Compulsive Disorder - Neuroscience Education Institute

Transcription

Handout for the Neuroscience Education Institute (NEI) online activity:
• Click to edit Master text styles
Binge Eating as an Impulsive• Second level
Compulsive
Disorder:
• Third level
Neurobiological
Links to
• Fourth
level
• Fifth level Addiction
1
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Describe the hypothetical shared neurobiology
impulsive-compulsive
disorders
• of
Click
to edit Master text
styles
••
•
•
••
Second
level conditions/behaviors that
Evaluate potential
may
considered impulsive-compulsive
Thirdbelevel
disorders
Fourth level
Describe
potential mechanisms for reducing
Fifth level
binge eating and/or weight
2
Pretest Question 1
Impulsivity is hypothesized to be related to the
_____, while compulsivity is hypothesized to be
•related
Click
Master text styles
to to
theedit
_____.
• Second level
1.
Amygdala,
• Third
levelventral striatum
2. Ventral striatum, amygdala
• Fourth level
3. Dorsal striatum, ventral striatum
•4. Fifth
level
Ventral striatum, dorsal striatum
3
Pretest Question 2
What is the theorized main action of lorcaserin?
1.
Enhances
appetite-suppressing
pathway
via agonism of
• Click
to
edit
Master
text
styles
5HT2C receptors on POMC neurons in the hypothalamus
2.
Enhances appetite-suppressing
pathway via antagonism
• Second
level
of 5HT2C receptors on POMC neurons in the
hypothalamus
• Third
level
3. Enhances appetite-stimulating pathway via agonism of
5HT2C receptors
• Fourth
levelon POMC neurons in the hypothalamus
4. Enhances appetite-stimulating pathway via antagonism of
5HT2Clevel
receptors on POMC neurons in the hypothalamus
• Fifth
4
"Most animals,
including homo sapiens,
biologically
to
•are
Click
to edit Master predisposed
text styles
overeat
when energy resources
• Second level
• Third
level
are
available…
[W]e do this with
• Fourth
levelwhen foods are of a
alacrity
• Fifth level
particularly appealing
composition."
—Davis C. ISRN Obes 2013:435027.
5
+
+
• Second levelEasily acquired,
energy dense food
Biological
• Third level
predisposition
• Fourth level
• Fifth level
Obesity epidemic
Reduced energy
expenditure
6
• Second level
• Third level
• Fourth level
NEUROBIOLOGY OF
• Fifth level
IMPULSIVITY AND
COMPULSIVITY
7
Possible Categorization of Impulsivity and
Compulsivity Endophenotypes as
Impulsive-Compulsive Disorders
Obsessive-compulsiverelated spectrum
disorders
•
•
•
•
•
Substance/
behavioral
addictions
Disruptive/impulse
control
Click to edit
styles
DrugMaster
addiction text
Pyromania
Gambling
Kleptomania
Second level
Internet addiction IED
addiction
Impulsive violence
Third levelFood
(binge eating,
BPD
obesity)
Self-harm/
Fourth level
Compulsive
parasuicidal
shopping
behavior
Fifth level
Antisocial behavior
OCD
Hair pulling
(trichotillomania)
Skin picking
Body dysmorphic
disorder (BDD)
Hoarding
Tourette's syndrome/
tic disorders
Stereotyped movement
disorders
Autism spectrum
disorders
Hypochondriasis
Somatization
Sexual
Hypersexual
disorder
Paraphilias
Conduct disorder
ODD
Mania
ADHD
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013.
8
Devaluation of a Reward Can Switch Goal-directed
Behavior into Stimulus-directed Behavior
•
•
•
•
•
novel
exciting
palatable
Salient
Stimulus
Stimulus
Click to edit Master text styles
How beneficial is the outcome?
Second levelReward Evaluation Is there any risk?
Third level
Favorable
Unfavorable
Fourth levelOutcome
Outcome
Fifth level
Engaging in the behavior would
lead to a positive result
Engaging in the behavior would
lead to a negative result
Very little to no risk is required
to achieve the reward
A high degree of risk is required
to achieve the reward
Goal-directed behavior
Action-outcome learning
Behavior
Stimulus-directed behavior
Stimulus-response learning
Everitt BJ and Robbins TW. Nat Neurosci 2005;8(11):1481-9.
12
Maladaptations of the Reward Pathway Can Shift
Behavior From Normal to Impulsive to Compulsive
NORMAL
IMPULSIVITY
Salient Stimulus
Salient
Stimulus
• Click
to edit Master
text
styles
• Second
level
Favorable
Favorable
Outcome
Outcome
• Pleasurable
Third level
Reward
Pleasurable Reward
• Fourth level
Binge
Knowing &
Learning
anticipating
• Fifth level
“Liking”
“Wanting”
Absence
Opioids
Dopamine
Anticipation
COMPULSIVITY
Stimulus
Favorable
Behavior
Outcome
Pleasurable Reward
Habits
Wyvell CL and Berridge KC. J Neurosci. 2000;20(21):8122-30.
Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 2013.
13
Reward-Seeking Behavior is Influenced
by Multiple Areas of the Brain
Prefrontal Cortex
Ventral
Tegmental
Area Incentive
Executive
Control
Motivation
• Second levelSubcortical Reward
Center
• Third level
• Fourth
level
Amygdala
Hippocampus
Context/
• Fifth level
Environment
Affect/
Emotions
Goto Y and Grace AA. Nat Neurosci 2005;8(6):805-12.
14
Normal Reward-Seeking Behavior
in Response to a Salient Stimulus
•
•
•
•
•
Cortical
Inhibitory
text
styles
Control
Click to edit Master
Second level Striatum
Third level
Goal-directed Stimulus-directed
Behavior
Behavior
Fourth level
Fifth level
Salient
Stimulus
Behavior
Dopaminergic
Neurons
Everitt BJ and Robbins TW. Neurosci Biobehav Rev 2013;37:1946-54.
15
Abnormal Reward-Seeking Behavior in
Response to a Salient Stimulus
•
•
•
•
•
Cortical Inhibitory
Control
Third level
Behavior
Behavior
Fourth level
Fifth level
Salient
Stimulus
Behavior
Dopaminergic
Neurons
16
Maladaptations in the Reward Circuitry
that Potentially Underlie Binge Eating Disorder
Normal
Impulsive Trait
• Risky behavior
• Inappropriate behavior
• Inability to stop actions
• Poor decision making
• Impatience
Cortical to edit Master text styles
• Inhibitory
Click
Control
• Second
level
Subcortical
Reward
Subcortical Reward
• Third
level
Normal
Center
Center
Eating
•
Fourth
level
Behavior
behavior
behavior
behavior
behavior
• Fifth level
Reduced
Cortical
Inhibitory
Control
Excitatory
Inputs
Modulating
Behavior
Increased
Excitatory
Inputs
Modulating
Behavior
Abnormal
Compulsive
Eating Behavior
May lead to compulsive
behavior – actions which
persist inappropriately
17
Dopaminergic Neurons Display
Both Tonic and Phasic Firing States
Tonic Firing
VMAT2
dopamine
transporter
(DAT)
presynaptic D2
autoreceptor
D1 D2 D3 D4 D5
• Slow, irregular firing
• Low level of
extracellular dopamine
D2
Phasic Firing
• Rapid, synchronous burst
• Spike in level of
extracellular dopamine
Covey et al. Trends in Neurosci 2014;37(4):200-10.
D1
Dopaminergic Release into the Striatum is
Differentially Regulated by Various Stimuli
No Stimulus
•
•
•
•
•
Salient Stimulus
Conditioned Stimulus
Second
level Activated State
Basal State
Conditioned State
Third level
Fourth level
Fifth level
Tonic level of
dopamine in
the striatum
Phasic level of
dopamine in the
ventral striatum
Phasic level of
dopamine in the
dorsal striatum
Grace et al. Trends in Neurosci 2007;30(5):220-7.
19
Dopaminergic Signaling to the Dorsal Striatum is
Influenced by Signaling in the Nucleus Accumbens
Striato-nigro-striatal loops regulate dopaminergic
activity in the striatum
• Click to edit Master textThestyles
striatum shows distinct
VentralDorsal
organization – ventral domains
Nucleus
• Accumbens
Second level
exert control over dorsal
Shell
Core
domains
• Third level
Compulsive behaviors, such
• Fourth level
as drug-seeking, correlate with
Dopaminergic
an increase in dopamine in the
Signaling
• Fifth level
dorsal striatum
Ventral
Tegmental Area
Substantia Nigra
pars compacta
Disruption of the ventral-dorsal
connection decreased drugseeking behavior in
reinforcement-trained rats
Belin D and Everitt BJ. Neuron 2008;57:432-41.
20
Frontal Cortical-Striatal Interactions
Implicated in Impulsivity and Compulsivity
Orbitofrontal
Cortex
Infralimbic
Cortex
Suppl. Motor
Cortex
VentralDorsal
Shell
Prefrontal
Cortex
Core
Cingulate
Cortex
Premotor
Cortex
IMPULSIVITY
Lesions in the infralimbic and cingulate
cortex increase impulsivity
The orbitofrontal cortex has been
implicated in reward-delay behavior
The orbitofrontal cortex shows increased
activity in response to food cues
COMPULSIVITY
The orbitofrontal cortex is important for
reversal learning
Cognitive flexibility relies on both the
prefrontal and orbitofrontal cortices
Compulsive habits rely on connections
between the striatum and motor cortices
Dalley et al. Pharmacol Biochem Behav 2008;90(2):250-60.
Robbins et al. Trends in Cogn Sci 2012;16(1):81-91.
Schienle et al. Biol Psychiatry 2009;65:654-61.
Reward-Seeking Behavior is Tightly
Regulated on Multiple Levels
•
•
•
•
•
•
The firing state of dopaminergic neurons can differentially
regulate reward-seeking behavior
Tonic firing produces a low-level of basal activity
Phasic firing results in rapid activation of dopaminergic
signaling that drives behavior
Click to• edit Master text styles
•
Second level
• The organization of the striatum is such that activity of the
Third level
ventral striatum influences activity of the dorsal striatum
• Compulsive behavior is theorized to result from the
Fourth level
disruption of this regulation
• Reward-seeking behavior is under a high degree of
Fifth level
regulation from different areas of the frontal cortex
How do the maladaptations thought to underlie
binge eating disorder result in long-lasting
changes that persist over time?
22
Synaptic Plasticity via Long-term Potentiation
is Important for Learning and Memory
Glutamate-mediated synaptic plasticity strengthens
the connection between input and output neurons
Presynaptic
• Second level
• Third level
• Fourth level
Postsynaptic
• Fifth level
Ca2+ Ca2+
Ca2+
Intracellular
signaling
pathways
Glutamate
Glutamate Receptor
Lamprecht R and LeDoux J. Nat Rev Neurosci 2004;5:45-54.
23
Dopaminergic Signaling Affects the Integration
of Glutamatergic Signaling in the Striatum
Glutamatergic
Inputs
Dopaminergic
Inputs
• Second level
•GABAergic
ThirdMedium
level
Spiny
Neurons in the Striatum
• Fourth level
D
D
• Fifth level
1
Activation of D1 receptors on
striatonigral MSNs enhances
glutamatergic signaling
2
Activation of D2 receptors on
striatopallidal MSNs reduces
glutamatergic signaling
Surmeier et al. Trends in Neurosci 2007;30(5):228-35.
24
Dopaminergic Modulation of Glutamatergic
Signals Can Affect the Activity of the Striatum
•
•
•
•
•
•
Signaling at glutamatergic synapses can be
strengthened via long-term potentiation
• Synaptic plasticity results in both an increase in the
number of receptors as well as the growth of new
Second level
dendritic spines
Third level
• GABAergic medium spiny neurons are the primary
site of activity within the striatum
Fourth level
• Incoming glutamatergic signals are differentially
Fifth levelregulated by D and D dopamine receptors
1
•
2
Activation of striatonigral MSNs enhance signaling,
while activation of striatopallidal MSNs reduces
signaling
25
The Eating Continuum Hypothesis
Intermittent
"loss of control"
eating
Homeostatic
eating
Passive
overeating
Binge eating
episodes
Binge eating
disorder with
food addiction
Davis C. ISRN Obes 2013:435027.
Homeostatic vs. Hedonic Hunger
• Following food deprivation, any food will
pathways
• activate
Click toreward
edit Master
text styles
•• However,
high-fat, high-sugar foods activate
Second level
reward pathways more reliably and more
• Third
level
potently
••
•
Fourth
level food deprivation, highly
Even without
Fifth
levelfoods will activate the release of
palatable
endocannabinoids and ghrelin
• This is not true of unpalatable foods
Lutter M, Nestler EJ. J Nutr 2009;139(3):629-32;
Monteleone P et al. J Clin Endocrinol Metab 2012;97:E917-24.
27
Highly Palatable ("Addictive") Foods
• Addictive potential is related to potency and rate
of absorption—and sugar is quickly absorbed
Carb
Pro
POMS
N=61
overweight
women with
>4 weekly
PM
emotional
eating
episodes
(carb:protein
≥6:1)
Spring B et al. Psychopharmacology 2008;197(4):637-47.
"Addictive" Foods
• Consumption of highly processed foods and
are both
associated
• drugs
Click of
to abuse
edit Master
text
styles with:
•
•
•
•
Second
level
– Compulsive
overuse even in the face of severe
adverse consequences
Third level
– Loss oflevel
control over intake
Fourth
– Inability
to cut down
Fifth
level
Davis C. ISRN Obes 2013:435027.
29
Brain Activation to Images of Food Differs in
Binge Eating Disorders vs. Overweight Controls
•
•
•
•
•
BED>BN, C-NW, C-OW:
Medial OFC (right hemisphere)
BED>BN:
Lateral OFC (right hemisphere)
Second level
No differences detected in ventral
Third level
striatum
Fourth level
BN>BED, C-NW, C-OW:
Fifth level
ACC (right hemisphere)
BN>BED, C-OW:
ACC (left hemisphere)
BED: binge eating disorder. BN: bulimia nervosa. C-NW: control, normal weight.
C-OW: control, overweight. OFC: orbitofrontal cortex. ACC: anterior cingulate cortex.
30
Schienle A et al. Biol Psychiatry 2009;65:654-61.
Brain Activation to Images of Food Can Differentiate
Between Binge Eating Disorder and Controls
• BED vs. C-NW: right insula1
•
••
•
••
•
– Alsoto
leftedit
lateral
OFC text styles
Click
Master
Second
level right ventral striatum2
BED vs. C-OW:
– Alsolevel
left insula, medial OFC, right ACC
Third
Fourth
BED vs.level
BN: left ventral striatum3
Fifth
level
– Also
left and right insula, right ACC
186%
accuracy, P<10-5, corr., 82% sensitivity, 90% specificity
271% accuracy, P=0.013, uncorr., 59% sensitivity, 82% specificity
384% accuracy, P<10-3, corr., 82% sensitivity, 86% specificity
BED: binge eating disorder. BN: bulimia nervosa. C-NW: control, normal weight.
C-OW: control, overweight. OFC: orbitofrontal cortex. ACC: anterior cingulate cortex.
31
Weygandt M et al. Hum Brain Mapping 2012;33:2135-46.
When Is Binge Eating an
Impulsive-Compulsive Disorder?
• Obesity, appetite, eating, and the dimensions of
impulsivity/compulsivity
•
•
•
••
•
•
Enhanced reward of food/enhanced motivation
Second level
and drive to consume food
Third
level
Increasing amounts of food to maintain satiety,
Fourth level
tolerance
Lack
control over eating; cannot stop
Fifth oflevel
• Great deal of time spent eating
• Conditioning and habits to food and food cues
• Distress and dysphoria when dieting
32
When Is Binge Eating an
Impulsive-Compulsive Disorder?
• Eating too rapidly or too much when not hungry, to
the point of being uncomfortably full
•
•
•
•
•
•
••
Overeating maintained despite knowledge of
Secondphysical
level and psychological consequences
adverse
caused by excessive food consumption
Third level
Eating alone; feeling disgusted with oneself, guilty,
Fourth
level
or depressed
Fifth
level can occur with or without purging
Binge eating
• Bulimia is binge eating with self-disgust and
purging leading to attempts to prevent weight gain
by excessive exercise, induced vomiting, abuse of
laxatives, enemas, or diuretics
33
• Second level
HOW
DOES THE
• Third level
NEUROBIOLOGY
OF FOOD
• Fourth level
CONSUMPTION
AND
• Fifth level
ADDICTION INFORM
TREATMENT?
34
The Hypothesized Modulation of Binge
Eating Behavior by Treatment
•
•
•
•
•
May not necessarily be the
edit
Masteror text
stylesof
“unlearning”
normalization
maladaptive behavior
Click to
Second level
Third levelMay restore balance so that impulses
triggered by conditioned stimuli no longer
trigger habitual behavior
Fourth level
Fifth levelMay compensate the impulse by
increasing top down inhibitory
control of behavior
35
Regulation of Eating Behaviors:
More Than Just Reward Pathways
Volkow ND et al.
Biol Psychiatry
2013;73:811-8.
Treatment
Reduced binge
eating behavior
Weight loss
SSRIs, high dose
++
Not clinically significant
TCAs
+/-
+/-
+
+
+/-
+
Duloxetine
Orlistat
++
• Click to edit ++
Master text styles
Zonisamide
+
+
• Second
level+
Naltrexone,
high dose
+
Lisdexamfetamine
+++
+++
•
Third
level
Opioid antagonists
+/CBT • Fourth level ++
Interpersonal therapy
++
• Fifth level ++
Dialectical behavior
Topiramate
Submitted to
FDA
therapy
Self-help
Behavioral weight loss
Bariatric surgery
++
+
++
++
++
McElroy SL. Ther Clin Risk Manage 2012;8:219-41.
37
Lisdexamfetamine
•
•
•
•
•
Second level NET
Third level
Fourth level
DAT
lysine
Fifth level
VMAT
38
Lisdexamfetamine is a Dopamine
and Norepinephrine Reuptake Inhibitor
Dopamine
Norepinephrine
• Second level
• Third levelVMAT2
dopamine
norepinephrine
•
Fourth
level
transporter
transporter
(DAT)
(NET)
presynaptic D
• Fifth level autoreceptor
VMAT2
2
D1 D2 D3 D4 D5
1
2A
2B 2C
presynaptic 2
autoreceptor
1
2
3
39
Lisdexamfetamine’s Hypothesized
Mechanism in Binge Eating Disorder
Lisdexamfetamine (LDX)
(hypothesized)
•
•
•
•
•
Cortical Inhibitory
Control
Third level
Behavior
Behavior
Fourth level
Fifth level
Salient
Stimulus
Dopaminergic
Neurons
Behavior
Lisdexamfetamine (LDX)
(hypothesized)
40
Controlled Released
Stimulants as Treatments
Immediate Release
Stimulants as Drugs of Abuse
and Sustained Drug Delivery
and Pulsatile Drug Delivery
• Slow
Click
to edit Master textRapid
styles
Drug
Drug
•
Second
level
Concentration
Concentration
• Third
level
Time
Time
Dose
Dose
Dose
Dose
• Fourth
Net
Effect level
Net Effect
• Slow-rising, steady-state drug level
• Transient and high drug level
Fifthin level
• • Increase
tonic dopamine firing
• Increase in phasic dopamine firing
•
Not at the mercy of fluctuating
dopamine levels
•
Highly reinforcing, pleasurable
effects of drugs of abuse
41
•
•
•
Increases tonic firing
Blunts the effect of phasic firing
Restores the balance of dopaminergic
signaling
•
•
Tunes the signals
Reduces impulsivity and compulsivity
drives
Similar to proposed MOA in ADHD
Striatum level
• Second
• Third level • Decreases the desire for food intake
(immediate)
play a role in relapse prevention once
• Fourth level• May
striatal balance is restored (long-lasting)
Hypothalamus
• Fifth level
•
Prefrontal Cortex
42
Peptides Regulate Appetite in the Hypothalamus
appetite
MC4R
NPY
AgRP
appetite stimulating
appetite suppressing
MSH
AgRP
NPY
POMC
NPY: neuropeptide Y. AgRP: agouti-related peptide.
MC4R: melanocortin 4 receptor. POMC: proopiomelanocortin.
Lisdexamfetamine Actions: Enhance POMC
appetite
MC4R
NPY
AgRP
MSH
AgRP
NPY
POMC
lisdexamfetamine
DA
NE
Treatment
Reduced binge
eating behavior
Weight loss
SSRIs, high dose
++
Not clinically significant
TCAs
+/-
+/-
+
+
+/-
+
Duloxetine
Orlistat
++
• Click to edit ++
Master text styles
Zonisamide
+
+
• Second
level+
Naltrexone,
high dose
+
Lisdexamfetamine
+++
+++
•
Third
level
Opioid antagonists
+/CBT • Fourth level ++
Interpersonal therapy
++
• Fifth level ++
Dialectical behavior
Topiramate
therapy
Self-help
Behavioral weight loss
Bariatric surgery
Overlap with
substance
use disorders
Submitted to
FDA
Overlap with
substance
use disorders
++
+
++
++
++
McElroy SL. Ther Clin Risk Manage 2012;8:219-41.
45
Phentermine Actions: Enhance POMC
appetite
MC4R
NPY
AgRP
MSH
AgRP
NPY
POMC
phentermine
DA
NE
Topiramate Potentiates Phentermine
appetite
MC4R
NPY
AgRP
MSH
AgRP
NPY
topiramate
glu
POMC
phentermine
DA
NE
GABA
Bupropion Actions: Enhance POMC
appetite
MC4R
NPY
AgRP
MSH
AgRP
NPY
POMC
bupropion
DA
NE
Naltrexone Potentiates Bupropion
appetite
MC4R
MSH
naltrexone
AgRP
NPY
NPY
AgRP
POMC
bupropion
DA
NE
Naltrexone Potentiates Zonisamide
appetite
MC4R
MSH
naltrexone
AgRP
NPY
zonisamide
NPY
AgRP
POMC
glu
GABA
Lorcaserin Actions: Enhance POMC
appetite
MC4R
NPY
AgRP
MSH
AgRP
NPY
POMC
5HT
5HT2C
lorcaserin
Histamine H1 Antagonism Combined With
Serotonin 2C Antagonism Stimulates Appetite
•
•
•
•
•
Second level
H1
5HT2C
Third level antagonist antagonist
5HT neurons
Fourth level
hypothalamus
Fifth level
raphe
enhanced
appetite
HA
neurons
52
Serotonin 2C Agonist Lorcaserin
Suppresses Appetite
•
•
•
•
•
Second level
Third level
lorcaserin
5HT neurons
Fourth level
hypothalamus
Fifth level
appetite
suppression
raphe
53
Summary
• Impulsivity and compulsivity are dimensions
• Click
to edit Master
text
of psychopathology
that
cutstyles
across many
disorders
• psychiatric
Second level
••
•
•
Third
Drugs level
and behaviors can both be associated
with
impulsivity/compulsivity
Fourth
level
Fifth level
54

Compulsive Disorder - Neuroscience Education Institute

Transcription

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