hour. Formulations:
  • 28.
  • 29.
  • 30. The abuse properties of stimulants stem from their ability to enhance dopamine release in the nucleus accumbens.
  • 31. The main mechanism of action of cocaine is to block reuptake of monoamines, principally dopamine(DA) but also norepinephrine(NE) and serotonin(5HT).  There is also a local anesthetic action.
  • 32. Amphetamine and methamphetamine are both pseudosubstrates  reverse transporters of dopamine (DAT)  act as inhibitors of the vesicular monoamine transporter(VMAT).
  • 33. Changes in dopamine neurons, include: -long lasting depletions of dopamine levels -axonal degeneration, -a state that clinically and pathologically is called “burn-out”
  • 34.
  • 35. Decrease in the release of GABA from GABA-ergic neurons causes DA neurons to be disinhibited and their firing rate increases (see example single-unit recording in red). This results in more DA being released in the nucleus accumbens.
  • 36.
  • 37. Marijuana delivers its active ingredients, the cannabinoids to the brain’s own cannabinoid receptors, triggering dopamine release in the nucleus accumbens.
  • 38. Receptors: *CB1 receptor is found primarily in the brain, and mediates the psychological effects of THC. *CB2 receptor is associated with the immune system
  • 39. Nonpsychotropic cannabinoids act as N-methyl-D- aspartate receptor blockers.  Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide.  Elevation of anandamide levels in cerebrospinal fluid is inversely correlated to psychotic symptoms.  Enhanced anandamide signaling leads to a lower transition rate from initial prodromal states of schizophrenia into frank psychosis.  Currently in Phase 2 clinical trials.
  • 40.
  • 41. Club drugs such as phencyclidine(PCP) and ketamine are antagonists at N-methyl-D- aspartate(NMDA) receptors and thus cause NMDA hypoactivity, which in turn leads to disinhibition of dopamine release. Gamma hydroxybutirate(GHB) is an agonist at GHB and GABA-B receptors. GHB is used in the treatment of fibromyalgia.
  • 42.
  • 43. The circuitry of hunger is interconnected with the circuitry of reward, however food consumption is also regulated by peripheral signaling systems (leptin and insulin). Dopamine projections extend to the mamilary nucleus (MAM) of the hypothalamus, an area important for regulatory control of eating Projections from the MAM nucleus extend to the nucleus accumbens.
  • 44.
  • 45. Dopamine activity in reward circuitry is thought to play a central role in sexual desire and arousal. Dopaminergic neurons also project to the hypothalamus, where they may have input to the regulation of sexual desire and arousal via neurons in the medial preoptic area (MPOA) and the projection of those neurons to the nucleus accumbens.