neurobiology of substance dependence
TRANSCRIPT
![Page 1: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/1.jpg)
Neurobiology of Substance Dependence
By-
Dr.Sunil SutharUnder Guidance of-
Dr.Suresh Gupta
![Page 2: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/2.jpg)
CLINICAL FEATURES OF SUBSTANCE DEPENDENCE
Core criteria
Tolerance
Withdrawal
Craving
Impaired control/Compulsive use/Relapse
Socio-occupational dysfunction
Persistent use despite psycho/physical harm
![Page 3: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/3.jpg)
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)
![Page 4: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/4.jpg)
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
![Page 5: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/5.jpg)
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
![Page 6: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/6.jpg)
To understand neurobiology……..
• Neuroanatomy of reward system
• Evidence from animal studies
• Drugs of abuse: action & withdrawal
• Genetic predisposition
![Page 7: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/7.jpg)
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.
![Page 8: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/8.jpg)
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
![Page 9: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/9.jpg)
• 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
![Page 10: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/10.jpg)
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.
![Page 11: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/11.jpg)
Dopamine Pathways: Reward, Pleasure, Euphoria, Motor Function, Decision making
Serotonin Pathways: Mood, Memory, Sleep, Cognition
Raphe
Prefrontal cortex
Nucleusaccumbens
Ventraltegmentalarea
![Page 12: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/12.jpg)
Dopamine
Ventral tegmental area, nucleus accumbens
Opioid Peptides
Nucleus accumbens, amygdala, ventral tegmental area
GABA
Amygdala, bed nucleusof stria terminalis
Glutamate
Nucleus accumbens
Neurotransmitters and anatomical sites involved in the acute reinforcing effects of drugs of abuse
![Page 13: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/13.jpg)
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.
![Page 14: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/14.jpg)
`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.
![Page 15: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/15.jpg)
Substance abuse can arise from impairment of top-down inhibitory
control (impairement of prefrontal cortex)
![Page 16: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/16.jpg)
behaviors implementation
![Page 17: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/17.jpg)
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 .
![Page 18: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/18.jpg)
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
![Page 19: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/19.jpg)
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).
![Page 20: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/20.jpg)
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.
![Page 21: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/21.jpg)
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.
![Page 22: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/22.jpg)
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
![Page 23: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/23.jpg)
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
![Page 24: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/24.jpg)
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
![Page 25: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/25.jpg)
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
![Page 26: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/26.jpg)
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
![Page 27: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/27.jpg)
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 plasticityRef: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001
![Page 28: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/28.jpg)
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
![Page 29: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/29.jpg)
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)
![Page 30: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/30.jpg)
Withdrawal: Corticotrophin Releasing Factor (CRF) Involvement
The CRF system mediates the affective and somatic symptoms of drug withdrawal
Heart rateBlood pressureBlood glucose
Koob, 2008, PNAS 105(26), 8809-10, Copyright 2008, National Academy of Sciences, U.S.A. Response to stressors
![Page 31: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/31.jpg)
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
![Page 32: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/32.jpg)
“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
![Page 33: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/33.jpg)
“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
![Page 34: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/34.jpg)
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
![Page 35: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/35.jpg)
DRUG USE(Self-Medication)DRUG USE
(Self-Medication)
STRESSSTRESS
CRFCRF
AnxietyAnxiety
CRFCRF
AnxietyAnxiety
What Role Does Stress Play In Initiating Drug Use?
What Role Does Stress Play In Initiating Drug Use?
![Page 36: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/36.jpg)
ProlongedDRUGUSE
ProlongedDRUGUSE
AbstinenceAbstinence
RELAPSERELAPSE
CRFCRF
AnxietyAnxiety
What Happens When A Person Stops Taking A Drug?
What Happens When A Person Stops Taking A Drug?
![Page 37: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/37.jpg)
Cue-induced relapseEnvironmental 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
![Page 38: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/38.jpg)
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
![Page 39: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/39.jpg)
• Variants of genes associated with drug abuse:
– FAAH missense mutation is associated with drug dependence.
– Polymorphism in promoter region of prodynorphin gene may beassociated 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
![Page 40: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/40.jpg)
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
ADH2ADH3
ALDH2ALDH3
CYP2A6
![Page 41: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/41.jpg)
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.
![Page 42: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/42.jpg)
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/behavioural
Habit Conditioned negative reinforcement
Cognitive/behavioural
(koob and nestler,1997)
![Page 43: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/43.jpg)
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
![Page 44: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/44.jpg)
Pharmacology Learning
Neuroplasticity
DRUG ENVIRONMENT
Motive circuit
Cortical and allocortical circuit
Molecular binding and cell signaling
SALIENCE AND SPECIFIC BEHAVIORAL RESPONSE
![Page 45: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/45.jpg)
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
![Page 46: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/46.jpg)
Stage 2: Transition to addictionAs 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 addictionLong-standing drug use
Enduring protein and cellular changes
Irreversible
![Page 47: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/47.jpg)
Ref. books…..
• Stahls essential psychopharmacology 3rd edetion.• Kaplan and Sadocks comprehensive text book 9th edition. • Neuroscience of psychoactive substance use and
dependence.WHO,2004.
![Page 48: Neurobiology of substance dependence](https://reader036.vdocuments.net/reader036/viewer/2022062308/55c4a55bbb61ebe80a8b4639/html5/thumbnails/48.jpg)