Neurobiology of substance dependence

1. Neurobiology of Substance
Dependence
By-
Dr.Sunil Suthar
Under Guidance of-
Dr.Suresh Gupta

2. CLINICAL FEATURES OF SUBSTANCE
DEPENDENCE
Core criteria
Tolerance
Withdrawal
Craving
Impaired control/Compulsive use/Relapse
Socio-occupational dysfunction
Persistent use despite psycho/physical harm

3. ADDICTION DEFINED NEUROBIOLOGICALLY
Maladaptive alterations
in
spontaneous behavior
&
the behavioral response to re-administration of the drug
due to
drug-induced changes in the CNS (transmitters, receptors,
circuits, volume)

4. Risk factor for substance
abuse/dependence
Environmental
• Availability of drugs
• Poverty
• Social change
• Peer culture
• Occupation
• Cultural norms,
attitudes
• Policies on drugs:
tobacco and alcohol
Individual
• Genetic disposition
• Victim of child abuse
• Personality disorders
• Family disruption and
dependence problems
• Poor performance at
school
• Social deprivation
• Depression and suicide
World Health Organization2004

5. Protective factor for substance
abuse/dependence
Environmental
• Economic situation
• Situational control
• Social support
• Social integration
• Positive life events
Individual
• Good coping skills
• Self-efficacy
• Risk perception
• Optimism
• Health-related behaviour
• Ability to resist social
pressure
• General health
behaviour
World Health Organization 2004

6. To understand neurobiology……..
• Neuroanatomy of reward system
• Evidence from animal studies
• Drugs of abuse: action & withdrawal
• Genetic predisposition

7. Natural rewards
• Food, water, sex, &
nurturing are natural
rewards.
• They allow organism to
feel pleasure when eating,
drinking, sex & being
nurtured.
• They reinforce the
behavior for repetition.
• These are required for
survival.
• Brain has pathway
responsible for reward.

8. The reward pathway
 Ventral Tegmental Area(VTA),
 Nucleus accumbens (NA) &
 Prefrontal cortex (PFC).
 VTA is connected to both NA &
PFC via this pathway sending
information via its dopaminergic
neurons,
 Dopamine released in NA &
PFC

9. • 3 brain areas mediate adaptive behaviour
Nucleus accumbens mediates reward related activities
(positive valence);
Amygdala involved in fear motivated behaviour (negative
valence)
Prefrontal cortex involved in decision making &
predicting rewarding behaviour by:
- salience attribuition of environmental stimuli &
- directing intensity of behavioural response.
• A balanced combination of motivational & affective states with
external stimuli predicts reward, & determines overall output
of a given behavioural response in acquiring natural reward

10. Dopamine
•Receptors: D1, D2
•Function: pleasure,
euphoria, mood, motor
function
Serotonin
•Receptors: 5HT3
•Function: mood, impulsivity,
anxiety, sleep, cognition
Cannabinoids
•Receptors: CB1
•Function: Pain, appetite,
memory
Opioid peptides (Endorphins,
Enkephalins)
•Receptors: Kappa, Mu, Delta
•Function: pain
The following neurotransmitters act on the
reward pathway:
In all rewards, dopamine is the final activation chemical.

11. Dopamine Pathways: Reward, Pleasure, Euphoria,
Motor Function, Decision making
Serotonin Pathways: Mood, Memory, Sleep, Cognition
Raphe
Prefrontal cortex
Nucleus
accumbens
Ventral
tegmental
area

12. Dopamine
Ventral tegmental area,
nucleus accumbens
Opioid Peptides
Nucleus accumbens,
amygdala, ventral tegmental
area
GABA
Amygdala, bed nucleus
of stria terminalis
Glutamate
Nucleus accumbens
Neurotransmitters and anatomical sites involved
in the acute reinforcing effects of drugs of abuse

13. Activation of reward pathway by an electrical
stimulus: animal model
• Rats trained to press lever for
electrical jolt to certain part of
brain, ie NA
• Rats keep pressing lever to
receive electric stimulus
because it is pleasurable.
• Reward feeling is positive
reinforcement, which occurs
due to increased dopamine
release.
• If dopamine release is
prevented rat won't press for
electrical jolt.

14. `
Rewarding input to the
nucleus accumbens is due to
bursts of dopamine release
and thus phasic dopamine
firing with "fun" and
potentiation of conditioned
reward as the result.
Connections of the
amygdala with the nucleus
accumbens communicate
that emotions have been
triggered by internal or
external cues and signal an
impulsive, almost reflexive
response to be taken.

15. Substance abuse can
arise from impairment
of top-down inhibitory
control (impairement of
prefrontal cortex)

16. behaviors
implementation

17. The amygdala can not only learn that a drug causes pleasure but can also associate cues
for that drug with pleasure. Thus, when cues are encountered, the amygdala signals
dopamine neurons in the ventral tegmental area (VTA) that something good is coming;
it may even signal the relief from drug craving (1 and 2). This leads to dopamine release
in the nucleus accumbens (3), which triggers GABA-ergic neuron .

18. HYPOTHESIS
Dopamine is the basis of the ‘rewarding’ drug
experience
Enhanced dopamine release in the meso-
cortico-limbic circuit results in maladaptive drug-
related behaviors

19. LACUNAE
Several drugs of abuse do not have prominent
dopaminergic actions.
Role of NTs like GABA, glutamate and limbic
and cortical brain areas unexplained.
Non-dopamine substrates can elicit addiction
behaviors (Giro et al, 1996; Rocha et al, 1998).

20. Development of addiction may consist in part
of a transition from dopamine-dependent
behaviors to glutamate-dependent behaviors (as is
true for natural rewards).
Cortical and allocortical areas prominent in
‘learning’ addiction behaviors.

21. Drug action in brain
 Acute drug administration modifies brain function,
 Repeated exposure causes pervasive changes in brain function &
persist long after individual stops taking drug.
 Effects of chronic drug administration have been identified at
cellular, molecular, structural & functional level.
 An addicted brain is different from a non-addicted brain.
 There are changes in brain metabolic activity, receptor
availability, gene expression & responsiveness to
environmental cues.

22. Name NT Circuit/
Area
Mechanism
Amphetamine DA VTA and
NA; brain
stem
Displaces DA,
NE from
storage sites
Alcohol GABA,
glutamate,
DA, 5-HT,
endorphins
Dose
dependent:
VTA;
Cortical,
limbic, basal
ganglia,
brain stem
Enhances
GABAergic,
inhibits
glutamatergic
actions
Cocaine DA,
5-HT, NE,
glutamate
VTA;
cortex,
limbic area
Re-uptake
inhibitor

23. Name NT Area/ circuit Mechanism
Nicotine DA,
glutamate,
GABA
VTA Direct receptor
action
Cannabis Ach, DA,
GABA,
histamine,
serotonin,
NE,
endorphins,
PGs
Basal ganglia,
cerebellum,
hippocampus,
dentate gyrus,
cortex, brain
stem
Enhance
formation of
DA, NE, 5-HT,
GABA

24. Name NT Area/
Circuit
Mechanism
Phencyclidine Glutamate Hippocampus,
anterior
forebrain
NMDA
receptor
antagonist
Opioids Opioid
receptors
Widespread:
CNS, ANS
G-protein
mechanisms:
cAMP
dependent
kinases

25. Molecular Biology of Addiction:
Addiction is a form of drug-induced neural plasticity
 Upregulation of cAMP pathway
• Occurs in response to chronic administration of drugs
• Resulting activation of transcription factor
CREB(cAMP response element-binding)
• Both mediate aspects of tolerance and dependency
 Induction of another transcription factor, d FosB -
• May contribute to sensitized responses to drug
exposure
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

26. Basis for Plasticity: Summary
Drugs enter the brain and bind to an initial
protein target
Binding perturbs synaptic transmission which in
turn cause the acute behavioral effects of the
drug
Acute effects of the drug do not explain addiction
by themselves
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

27. Addiction produces a change in brain structure
and function (adaptation to the drug)
molecular and cellular changes in particular
neurons alter functional neural circuits
This leads to changes in behavior consistent
with addicted states
Addiction is therefore a form of drug induced
neural plasticity
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

28. Addiction process behaviour
Two factors modulate behaviour in addiction
(1) Reinforcement: stimulus increases the probability of
response. positive reinforcement for pleasure from
drug. negative reinforcement to relieve withdrawal
symptoms – self-medication.
(2) Neuro-adaptation: Initial drug responses are
attenuated or enhanced by repeated drug exposure

29. Withdrawal
 Result of an abrupt cessation of the drug.
 This syndrome involves:
• disturbance of the autonomic nervous system
• activation of the thalamus
• release of corticotrophin releasing factor (CRF)
• activation of the locus coeruleus (LC)

30. Withdrawal: Corticotrophin
Releasing Factor (CRF)
Involvement
The CRF system mediates the affective and somatic symptoms of
drug withdrawal
Heart rate
Blood pressure
Blood glucose
Koob, 2008, PNAS 105(26), 8809-10, Copyright 2008, National Academy of Sciences, U.S.A.
Response to stressors

31. Withdrawal: Neurotransmitter
Involvement
Withdrawal
Dopamine: dysphoria Dynorphin: dysphoria
Serotonin: dysphoria CRF: stress
Opioid Peptides: increased pain
GABA: anxiety, panic attacks NE: stress
Glutamate: hyperexcitability
Patient feels dysphoric, irritable, depressed and angry

32. “Drug craving” behavior:
Type one
 Cue triggered: animal develops conditioned self-
stimulation in association with sensory stimuli or
preferred place
 If removed from environment for extended time
 And reintroduced to sensory stimuli or preferred place,
quickly reinstates behavior despite lack of reward
 Originates in hippocampus & amygdala; “emotional
memories”
 Neurotransmitter: glutamate

33. “Drug craving” behavior:
Type two
 Stress triggered: animal develops conditioned self-
stimulatory behavior
 Reward stopped & behavior extinguishes
 Relatively minor stress reinstates behavior & place
preference even in absence of further reward
 Mediated by corticotropin releasing factor in amygdala, &
NE from brainstem

34. Relapse studies
Stress induced relapse
‘Non-specific’
Pathways
•Mesolimbic dopamine system
•Corticotropin releasing factor (CRF): activates
HPA axis – peripheral glucocorticoid release
increased – facilitates excitatory input to VTA
DA neurons

35. DRUG USE
(Self-Medication)
STRESS
CRF
Anxiety
CRF
Anxiety
What Role Does Stress Play
In Initiating Drug Use?

36. Prolonged
DRUG
USE
Abstinence
RELAPSE
CRF
Anxiety
What Happens When A Person
Stops Taking A Drug?

37. Cue-induced relapse
Environmental stimuli – Pavlovian conditioning
Pathways
•Mesolimbic dopamine system: activation
•Amygdala
conditioning processes for stimuli
Cue-evoked recall
Activates VTA DA neurons (glutamatergic pathway) –
increased DA in NAc
•Hippocampus, anterior cingulate cortex

38. The Development of
Addiction: Genetics
Inheritability has been found to range from 40-60%
Some variability between: gender and substances
Specifically:
4-fold increased risk in 1st degree relatives
4-fold increased risk also in adopted away children

39. • Variants of genes associated with drug abuse:
– FAAH missense mutation is associated with drug dependence.
– Polymorphism in promoter region of prodynorphin gene may be
associated with protection against cocaine dependence .
– Gene variants in nicotinic alpha 7 promoter associated with
decreased expression of nicotinic alpha 7 subunit message
in different regions of schizophrenic brains and with sensory
gating defects in schizophrenics.
– 5HT1B receptor variant is associated with conduct disorder
and Alcoholism.
Genes Implicated in Addiction

40. Genes Affecting Drug metabolism
•Ethanol  Acetaldehyde  Acetate
-Individuals with defects in this metabolism pathway have a 5-
10-fold reduction in risk for alcoholism
•Nicotine  Cotinine
- Individuals with defects in this metabolism pathway appear
to smoke fewer cigarettes
ADH2
ADH3
ALDH2
ALDH3
CYP2A6

41. Comorbidity of substance
dependence and mental illness
Several hypotheses as to why mental illness and
substance dependence may co-occur:
1. There may be a similar neurobiological basis to both;
2. Substance use may help to alleviate some of the
symptoms of the mental illness or the side effects of
medication;
3. Substance use may precipitate mental illnesses or lead
to biological changes that have common elements with
mental illnesses.

42. Relationship of Addiction
Behaviour and Treatment
Addictive
component
Behavioural
construct
Treatment
focus
Pleasure Positive
reinforcement
Motivational
Self-medication Negative
reinforcement
AA and Motivational
Habit Conditioned
positive
reinforcement
Cognitive/behaviou
ral
Habit Conditioned
negative
reinforcement
Cognitive/behaviou
ral
(koob and nestler,1997)

43. TO SUMMARISE
Neuroplastic changes produced in various nuclei by repeated drug
action integrated with environmental stimuli form behaviors
characteristic of addiction
Corticofugal glutamate projection is necessary for the initiation of
drug seeking
Different modes of stimuli inducing drug seeking involve distinct
components of the circuit
All modalities of drug-seeking stimuli require dopamine
transmission

44. Pharmacology Learning
Neuroplasticity
DRUG ENVIRONMENT
Motive circuit
Cortical and
allocortical
circuit
Molecular
binding and
cell signaling
SALIENCE AND SPECIFIC
BEHAVIORAL RESPONSE

45. Neurobiological stages of addiction
Stage 1: Acute drug effects
Based on supraphysiological release of DA in the
circuit
Induction of immediate early genes like c-fos
(Graybiel et al, 1990)
Short-lived changes: hours to days

46. Stage 2: Transition to addiction
As a result of repeated drug use
Mediated by ΔFosB (Nye et al, 1995)
Reversible: diminish over days to weeks of
discontinuation
Stage 3: End-stage addiction
Long-standing drug use
Enduring protein and cellular changes
Irreversible

47. Ref. books…..
• Stahls essential psychopharmacology 3rd edetion.
• Kaplan and Sadocks comprehensive text book 9th edition.
• Neuroscience of psychoactive substance use and
dependence.WHO,2004.