Drug Dependence and Tolerance

Question 1

How do we diagnose addiction?

Answer 1

Question 2

Factors Contributing to Vulnerability to Develop Addiction?

Answer 2

Also: mental illness-
Emotional disorders key predictor of alcohol use
It is accompanied by more severe symptoms, longer
illness duration, higher relapse

Question 3

Describe the stages of the addiction cycle

Answer 3

Question 4

What is drug dependence?
9 physical withdrawal effects vs 3 psychological withdrawal effects?

Answer 4

An adaptive state, from repeated drug use –> results in withdrawal symptoms upon cessation

Physical withdrawal: characterised by abstinence syndrome (LC) –> Sweating, gooseflesh, irritability, aggression, joint aches, diarrhoea, abdo pain, nausea, insomnia

Psychological: (anxiety, social withdrawal, depression)

Question 5

4 brain circuits associated with addiction?

Answer 5

Orbitofrontal cortex: gives value to reward

Nucleus accumbens + ventral palladius: gives sense of reward

Amygdala & hippocampus = learning and memory: emotional learning of the high

Prefrontal cortex + Anterior cingulate cortex: cognitive control = executive centres, help make judgements, which in addiction are poor

Question 6

Describe neurobiological Changes during the Addiction Cycle and compare it to a non dependent individual.

In Non-dependent individual: DA neurones ? –> ?.
? rewards release ? here = ?

Drugs ? this pathway –> much more ? released giving ?

So in a dependent individual, the reward pathway is ? –> therefore ?, only drugs are

Answer 6

In Non-dependent individual: DA neurones in reward pathway go from ventral tegmental area –> n.accumbens. Natural rewards release DA here = sense of reward

Drugs hijack + overstimulate this pathway –> much more DA released giving a ‘high’ = aka acute positive reinforcement (stage 1)

So in a dependent individual, the reward pathway is suppressed, less DA released –> therefore natural rewards ya no euphoric, only drugs are

Question 7

How is drug abuse linked to stress pathways?

Which drugs reduce stress and which drugs increase stress?

Either way, drugs of abuse…

Answer 7

Hay recruitment of stress pathways: e.g. stimulation of the amygdala by CRF activates the HPA axis.

Opioids inhibit HPA –> reducing stress
Cocaine activates HPA=increased stress

Either way, drugs of abuse send your stress regulatory system haywire –why addictions=lack of coping as they influence HPA dramatically

Question 8

Give the different acute targets for drugs inc opioids, coke, amphetamines and alcohol

Answer 8

Opioids: Agonist at mu (& delta,kappa) opioid receptors
Cocaine: DA transporter blocker - (indirect DA agonist)
Amphetamine: DA releaser - also an indirect DA agonist
Alcohol: Facilitates GABAA + inhibits NMDA receptor function

Question 9

Give the different acute targets for drugs inc nicotine, cannabinoids, phencyclidine and hallucinogens

Answer 9

Nicotine - Agonist at nACh receptors
Cannabinoids - CB1 receptor agonist
Phencyclidine - NMDA receptor antagonist
Hallucinogens - 5-HT2A agonists

Question 10

MOA of amphetamines + what can happen with prolonged use?
3 Therapeutic uses of amphetamines?

Answer 10

Amphetamines (e.g. MD) reverse the DA reuptake transporter + displaces cytosolic DA from vesicles

Prolonged use degenerates amine-containing nerve terminals –> cell death, can lead to amphetamine psychosis = schizophrenia w hallucinations!

Methylphenidate –> treat ADHD
Appetite suppressants in obese
Treat narcolepsy (inability to regulate sleep-wake cycles)

Question 11

Describe the moa of cocaine
compare 3 methods of Administration?

Answer 11

blocks reuptake of DA –> accumulates in synaptic cleft –> increases D1 +D2 receptor stimulation in nucleus accumbens

Inhaled= less intense, but causes nasal mucosa necrosis
Smoked in its free base form (crack)= as intense as IV route

Question 12

compare pharmacological effects of amphetamine vs cocaine

Answer 12

Amphetamine:
euphoria + locomotor stimulation (may increase aggression)
Increased alertness
Excitement
Decreased physical + mental fatigue
Anorexia
Peripheral sympathomimetic actions - increased BP + decreased gastric motility

Cocaine:
Euphoria, locomotor stimulation, heightened pleasure
(lower tendency for the development of delusions, hallucinations and paranoia than amphetamines)

Question 13

Describe heroin; when is tolerance seen?

Answer 13

Opioids produce intense euphoria by acting on MOP e.g Diamorphine (heroin) –> high abuse potential

Tolerance seen within 12-24hrs - therefore heroin is very easy to OD on!

Question 14

How is opioid addiction treated?

Answer 14

methadone (MOP agonist with long half-life) + partial agonists (e.g. buprenorphine)
Both stimulate the receptors giving dampened high (which prevents withdrawal) + also prevents any extra effect from heroin or morphine etc

Question 15

Describe alcohol’s moa
how can the rewarding effect of alcohol be reduced?

Answer 15

Alcohol inhibits presynaptic Ca entry via vgCCs, inhibiting release of GABA.
This disinhibits dopaminergic neurones in mesolimbic pathway –> inducing release of endogenous opioid peptides

The rewarding effect of alcohol is reduced by naltrexone (an opiate antagonist)

NOTE - GABAa is not in Mesolimbic pathway!!

Question 16

Describe nicotine’s moa

Answer 16

Acts at a4β2 ligand gated nACh receptors in different areas of the brain:
In the cortex + Hippocampus (cognition –> alertness)
In the VTA (releases DA into reward pathway –> decreased irritability)

It enhances transmitter release + neuronal excitability –> therefore leads to release of endogenous opioid peptides

Question 17

Describe stage 2 of the addiction cycle

Answer 17

Stage 2 – Repetitive Use and Withdrawal
Once someone becomes dependent on a drug, they will experience physical and psychological withdrawal when they are not taking it

Question 18

Describe the mechanism of tolerance to opioids

Answer 18

Bombarding opioid receptors every day for long periods= desensitisation (receptor will oppose the normal drug effects)

Desensitisation occurs bc proteins (GRK + beta-arrestin) phosphorylate G protein coupled receptor - inhibting GPC signalling pathway upon binding of opioid
This is reversible alhamdulilah

Question 19

compare types of withdrwals from different drugs:
Psychostimulants, MDMA, Heroin, nicotine, alcohol

Answer 19

Psychostimulants: deep sleep, lethargy, depression, anxiety & hunger
MDMA: Depression, anxiety, irritability, aggression
Heroin: Sweating, gooseflesh, irritability, aggression
Nicotine: Irritability, hunger, weight gain, impaired cognitive and motor performance, craving (persisting many years)
Alcohol: Tremor, nausea, fever, hallucinations, sweating

Basically the opp of the drugs effects

Question 20

Describe 3 mechanisms of dependence using imaging.

Less ? activity in ?

Addict brains also had fewer ?–> therefore reduced ?

? connections are ? in addiction, whilst ? connections are ? – these are the changes that drive the addiction

Answer 20

Less frontal cortex activity in addicts (so poor decision making)

Addict brains also had fewer D2 (DA) receptors within reward centres–> therefore reduced DA binding, suppressing reward pathways!

Excitatory connections are Strengthened in addiction, whilst inhibitory connections are Downregulated – these are the changes that drive the addiction