W20 Pharmacological basis of Drug abuse Flashcards
What is Drug dependence? (addiction)
What is tolerance?
What is withdrawal?
- Desire to seek/experience drug effects takes precedence over other needs and dominates lifestyle – harm to self and community
- Psychological: Craving, compulsion, loss of control, ‘addiction’
- Physiological: When stopping a drug causes a withdrawal syndrome
Tolerance:
* When continued use of a drug results in the need for increasing doses for equivalent effect
Withdrawal:
* Physical symptoms as a result of not taking drug
The integral relationship between Reward and Reinforcement:
What is a reward?
What is a reinforcement?
Reward= subjective, varies from person
Reward= feeling of happiness or well-being: linked to EUPHORIA (anything that produces pleasure/satisfaction -A stimulus that increases the likelihood of the behavior being repeated.)
Reinforcement= objective
Reinforcement= Performing a behaviour in order to obtain a stimulus. ie. a reward.
Rewarding substances and behaviours can lead to ADDICTION
The biological basis for reward & reinforcement:
e.g. Rat brain
What is the most rewarding site in the brain?
3 areas responsible for reward and reinforcement?
- Most rewarding sites in the medial forebrain bundle (MFB)
- Most sensitive locations
= 1. ventral tegmental area (VTA)
2. nucleus accumbens (3. mesolimbic pathways responsible for reward & reinforcement) - Contains DA, NA and 5HT pathways
- Intra-cranial self-stimulation blocked by D1/2 antagonist
- Blocked by lesions to DA pathways
Dopamine and its receptor targets;
how many receptor targets does dopamine act on? names?
which receptors stimulate and which inhibit adenylyl cyclase?
which receptor is the most abundant?
Dopamine acts on 5 receptor types (D1–D5, all metabotropic): - GPCRs
- D1 and D5 receptors couple to G stimulatory sites and activate adenylyl cyclase
- D2 through D4 receptors couple to G inhibitory sites, which inhibit adenylyl cyclase and activate K+ channels.
- The D1 (post-synaptic) receptor is the most abundant in the central nervous system, followed by D2 (pre-autoreceptors and post- synaptic).
- Autoreceptors are release regulators to maintain NT homeostasis.
The dopamine reuptake transporter (DAT) retakes the dopamine from the synaptic cleft
Dopamine and its function (normal)
What effects does dopamine have?
What are some functions of dopamine receptors?
*Rewarding/motivating effects (Pleasure driven)
- In a healthy person, the reward system reinforces natural reward systems for food, sex and social interaction (e.g, eating food, listening to music and others)
*Other specific functions (know roughly-dont memorise)
*D1: memory, attention, impulse control, regulation of renal function, locomotion
*D2: locomotion, attention, sleep, memory, learning
*D3: cognition, impulse control, attention, sleep
*D4: cognition, impulse control, attention, sleep
*D5: decision making, cognition, attention, renin secretion
Most drugs of abuse increase dopamine release in the nucleus accumbens:
or Self-administered:
What are examples of drugs that increase DA release?
Amphetamine,cocaine, nicotine, alcohol, heroin, codeine, morphine, methadone, PCP
THC, caffeine, diazepam, opioids
LSD- X
Drugs with different pharmacology increase DA levels in the nucleus accumbens -
What are the modes of action of cocaine and amphetamine?
- Cocaine inhibits DA uptake (transporter in pre-synaptic neurone)
- Amphetamine increases DA release (from vesicles)
- Both increase DA levels in the synaptic cleft
Opiates - morphine, heroin, methadone MOA?
- Opiates inhibit GABA neurones via binding to mu/μ-opioid receptors
- Also inhibit GABA release from nerve terminals
- Disinhibits projection neurones increased firing
- Increase DA release in accumbens
Cannabis MOA?
- THC inhibits GABA neurones via CB1/CB2 receptors
- very similar effects to opiates
Alcohol MOA?
Alcohol effect on GABA A, NMDA receptors and Calcium channel?
- Ethanol increases excitation of VTA neurones by blocking K-channels
- reduces action potential repolarisation
- increased firing
- increases DA release
- (GABAA allosteric modulator, NMDA receptor antagonist, Calcium channel antagonist)
Role of VTA neurons?
- Ventral Tegmental Area neurons are part of the brain’s reward system and play a significant role in the release of dopamine (DA).
They fire frequently- leading to more action potentials and an increased release of dopamine.
Nicotine moa?
- Nicotine acts at multiple sites via nicotinic ACh receptors
- Depolarises and excites VTA neurones
- Indirectly excites VTA neurones by increasing glutamate release
- Increased firing - increases DA release in NAcc
- Also directly excites NAcc spiny neurones, and indirectly by glutamate release
Receptor desensitisation/tolerance
Concentration-response curve:
The curve shifts to the right over time after repeated dosing of a drug and requires a higher concentration to produce the same effect.
Feature of graph: A rightward shift in drug potency (EC50 values)
- Sustained or repeated agonist exposure often leads to reduced responses (all types of receptors)
Molecular basis of dopamine action
(Refresh GPCR signalling)
- When resting/inactive, Ga binds GDP and forms a complex with Gby
- Upon ligand binding, GPCRs gets activated and catalyse exchange of GDP for GTP on Ga
- Ga-GTP and Gbg dissociate from each other and activate effector proteins (dissociate into Ga-GTP and By)
- The GTPase activity of Ga converts bound GTP back to GDP
- Ga-GDP reassociates with Gbg, returns to inactive state
(steps 1-5, G-protein cycle repeats several times)
Receptor desensitisation- what is the other term for it?
What is the difference between Receptor tolerance and Receptor desensitisation or tachyphylaxis?
Tachyphylaxis= Short term (secs to mins)
Tolerance= Longer time (days, weeks, months)
Receptor tolerance is a slower, long-term adaptive response where the effectiveness of a receptor-mediated response decreases over days, weeks, or months with continuous or repeated exposure to a drug or agonist
e.g. used to get hit as a child and now doesnt feel pain when hit or caffeine over time
-extra conc needs to produce same desired effect
Receptor desensitization, also known as tachyphylaxis, refers to a rapid, short-term decrease in the responsiveness of a receptor to a stimulus following repeated or continuous exposure to an agonist
- receptor can no longer produce its own function after repeated exposure
e.g. b-arrestin or getting used to a loud noise and you can no longer hear it
