WEEK 6: LECTURE 12 ADDICTION AND WITHDRAWAL Flashcards
What are the 2 Main Dopamine pathways?
- mesocorticolimbic
- Nigrostriatal
DA encodes?
DA encodes REWARD AND APPROACH OF REWARD TO SHAPE BEHAVIOUR
Mechanisms of Cocaine and Methamphetamine
Mechanisms of Cocaine and
Methamphetamine (‘INCREASE IN DA’)
Define Addiction - SUBSTANCE-USE DISORDERS (SUDs)
‘compulsive engagement in rewarding stimuli despite adverse consequences.’
Addiction – Substance-Use Disorders (SUDs)
*DSM 5 – 11 criteria, broadly organised into 4 categories = 4
list and explain them
- IMPAIRED CONTROL = a ‘craving’ or strong urge to use the substance; desire or failed attempts to cut down or control substance use.
- SOCIAL PROBLEMS = Substance use causes failure to complete major tasks at work, school or home; social, work or leisure activities are ‘given up or cut back’ because of substance use
- RISKY USE = SUBSTANCE IS USED IN RISKY SETTINGS - continued to use despite known problems
- DRUG EFFECTS: TOLERANCE (need for larger amounts to get the same effect); WITHDRAWAL symptoms (different for each substance)
OTHER ADDICTIVE BEHAVIOURS = 4
- BEHAVIOURAL
- GAMBLING
- SIMILAR BUT DIFFERENT - ‘COMPULSIVE:’
- EATING DISORDERS - BINGE EATING DISORDER, ANOREXIA NERVOSA etc
Using drugs does not lead to addiction but …PEOPLE WHOP AE VULNERABLE TO ADDICTION HAVE…
USING DRUGS DOES NOT = ADDICTION
- Vulnerabilities
- 3. GENE-ENVIRONMENT INTERPLAY
- 4. PAST TRAUMA/STRESSORS
- 5. DEVELOPMENT
- 6. SOCIETAL/CULTURAL FACTORS
List addiction phases = 5
- Non-problematic or recreational use
- escalation of drug use
- Compulsive and/or problematic use
- abstinence (withdrawal)
- relapse
it is cyclical
Stages of Addiction:
‘Neurocircuitry Perspective’
= 3 and where and what
- preoccupation/anticipation
- in PREFRONTAL CORTEX
- Executive function deficits - Binge/intoxication
- in BASAL GANGLIA
- Incentive salience - WITHDRAWAL/NEGATIVE IMPACT
- in ‘EXTENDED AMYGDALA’
- Reward deficit and stress surfeit
IT IS A FEEDBACK LOOP
Understanding ‘BINGE’ and INTOXICATION = 6
- occurs in MESOLIMBIC SYSTEM - NAc (nucleus accumbens) is the REWARD.\/MOTIVATION HUB
- All drugs pof abuse ACTIVATE THE MESOLIMBIC SYSTEM
- 3. ‘STIMULANT DRUGS’ = fast and steep DA release in the NAc - acute rewarding effects
-4. ‘OTHER DRUGS’ = NAc activity not necessary for Rewarding effects, but they indirectly activate nac which still reinforces behaviour - BUT NEED REPEATED EXPOSURE –> ADDICTION
- REPEATED ACTIVATION of NAc REINFORCES DRUG-TAKING BEHAVIOUR
What is Chronic drug use? 3
- drug-related cues become conditioned stimuli after repeated use
- whenever cues appear INCREASE STRIATAL DOPAMINE —> INCREASED MOTIVATION
- ONE ASPECT UNDERLYING CRAVINGS
CHRONIC DRUG USE - EXPLAIN THE PROESS = 9
- REPEATED EXPOSURE –> ‘MALADAPTIVE SENSITISATION’
- Enhanced Dopamine neurotransmission in response in response to drug challenge
—3. increased DA release
—4. inhibition of D2 autoreceptors
—5. D1 receptors more sensitive in NAc - HYPERACTIVATION of the MOTIVATION/DRIVE CIRCUIT —> greater ‘wanting’ to drug and its cues and contexts
- Increase in ‘wanting’ for the drug and its cues without a change in ‘liking’
- Strong drug-taking urges –> ‘Compulsive use’
- eventually repeated use –> HABIT FORMATION
What is HABIT FORMATION? = 5
- No longer ‘goal directed’
- action no longer dependent of the outcome value
- automatic/compulsive
- continued use despite punishment or aversive effects
- shift from ventral to dorsal striatum activity
understanding habit formation - cell activity = 8
- VENTRAL STRIATUM. NUCLEUS ACCUMBENS
2 ‘outcome/value dependent behaviour’
- DORSOMEDIAL STRIATUM
- ‘outcome/value dependent behaviour’
- DORSOMEDIAL STRIATUM
- ‘stimulus/cue dependent outcome independent behaviour’
- DORSOLATERAL STRIATUM
- stimulus/cue dependent outcome independent behaviour’
Chronic Drug Use – Withdrawal/negative affect
Understanding what NEUROADAPTATION IS…4 and explain
- REPEATED HYPERDOPAMINERGIC SIGNALLING –> compensatory hypodopaminergic state
- REDUCED LEVELS OF D2 RECEPTORS and in the amount of DA released by DA cells
- Less BASAL DOPAMINE SIGNALLING –> Decreased sensitivity to natural rewards —>ANHEDONIA
- WITHDRAWAL with NEGATIVE AFFECT 9irritable, stress malasie), improved temporarily with Drug use
Preoccupation and Anticipation… NEUROADAPTATION = 4
- NEUROADAPTATION —> reduced D2 receptors
- Reduced D2 receptors impact PFC functioning —> ‘impaired cognitive control’
- Weakened executive control network
- Inability to ‘inhibit’ drug seeking behaviours contributes to impulsivity and compulsive drug seeking
What is Craving?
- Drug related cues result in DA increase – increase LIKELIHOOD OF RELAPSE
- CRAVING INCUBATION - PROGRESSIVE INCREASE IN CUE-INDUCED CRAVING FOR THE DRUG FOLLOWING WITHDRAWAL
(Some) Mechanisms Underlying Craving Incubation = 3
- CENTRAL AMYGDALA EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) ACTIVITY
- D3R ACTIVITY IN NUCLEUS ACCUMBENS 9NAc) CORE OR SHELL, or CENTRAL AMYGDALA
- ACCUMULATION OF ‘CA+2’ permeable GluA2-lacking AMPA receptors in NAc
How to break out of the FEEDBACK LOPP OF ADDICTION? =
- Detoxification
- inpatient rehab – shelter from cues, drug seeking behaviour
- therapy to give coping strategies’ craving executive dysfunction, emotional processing
- Medication
DE-ADDICTION… PHARMACOLOGICAL METHODS…5
- usually USED IN COMBINATION WITH NON-PHARM AND PSYCHOSOCIAL INTERVENTIONS
- REPLACEMENT with safer option
- reduce cravings and withdrawal effects
- deter via increased negative effects
- NO FDA- approved treatment for stimulant abuse yet
HOW TO Replacement with safer option WITH EXAMPLES…5
- REPLACEMENT with LESS ADDICTIVE, SAFER OPTION ‘AGONIST’
- SMOKING: Nicotine replacement therapy
- OPIODS
- — METHADONE AND BUPRENORPHINE
- — ‘Methamphetamine’ : MODAFINIL
EXPLAIN WHAT ‘METHADONE’ IS: =
- no ‘HIGH’
- REDUCE CRAVING and PREVENT WITHDRAWAL
- lasts longer - so can administer once per day
- Occupies OPIOID RECEPTOR BINDING SITES – less effect on another opioid, if taken
- LONG-TERM MANAGEMENT: months to years
- CONTROLLED ADMINISTRATION - lower risk of overdose, reduce IV drug use
REDUCE CRAVINGS AND WITHDRAWAL SYMPTOMS FOR ALCOHOL, SMOKING AND OPIODS - MEDS = 6
ALCOHOL
1. NALTREXONE - opioid receptor antagonist - reduce craving and rewarding effect of alcohol/opioid use
- ACAMPROSATE - modulate GABA And GLUTAMATE RECEPTORS to RESTORE BALANCE
3 - inhibit NMDA glutamate receptor activity which are hyperexcitable and associated with physical symptoms of withdrawal and craving
SMOKING
4. BUPROPION - anti-depressant, inhibit DAT and NET. Increase DA for anti- craving and anti-withdrawal –combat hypodopaminergic state
5 - can also be used in combination with NALTREXONE for ALCOHOL TREATMENT
OPIOIDS
6 - NALTREXONE
DE-ADDICTION — INCREASE NEGATIVE EFFECTS …6
- DISULFIRAM
- inhibits metabolism of alcohol - in hibits acetaldehyde dehydrogenase
- build up of acetaldehyde –> unpleasant side effects
4.* E.g. flushing, headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, marked uneasiness, weakness, vertigo, blurred vision, and confusion
- NOT A FIRST LINE TREATMENT, POOR ADHERENCE
- LOOK AT CHEMICAL EQUATION.. SLIDE 21 FOR ETHANOL —> DISULFIRAM (ANTABUSE)–> ACETATE
DE-ADDICTION …NEW TARGETS AND METHODS…9
- COMBAT ‘ALTERED PLASTICITY’ during Addiction
- BRAIN STIMULATION —> activity-induced plasticity changes
- E.g. repetitive transcranial magnetic stimulation (rTMS)
- REDUCE CRAVING BY:
- COMBAT HYPODOPAMINERGIC STATE:
—- 6. INCREASE SYNAPTIC DA
—- 7. UPREGULATE D2 RECEPTOR ACCUMULATION
- COMBAT HYPODOPAMINERGIC STATE:
- STRENGTHEN PFC GLUTAMATE SYNAPSES
—-9. improve executive deficits
- STRENGTHEN PFC GLUTAMATE SYNAPSES
- Neurological changes with chronic drug use = 6
- Cue-induced craving
- Maladaptive sensitisation to the drug
- Reduced basal dopamine signalling (neuroadaptation)
- Weakened executive functions
- Habit formation
- Craving incubation
- Pharmacological approaches to deaddiction = 4
1 * Replacement with safer alternative
2 * Reduce craving and withdrawal symptoms
3 * Increase negative effects
4 * Alter plasticity
