1 of 42

Neurobiology of Addiction

1

bit.ly/neurobioaddict

2 of 42

Prefrontal Cortex Regulation of Emotion & Anxiety

PFC “Gateway” of Emotional Regulation
Anxiety Disorders: when regulation fails
Modulate Emotional Regulation

Brain, Reward, and Drug Addiction

Representation of reward in the brain
Neurotransmitter systems involved in reward
Outside the basal ganglia
Addiction & reward system
Negative reinforcement in addiction
Drug addiction—dynamic illness
Neuroimaging & addiction risk, prevention, tx

2

bit.ly/neurobioaddict

3 of 42

Prefrontal Cortex (PFC) Regulation of Emotion and Anxiety

PFC “Gateway” of Emotional Regulation

Fear Extinction (Behavioral)
Reversal Learning (Behavioral)
Reappraisal (Cognitive)
Controllability (Cognitive)

Anxiety Disorders: when regulation fails

Modulate Emotional Regulation

Personality
Stress
Sex Hormones
Development
Genetics

3

bit.ly/neurobioaddict

4 of 42

vmPFC Gateway Old & New Structures

bit.ly/neurobioaddict

4

Behavioral

Cognitive

5 of 42

Fear Conditioning Extinction Protocol

(Un)Conditioned Stimuli
± Shock Outcome
(Un)Extinguished Fear

5

bit.ly/neurobioaddict

Figure 43.2 Fear conditioning and extinction protocol.

CS Conditioned Stimulus
CS+ aversive outcome
CS– unreinforced stimulus
E extinguished
U unextinguished

During fear conditioning two stimuli are paired with an aversive outcome (CS+’s), and the third stimuli is unreinforced (CS−).

Fear responses generally increase to the CS+’s and remain low to the CS−.

During extinction training, one of the CS+’s is extinguished (CS+E) by being repeatedly presented in the absence of the aversive outcome. The other CS+ remains unextinguished (CS+U).

Fear responses to the CS+E decrease across training and eventually are comparable to those expressed in the presence of the CS−.

During extinction recall, all three CSs are presented.

In healthy populations, fear responses are low to the CS+E and the CS−, whereas they are high to the CS+U.

6 of 42

Cortex Top Down Control Over Emotional Expression

Prelimbic, Infralimbic
dorsal Anterior Cingulate
ventromedial PreFrontal

bit.ly/neurobioaddict

6

Figure 43.3 Distinct regions of the rodent (prelimbic and infralimbic) and human (ventromedial and dorsal anterior cingulate cortex) PFC increase and decrease expression of conditioned fear, respectively, via interactions with the amygdala.

Animal studies

Delayed fear extinction over days ← Infralimbic (IL) knockout lesions, IL protein synthesis inhibition
Neural activity increased in IL w/ fear-conditioned tone during extinction recall, not training
Freeze responses inversely correlated w/IL activity w/fear-conditioned tone (no response w/PL)
Directly stimulating IL (and thalamic, hippocampal inputs to vmPFC) w/fear-conditioned stimuli reduced freezing during extinction training and the next day w/o stimulation during extinction recall
“Priming extinction circuitry w/aversive contexts: IL stimulation w/brief exposure to conditioned context increased rate of extinction in context over days, as well as to different aversive context (but not neutral context)
DBS ventral striatum w/extinction training enhances recall; DBS alone induced plasticity of IL vmPFC, PL of vmPFC, amygdala (i.e., DBS “primed” extinction circuitry)
PFC may have more complex associations w/Amygdala subnuclei (e.g., central amygdala [CeA], basolateral nucleus [BLA])

medial PFC (mPFC), between PL and IL, activate intercalated cells (ITC) b/w CeA and BLA

ITC knockout lesions s/p extinction prevent extinction recall
fMRI studies yet to be done in humans to study amygdala subnuclei

fMRI Human Studies

Human amygdala & dACC ~ Rodent amygdala & PL (both increased activity w/fear acquisition, recall)
Fear conditioned responses ~ dorsal anterior cingulate cortical thickness dACC
Averse condition olfactory stimuli ~ increased activity Orbital Frontal Cortex
Recall extinguished stimuli ~ increased activity vmPFC (not during original conditioning)
Recall extinguished stimuli ~ increased thickness vmPFC
Anatomy

IL sends glutamatergic neurons to amygdala
Dorsomedial (dm) PFC positive connectivity w/amygdala (e.g., processing emotional faces)

Coupling strength ~ reaction times identifying facial emotions

High anxiety people had greatest dmPFC-amygdala coupling while processing fearful faces while anticipating a shock

Neural signal from PFC for outcome expectancy, error detection

Opioid signal in periductal gray :

Regulates error detection in extinction
Mediates mPFC during extinction
May help determine appropriate fear response

7 of 42

Reversal Learning Protocol

7

bit.ly/neurobioaddict

8 of 42

PFC & Cognitive Reappraisal (CR)

CR ~ ↑ activity vmPFC, dlPFC, MFG ~ ↓ amygdala ~ reduced skin conductance

Same vmPFC subregion active in extinction, common pathway for emotional regulation?

Compared to extinction, Reappraisal recruits more lateral PFC (lateral orbital gyri, [superior, middle, inferior] frontal gyri), as well as medial PFC (superior frontal gyri, ACC)

How does PFC affect emotion response CR?

Direct: ↑ PFC, ↓ amygdala, nucleus accumbens
Mediator: CR success ↓ amygdala, ↑ nucleus accumbens/ventral striatum
Both? Appraise emotions, recruit subcortical regions ↑ or ↓ regulate emotions

Conscious attempt altering meaning of emotional event, usually downregulate (–) affect response

i.e., indirect emotional regulation
e.g., calm visceral fear of snake my rationalizing it is in a cage in zoo

Used in CBT by gathering evidence contradicting initial, unrealistic thought, then substitute realistic thought

Emotions = reactions to thoughts
Δ thoughts = Δ emotions

Employs human verbal reason, likely higher cortical structure

8

bit.ly/neurobioaddict

9 of 42

Perception of control protects from mental illness 2/2 traumatic experiences, modified by greater PFC activity

15-20% of people w/severe trauma develop PTSD

Perception of control protective factor

Control during trauma
Control over emotions post-trauma

2 dogs in adjacent cages shocked, one has power to stop shocks for both dogs

No control, inescapable shocks → stress, ↓ serotonin in dorsal raphe nuclei (DRN), learned helplessness to future shocks even when given control
Control, escapable shocks → no stress, no change in serotonin in DRN, “behavioral immunization” to future inescapable shock

vmPFC necessary and sufficient for control

Knockout during escapable shock similar to inescapable shock: prevents immunization, ↑ fear, no escape
Enhancement (picrotoxin) during inescapable shock, similar to escapable shock: immunization, ↓ fear, escapes

PL glutamatergic (+) neurons synapse on DRN GABAergic (–) neurons

i.e. , vmPFC inhibits DRN in escapable shock and future shocks (immune)

9

bit.ly/neurobioaddict

10 of 42

vmPFC Gateway Old & New Structures

bit.ly/neurobioaddict

10

Behavioral

Cognitive

11 of 42

11

bit.ly/neurobioaddict

12 of 42

Anxiety D/O deficits in Conditioning-Extinction

Anxiety

Altered PFC activity in “anxiety provocation studies”, Δ activity inconsistent (↑ vs ↓)
Moderate ↑ fear responses in anxious people during conditioning & extinction

PTSD

↑ fear w/conditioned response and (reinforced or safe cues), unable to recognize safety
Delayed extinction; impaired extinction recall
PET metabolism: ↑ dACC, ↑ amygdala, ↓ vmPFC, ↓ hippocampus

Panic D/O, failed extinction

Similar deficits in PTSD and cognitive reappraisal (↓ lateral PFC)

12

bit.ly/neurobioaddict

13 of 42

Modulating Emotional Regulation

Personality ● Stress ● Sex Hormones ● Development ● Genetics

13

bit.ly/neurobioaddict

14 of 42

Personality modulates emotional regulation

↑ anxiety trait ~ weak reciprocal connections bw amygdala, vmPFC

Amygdala resting state indicates susceptibility to anxiety

~ ↑ vmPFC activity in ↓ anxiety trait
~ ↓ vmPFC activity in ↑ anxiety trait

Reappraisal in high anxiety trait, ↑ activity lateral & medial PFC, ↑ neural effort?

14

bit.ly/neurobioaddict

15 of 42

Stress modulates emotional regulation

Stress hormones target PFC structure and neural function

Chronic stress/corticosterone tx ~

↓ dendritic length
↓ dendritic branching
↓ dendritic spines
↓ neuronal response to 5HT, dopamine
Normal fear conditioning, but impaired fear extinction

15

bit.ly/neurobioaddict

16 of 42

Sex hormones modulate emotional regulation

Observed women greater risk for anxiety d/o than men

Studies in rodents & humans, extinction retention…

Optimal ↑ progesterone, ↑ estradiol: proestrus (~ human midluteal phase),
Impaired ↓ progesterone, ↓ estradiol: estrus (~ human follicular phase)

↓ neural activity vmPFC, hippocampal, amygdala

16

bit.ly/neurobioaddict

17 of 42

Development modulates emotional regulation

Less known about extinction in childhood and adolescence

Anxiety d/o emerge during adolescence, neuronal reorganization in PFC, ↑ emotionality, ↓ impulse control

Adolescent rats normal conditioning and extinction, ↑ recovery of fear next day, ↓ PFC functioning

17

bit.ly/neurobioaddict

18 of 42

Genetic extinction impairments, ↓ vmPFC

Conditioning, extinction 35-45% heritable (twin studies)

Similar to heritability of PTSD

Impaired fear extinction ~ SNPs in genes for 5HT transporter, BDNF, pituitary adenylate cyclase-activating polypeptide (PACAP)

Extinction impairments in mice had ↓ gene activity in ↓ IL, ↓ BLA, ↑ CeA

BDNF–SNP extinction impairments ↓ vmPFC, ↑ amygdala activation during extinction

18

bit.ly/neurobioaddict

19 of 42

Prefrontal Cortex (PFC) Regulation of Emotion and Anxiety

PFC “Gateway” of Emotional Regulation

Fear Extinction (Behavioral)
Reversal Learning (Behavioral)
Reappraisal (Cognitive)
Controllability (Cognitive)

Anxiety Disorders: when regulation fails

Modulate Emotional Regulation

Personality
Stress
Sex Hormones
Development
Genetics

19

bit.ly/neurobioaddict

20 of 42

Brain, Reward, and Drug Addiction

Representation of reward in the brain
Neurotransmitter systems in reward processing

Dopamine hypothesis of reward
Beyond dopamine and prediction error

Outside the basal ganglia

Amygdala and reward processing
Lateral habenula and reward processing
Medial PFC — expectations & violations
OFC & value estimation

Addiction & reward system

Initiation & Transition to compulsive use
Individual differences in reward system, risk for addiction

Negative reinforcement in addiction

Examples & Models

Drug addiction—dynamic illness

Negative reinforcement and dynamics

Neuroimaging & addiction risk, prevention, treatment

Neural measure of addiction severity
Treatment centered approaches
Identifying risk for future dependence
Reshaping addiction research

20

bit.ly/neurobioaddict

21 of 42

Substance Use Disorder (SUD) Introduction

≥ 15% US adults lifetime prevalence of SUD

≥$600 billion/year cost in US of SUD

20.4 million Americans ≥12y/o (8.3%) used substances in last mos (2006)

Comorbid SUD and Mood/Anxiety D/O

Few people w/SUD seek treatment

Greater impairment, severity for PTSD w/SUD

Antisocial PD w/SUD, early onset, multisubstance, severe, more psychosocial dysfunction

SUD highly dynamic, flux intense use, sobriety

Reward processes

Hedonic pleasure, “liking”
Incentive motivation, “wanting”

Negative reinforcement processes

21

bit.ly/neurobioaddict

22 of 42

Reward Circuit Complexity

dPFC – dorsal prefrontal cortex
dACC – dorsal anterior cingulate cortex
vmPFC – ventral medial prefrontal cortex
OFC – Orbital frontal cortex
Thal – Thalamus
Amy – Amygdala
Hipp – Hippocampus
S – Shell
VP – Ventral pallidum
LHb – Lateral Habenula
Hypo – Hypothalamus
STN – subthalamic nucleus
SNc – Substantia nigra pars compacta
VTA – Ventral tegmental area
PPT – Pedunculopontine nucleus

Red arrow = input from the vmPFC
Dark orange arrow = input from the OFC
Light orange arrow = input from the dACC
Yellow arrow = input form the dPFC

22

bit.ly/neurobioaddict

23 of 42

Extensive Forward-Backwards Projections

Unidirectional
Reciprocal

23

bit.ly/neurobioaddict

24 of 42

Neurotransmitter Systems in Reward Processing

Glutamate, excitatory, >½ all brain synapses

Glu-DA ixns ~ synaptic plasticity of striatum, frontostriatal communication

5HT-DA Opposition, ixn b/w reward/punishment and behavior activation/inhibition

DA 2 receptor subtypes

D1-like (D1, D5)
D2-like (D2, D3, D4)

5HT 14 receptor subtypes

GABA neurons encode expected reward

Active bw cue presentation and reward

Dopamine (DA) Anhedonia Hypothesis

DA antagonists affect ability to act on value predictions of food/water, do not ↓ value

Prediction Error

VTA neurons phasic DA firing 2/2 unexpected reward, or omitted expected (learned) reward
Firing shifts from reward onset to predicted cue

↑ DA in “wanting” incentive, not “liking” hedonism

DA (+) surprise, less evidence for disappointment

DA not simple mediator of reward, others?

24

bit.ly/neurobioaddict

25 of 42

Outside the Basal Ganglia

No unified theory of basal ganglia function

Series parallel loops b/w corticobasal ganglia and thalamocortical radiations

Subcortical and cortical nodes (amygdala, lateral habenula, mPFC, ACC, OFC)

Amygdala: emotional (fear) processing

Lateral, basal, central nuclei: reward learning, motivation
Reward & punishment predictions
Associative learning, attention to cues
Rate learning from prediction errors

25

bit.ly/neurobioaddict

26 of 42

Outside the Basal Ganglia

Habenula: disappointment, negative predictive errors

Transient ↓ firing rate response to cues predicting rewards (w/o reward)
Drives midbrain DA activity thru GABA neurons in rostromedial mesopontine tegmental nucleus
Responds to absence of reward and punishment

Opposite function of DA-midbrain?

26

bit.ly/neurobioaddict

27 of 42

Outside the Basal Ganglia

Anterior Cingulate Cortex: anticipated, experienced, fictive rewards; mPFC is action-outcome predictor, signal (–) surprise

DA neurons project to ACC, firing rate ↑ (+) predictive errors, slight ↓ (–) errors

Distinct nerve populations w/in ACC for +/–?

Sets rate of learning in reinforcement, mediates how stimulus-response affects behavior
Predict based on extended history vs recent events

fictive (adj) creating or created by imagination

27

bit.ly/neurobioaddict

28 of 42

Outside the Basal Ganglia

Orbitofrontal Cortex: decision-value, behavioral measures of goal-values

Interconnections w/basolateral amygdala, striatum
Rigid model-free: cached values representing a summary of decision-value

Dorsal striatal DA neurons

Flexible model-based: computes decision-values as and when needed from a model of environment built from experience

OFC predicting reward and related events

28

bit.ly/neurobioaddict

29 of 42

Addiction and the Reward System

All drugs of abuse act on mesolimbic-DA system: nicotine, EtOH, cannabinoids, opiates, stimulants

↑ DA transmission in nucleus accumbens

Risk of Addiction, Individual Reward Systems

Only 20% of people who use substances develop addiction
↑ Risk for neurobiological variants:

↓ D2-like receptor function DA neurons in striatum, midbrain, ↓ impulse control
↓ Glu-receptor plasticity in PFC
Substance reinforcement sensitivity varies

29

bit.ly/neurobioaddict

30 of 42

Addiction and the Reward System

Initiation

Novelty seeking, best predictor substance use, inverse assoc. available midbrain D2 receptors
↓ D2 receptors, ↑ substance liking, repeat use

Transition to Compulsive Use

Substance ↑ DA, (+) prediction error cannot be compensated, forever ↑ value
Control shifts from PFC to Striatum, from ventral to dorsal striatal circuits
Impaired PFC, basal ganglia

Cognitive, emotional deficits

↑ salience to substances, related cues
↓ impulse control

30

bit.ly/neurobioaddict

31 of 42

Negative Reinforcement & Addiction

Examples

Anxiety sensitivity ~ substance use

↑ anticipation of aversive events

Negative affect in smokers ~ ↑ smoking
vmPFC damage ~ disability to learn from negative feedback

More research to be done…

Antireward System Mechanisms

Escape/avoid stress or withdrawal
Negative affective state
Learn internal cues falling substance levels

Interoception

Behavior to avoid negative state: substance
External cues may be conditioned to internal stressors/withdrawal

31

bit.ly/neurobioaddict

32 of 42

Models of Negative Reinforcement & Addiction

Destabilized internal state “out of balance”,

non-adaptive restorative behaviors attempt to improve negative-affect state

Self-medication

Escaping negative distress occurring before first substance use

Substance use does not cause distress
Negative affect leads to use

Opponent-Process

Internal reward dysfunction
Use ↑ reward threshold, compulsive use

Withdrawal-based negative reinforcement

Avoidance/suppression of withdrawal by using, ↑ future use

Classical conditioning

Strength conditioned response ~ Degree of Dependence
Internal > external cues predict substance use

32

bit.ly/neurobioaddict

33 of 42

Addiction: Dynamic Illness

Chronically relapsing disease

Cognitive behavioral, person-situation interaction

Person: ↓ self-efficacy
Situation: high-risk environments
Interaction: insufficient mobilization of coping skills

Brain reward systems sensitized to substances and associated stimuli

Relapse is continuous, multidimensional:

Threshold, duration, prior sobriety, number of substances, consequences

33

bit.ly/neurobioaddict

34 of 42

Addiction: Dynamic Illness

Aberrant learning processes w/in subcortical circuitry

Substance-seeking behavior compulsive and habitual
Relapse to drug-seeking manifest after long periods of sobriety

Imbalances bw overactive “impulsive” amygdala systems

Signal pain/pleasure of immediate prospect
Weakened “reflective” PFC signaling pain/pleasure future prospect
Substance/stimuli overwhelm goal-driven cognition (willpower to resist)

34

bit.ly/neurobioaddict

35 of 42

Addiction: Dynamic Illness

Increasing dysregulation of brain reward systems, compulsive use, loss of control

Hedonic homeostatic dysregulation, sensitization, counter-adaptation

Neurobiological mechanisms

Mesolimbic DA system
Opioid peptidergic systems
Brain and hormonal stress systems

Brain processes affect

Learning, substance & conditioned cue, homeostatic regulation, inhibition, decision making

35

bit.ly/neurobioaddict

36 of 42

Examples of neuroimaging aiding addiction research

36

bit.ly/neurobioaddict

37 of 42

37

bit.ly/neurobioaddict

38 of 42

38

bit.ly/neurobioaddict

Predicting Relapse: “Identifying neural biomarkers for predicting relapse in substance-dependent individuals—fMRI activation patterns in regions including the insula (1) and striatum (2) during a binary forced choice task predicts relapse in methamphetamine-dependent individuals.”

“Figure 2. Areas of differences in activation between relapsing and nonrelapsing methamphetamine-dependent subjects. Numeric results are shown as percentage signal change of functional clusters. All graphical results are presented as volume-thresholded t maps of the planned comparisons across the different conditions. The numbers to the left of each image in the left-hand column are z coordinates from the Talairach atlas; the numbers in the black boxes correspond to the labels along the bar graphs. R indicates right; L, left; and ROC, receiver operating characteristic.” https://jamanetwork.com/journals/jamapsychiatry/article-abstract/208753

39 of 42

39

bit.ly/neurobioaddict

Risk Factors for Dependence: “Identifying neural risk factors for future substance dependence—midbrain D2 receptor availability, measured through PET, is linked to trait impulsivity, likely via increased stimulated dopamine release in the striatum.”

“(A) Rendering of two separate SPMs depicting negative correlations between BIS-11 scores and D2/D3 binding and positive correlations between BIS-11 scores and amphetamine-induced DA release (corrected for multiple comparisons at the cluster-level, pcorrected < 0.05; clusters defined using a height threshold of t > 3). For the D2/D3 binding, inverse associations emerged in the DA midbrain [anteriorly in the VTA, centered at 6, −3, −11 (x, y, z; MNI space) and posteriorly in the retrorubral fields)] as well as more anteriorly in the mammillary bodies and hypothalamus (not shown). Peak coordinates for the striatal AMPH-induced DA release correlations = −16, 15, 5 (left) and 20, 23, −3 (right); cluster sizes = 167 voxels (left) and 216 voxels (right). Colorbar represents Fisher-transformed z-statistic values for the correlations (d.f. = 31). SPMs rendered on a T1-weighted MRI template brain, with cuts at z = −11 and y = 16.” https://www-ncbi-nlm-nih-gov.proxy.cc.uic.edu/pmc/articles/PMC3161413/

“(B) Path analysis demonstrating that the influence of midbrain D2/D3 availability on trait impulsivity is mediated through an impact on striatal amphetamine-induced DA release. Path “A” shows path coefficients for the effect of midbrain D2/D3 binding (cluster highlighted with red circle) on striatal DA release (left/right striatum). Path “B” shows the path coefficient for the effect of striatal DA release on trait impulsivity (left/right striatum). Paths “C” and “C’” show coefficients for the total (dashed line) and direct (solid line) effects of midbrain D2/D3 binding on trait impulsivity. All coefficients standardized. Sobel test for mediation: Z = −1.94, p = 0.05, with left and right striatum modeled simultaneously.” https://www-ncbi-nlm-nih-gov.proxy.cc.uic.edu/pmc/articles/PMC3161413/

40 of 42

Brain, Reward, and Drug Addiction

Representation of reward in the brain
Neurotransmitter systems involved in reward processing

Dopamine hypothesis of reward
Beyond dopamine and prediction error

Outside the basal ganglia

Amygdala and reward processing
Lateral habenula and reward processing
Medial PFC — expectations & violations
OFC & value estimation

Addiction & reward system

Initiation & Transition to compulsive use
Individual differences in reward system, risk for addiction

Negative reinforcement in addiction

Examples & Models

Drug addiction—dynamic illness

Negative reinforcement and dynamics

Neuroimaging & addiction risk, prevention, treatment

Neural measure of addiction severity
Treatment centered approaches
Identifying risk for future dependence
Reshaping addiction research

40

bit.ly/neurobioaddict

41 of 42

Prefrontal Cortex Regulation of Emotion & Anxiety

PFC “Gateway” of Emotional Regulation
Anxiety Disorders: when regulation fails
Modulate Emotional Regulation

Brain, Reward, and Drug Addiction

Representation of reward in the brain
Neurotransmitter systems involved in reward
Outside the basal ganglia
Addiction & reward system
Negative reinforcement in addiction
Drug addiction—dynamic illness
Neuroimaging & addiction risk, prevention, tx

41

bit.ly/neurobioaddict

42 of 42

References

Graham BM, Milad MR, Charney DS, Buxbaum JD, Sklar P, Nestler EJ. 43. Prefrontal Cortex Regulation of Emotion and Anxiety. In: Neurobiology of Mental Illness. Oxford University Press, Incorporated; 2013. Accessed November 22, 2023. http://ebookcentral.proquest.com/lib/uic/detail.action?docID=1611805
Pariyadath V, Paulus MP, Stein EA, et al. 55. Brain, Reward, and Drug Addiction. In: Neurobiology of Mental Illness. Oxford University Press, Incorporated; 2013. Accessed November 22, 2023. http://ebookcentral.proquest.com/lib/uic/detail.action?docID=1611805
Stahl SM 13. Impulsivity, Compulsivity and Addiction. In: Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 5th edition. Cambridge University Press; 2021.

42

bit.ly/neurobioaddict