Transcript The Development of Addiction

Drug abuse
By
Mohie aldien elsayed (MD)
Learning Objectives
• To be able to:
• Identify the anatomical areas of the brain involved
in the reward pathway
• Outline the neurotransmitter systems which
activate the reward pathway
• Identify the anatomical areas and receptors
involved in activation from psychoactive drugs
• Identify the anatomical areas and receptors
involved in the withdrawal from psychoactive drugs
• Understand concepts relating to the development
of addiction
Corpus Callosum
Connects Hemispheres
Creativity and Problem Solving
Frontal Cortex
Planning, Strategizing, Logic, Judgment
Cerebellum
Coordinates muscles/ movement
and thinking processes
Thalamus
Nucleus
accumbens
Extended Amygdala
Emotional responses: fear
and anger
Ventral
tegmental
area
Locus
coeruleus
Hippocampus
Forms Memories
Coordinates thinking processes
Dopamine Pathways: Reward, Pleasure, Euphoria,
Motor Function, Decision making
Prefrontal cortex
Hippocampus
Nucleus
accumbens
Ventral
tegmental
area
Raphe
Serotonin Pathways: Mood, Memory, Sleep, Cognition
Reward Pathway
• There is a axonal network in the brain labeled the ‘reward pathway’
• This reward pathway is activated by:
- Food, water and sex, activities (such as sky diving, paragliding etc) and exercise
-This reward pathway is also activated by drugs and alcohol
Dopamine (Ventral tegmental
Serotonin
area, nucleus accumbens)
•Receptors:
•Receptors:
D1, D2
•Function: pleasure,
euphoria, mood, motor
function
Cannabinoids
•Receptors:
CB1, CB2
•Function: Pain, appetite,
memory
5HT3
•Function: mood, impulsivity, anxiety, sleep,
cognition
Opioid peptides (Endorphins, Enkephalins) Nucleus accumbens, amygdala, ventral tegmental area)
GABA (Amygdala, bed nucleus
of stria terminalis)
•Receptors:
Kappa, Mu, Delta
•Function: pain
Glutamate (Nucleus accumbens)
In all rewards, dopamine is the final activation chemical
Drug Action & Reward Pathway
Alcohol
•Binds/Inhibit GABAA: Dopaminergic
activity is eventually increased in the
VTA by inhibiting GABAergic
interneurons
•Also binds to NMDA, endorphins, activates
secondary messages and has direct serotonergic
effects
Heroin (Opioid)
Binds to opioid receptors that inhibit
GABAergic neurons that project to
dopaminergic neurons in the VTA
Methadone and levo-alphaacetylmethadol (LAAM). Naltrexone
Naltrexone
Cocaine
Nicotine
Blocks the function of DAT (by binding
the DAT
and slowing
nto
icotine
replacement
producttransport)
(such as
Activates cholinergic neurons that
project to dopaminergic neurons of
the VTA
patches or gum) or an oral medication
(such as bupropion)
Intoxication & Withdrawal:
Neurotransmitter Involvement
Intoxication
Dopamine: euphoria
Serotonin: elevated mood
Opioid Peptides: analgesia, relaxation
GABA: decreased anxiety, less panic, relaxation
Withdrawal
Dopamine: dysphoria
Serotonin: dysphoria
Opioid Peptides: increased pain
GABA: anxiety, panic attacks
NPY: stress
Dynorphin: dysphoria
CRF: stress
Norepinephrine: stress
Glutamate: hyperexcitability
GABA
GABA +
Alcohol
GABA +
Alcohol
Acute
Intoxication
Chronic
Intoxication
Stress:
Heart rate
Blood pressure
Blood glucose
Response to
stressors
Adapted from Koob & Moal, 2006, reprinted with permission
No Alcohol
The Development of Addiction
• The use of the drug of abuse is increased to maintain euphoria or to avoid
dysphoria or withdrawal
• The number of receptors gradually increases to counter for the continual
presence of the drug of abuse
• The amount of neurotransmitter gradually decreases through depletion and
feedback inhibition
• The reinforcing properties of the drug are thus gradually decreased (tolerance)
• The need for drug to maintain this new homeostasis is therefore increased
(dependence begins)
*The resulting behaviours activate the reward pathway and a relationship is
developed and becomes dominant.
*Behavioural repertoire is narrowed and eventually other important behaviors
are ignored (e.g. familial, financial)
•The reward and cognitive (decision making systems) are compromised resulting
in an imbalance in impusive behaviours (e.g. violence, crime)
PFC
Amygdala
NAc
The Development of Addiction:
Long Term Changes
There is evidence of prolonged drug abuse resulting in both structural
and functional brain changes
Decreases in CREB transcription factor in NAc (and extended
amygdala)
Decreases in metabolism in Orbito Frontal Cortex (OFC)
Decreases in dopamine D2 receptor binding (see figure below)
Volkow et al.
Synapse 14 (2), 1993, pp. 169-177. ©
1993 Synapse. Reprinted with
permission of John Wiley & Sons, Inc.
The Development of Addiction:
Long Term Changes
Dopamine transporter (DAT) binding following
heavy methamphetamine (METH) use
Control
METH user
Volkow et al. Am. J. Psychiatry 158(3), pp. 377-382, 2001
Reprinted with permission from the American Journal of Psychiatry (Copyright 2001).
American Psychiatric Association.
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
The Development of Addiction:
Genetics
Polymorphism is an altered base
pair sequence
(altered mRNA = altered protein = altered function)
Polymorphisms may
- alter synthesis of dopamine
- alter neurotransmitter release
which may diminish function of prefrontal
cortex and exaggerate amygdala
Functional consequences relating to addiction include
altered: initial response to intoxication, tolerance
development, withdrawal effects, psychiatric comorbidity
Goals of Drug Treatment:
Keeping an Eye on the Target
Functionality in
Family, Work,
and Community
Drug Abuse Treatment Core Components
and Comprehensive Services
Medical
Financial
Housing &
Transportation
Core
Treatment
Intake
Assessment
Child
Care
Treatment
Plans
Group/Individual
Counseling
Abstinence
Based
Pharmacotherapy
Mental
Health
Urine
Monitoring
Case
Management
Continuing
Care
Self-Help
(AA/NA)
Family
AIDS /
HIV Risks
Vocational
Legal
Etheridge, Hubbard, Anderson, Craddock, & Flynn, 1997 (PAB)
Educational
When to Consider Pharmacotherapy
Assess Pt For:
•
Severity of Concomitant Medical Illness: Patient’s ability to
tolerate medication?
•
Pregnancy: opioid therapy should be offered to pregnant
opioid/heroin addicts; medications that can be associated
with adverse physical effects should be avoided (e.g.:
disulfiram (Antabuse)
•
Phase of Recovery: Medications for medical withdrawal or
medication to assist with maintenance of abstinence
following withdrawal
Phases of Substance Use that are
Targets for Pharmacotherapy
• intoxication/overdose
• withdrawal/detoxification
• abstinence initiation/use reduction
• relapse prevention
• sequelae (psychosis, agitation, etc.)
Substances for which
Pharmacotherapy
is Available
• Opioids
• Alcohol
• Benzodiazepines
Substances for which
Pharmacotherapy
is Not Available
• Cocaine
• Methamphetamine
• Hallucinogens
• Cannabis
• Tobacco (nicotine dependence)
• Solvents/Inhalants
PHARMACOTHERAPIES
Opioid Addiction
› Methadone
› Buprenorphine
› Naltrexone
Tobacco Addiction
 Alcohol Addiction
› Naltrexone
› Acamprosate (Campral®)
› Disulfiram (Antabuse®)
› Topiramate (Topamax®)
› Nicotine Replacement
Therapy (NRT)
 Electronic Cigarettes, gum,
patches
Bupropion (Zyban®)
›
› Varenicline (Chantix®)
Lori L. Phelps California Association for Alcohol/Drug Educators, 2013
Similarities & Differences Alcohol
Intended Intoxica W/d – detox
effect
tion
4-12n hrs. p last drink Course hand tremor,
AlcoholCNS
Depressant/
relaxation,
loss of
inhibition
sweating
Slurred
speech;
 Relapse Prevention
loss of
*Disulfiram
coordinati *Naltrexone (oral
and injectable)on;
mu blocker
*Acamprosate
ataxia;
(↓glutamate
decreased release )
coordinati *to help sleep
Consider low dose
on,
trazodone (e.g.
attention/ 25 mg) or qHS
concensedating anti
Depressant
tration,
(especially if pt has co-morbid depression,
memory
e.g.:mirtazepine).
judgment
Sedatives /Hypnotics
Anxiolytics
Induced
effect
Benzodiazapi
nes&
Barbituates
Use: to
produce
Drowsiness,
 anxiety
IntoxBenzo’s rarely
fatal when taken
alone; sx’s =
Lethergy,
Confusion;
Barb’s –fatal in
OD-coma,resp –
cardiac arrest
W/d –
detox
Ativan-10 hrs W/d sx’s-6-8
hrs p last dose
Valium –w/d up to 1 wk
W/d= v/s
Need to taper off drug
Stimulants amphetamines/cocaine
Intended effect
Excite – CNS
Limited clinical
use – high abuse
potential
Cocaine-highly
addictive
IntoxHigh-euphoric
feeling;hyperactivity/vigilance
Talkativeness,
grandiosity,hallucin
ations, anxiety
Repetitive
behaviors, anger ,
fighting
W/d – detox
Occurs-few hrsdays
C/b marked
dysphoria;
fatigue; vivid &
unpleasant
dreams; hyper or
insomnia;
psychomotor act.
Opioids: morphine, heroin, meperidine, codeine, hydromorphone,
Induced
effect
Intox –
develops
Popular for quickly c/b
apathy,
abuse –
lethergy,listless
desensitize
user to both ness,judgment
physio/psych , psycho-motor
pain-induce retardation or
agiation,
euphoria,
constricted
well-being
pupils,slurred
speech Severe o
d coma,
Resp.
arrest/death
W/d detox: Drug intake ceases or 
markedly; c/b Anxiety /restless., aching
back ,legs, craving for opioids
Heroin –w/d 6-24 hr;
peak 2-3 days; Ends=5-7 days
•Long acting mu agonist (Methadone
;Buprenorphine )
•Naltrexone
Hallucinogens
Intended
effect
Distort users
perception of
reality
Intoxification/OD
Intox= (Psychologic)
anxiety,depression,
Paranoid delusions,
hallucinations
(Physio)  B/P,T,P
dilated pupils,sweating,
blurred vision,tremors,
decreased coordination
Withdrawal/Detox
No withdrawal
symptoms known
-may crave drug
Produce flashbacks
May continue up to
5 years after use.
Drug Action: Direct
e.g. Cocaine
•The mechanism of action for cocaine is via reuptake
inhibition of dopamine
•Dopamine release is promoted via the protein responsible
for the reuptake of dopamine (dopamine transporter; DAT)
Cocaine binds DAT =
extracellular dopamine
Thank you