neuropharmacology of drugs of abuse Flashcards
Brain circuits associated with addiction
nucleus accumbens and ventral tegmental area
Play critical role in reward processing
OFC (orbitofrontal cortex)- part of frontal cortex- gives saliency to rewards
Amygdala- Emotional centre. Consider the emotional relationship someone with drug dependence has with the drug
Hippocampus- Take account how strong the memory is for drug abuse individuals
Cordate putamen- part of striatum- role is in habit formation (in middle of hippocampus and Nacc)
Discuss the effect of acute administration of drugs of abuse on the brain
Reward system is involved (Ventral tegmental area- NAc)
but hypothalamus, amygdala all involved
Drugs of abuse increase activation of CRF
4 dopamine pathways
The Mesolimbic Pathway. The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
The Mesocortical Pathway. Projects from the VTA to the prefrontal cortex
The Nigrostriatal Pathway
The Tuberoinfundibular (TI) Pathway.
What are the acute targets for each drug of abuse
Opioids - Agonist at mu (and delta and kappa) opioid receptors
Cocaine - Dopamine transporter blocker - indirect DA agonist
Amphetamine - Dopamine releaser - indirect DA agonist
Alcohol - Facilitates GABAA + inhibits NMDA receptor function
Nicotine - Agonist at nACh receptors
Cannabinoids - Agonist at CB1 receptors
Phencyclidine - NMDA receptor antagonist
Hallucinogens - 5-HT2A agonists
All of drugs of abuse- including opiods, cocaine, alcohol—- activate the reward pathway and increase dopamine in the nucleus accumbens
BUT via DIFFERENT mechnaisms
eg. opioids such as heroine release dopamine in Nac by activating dopamine receptor
Cocaine blocks dopamine transporter, indirect dopamine agonist
Pharmacological effects and therapeutic uses of amphetamine
Amphetamine-like drugs (methylphenidate & MDMA)
Release cytosolic monoamines (DA)
Prolonged use neurotoxic
Degeneration of amine-containing nerve terminals, cell death
Pharmacological effects:
alertness and locomotor stimulation ( aggression)
Euphoria / excitement
Stereotyped behaviour
Anorexia
physical and mental fatigue (improves monotonous tasks)
Peripheral sympathomimetic actions ( increased blood pressure & gastric motility)
Confidence improves/lack of tiredness
Therapeutic uses
ADHD (methylphenidate), appetite suppressants, narcolepsy
How do central stimulants like cocaine work
Blocks catecholamine reuptake ( DA, stimulant effect) Pharmacological effects: Euphoria Locomotor stimulation Fewer stereotyped behaviours than amphetamine Heightened pleasure Lower tendency for delusions, hallucinations and paranoia
Pharmacokinetics:
HCl salt, inhaled and i.v. administration
Nasal inhalation less intense, leads to necrosis of nasal mucosa
Freebase form (‘crack’), smoked, as intense as i.v route
How do psychomimetics like ecstasy work
MDMA (ecstasy)
Inhibits monoamine transporters (mainly 5-HT)
Also releases 5-HT
Large 5-HT (followed by depletion)
5-HT linked to psychotomimetic effects
DA linked to euphoria (followed by rebound dysphoria)
How opioids like heroin work
Opioids produce intense euphoria via acting on MOP
Diamorphine (heroin) high abuse potential
Tolerance
Seen within 12 – 24 hours
Diamorphine more lipid soluble than morphine – more rapid effect when given iv
Heroin derived from acetylation of morphine or extracts of opium poppy. In some countries codeine is demethylated in labbs to morphine (‘homebake’ procedure. Yields a white crystalline powder which is cut with inert sugars (e.g. glucose) and sold as heroin. Sometimes other substances are mixed with the heroin that will affect the pharmacology and toxicology e.g. lignocaine, strychnine and paracetamol. Purity of heroin can vary from 5-70%. Stree names for heroin include smack, skag
Tolerance to opioids seen within 12-24 h
In rats abrupt discontinuation of the opioids results in irritability, loss of weight, body shakes, writhing, jumping & signs of aggression – much less apparent if drugs withdrawn gradually. In humans this is seen as restlessness, runny nose, diarrhoea, shivering and goose pimples (cold turkey). NAergic pathways may play a role in abstinence syndrome – lofexidine (central 2-agonist) can suppress some of the symptoms (especially diarrhoea & vomiting).
Dependence – in locus coeruleus receptors inhibit adenyly cyclase activity – with chronic ingestion activity of enzyme increases to compensate – withdrawal of the opioid then results in excessive accumulation of cAMP and rebound neuronal excitability.
Methadone – if take morphine with methadone then don’t get the high.
Psychological dependence responsible for the craving and drives the drug seeking behaviour.
opioid disinhibition effect
Interneurones there to control release of dopamine into nucleus accumbens
opioid receptors such as MOP and DOP located in synpatic boutons of GABA nergic neurones
heroine- activation of these opioid receptors result in inhibition of release of GABAless of inhibitor neurotransmitter- will start firing a lot of dopamine
mechanism of general depressants- alcohol
Mechanism of action:
Potentiates GABA-mediated inhibition
Inhibits presynaptic Ca2+ entry through voltage-gated Ca2+ channels
Inhibits transmitter release
Disinhibits mesolimbic DAergic neurons ( reward)
Induces the release of endogenous opioid peptides
Reward effect by naltrexone (endogenous opioid involvement)
Pharmacological effects
Slurred speech, motor in-coordination, ’d self confidence, euphoria
Impaired cognitive and motor performance
Higher levels linked to labile mood: euphoria and melancholy, aggression and submission
mechanism of social drugs like nicotine and tobacco
Nicotine, highly addictive
Pharmacological effects
nACh receptors, 4β2 subtype
Receptors, ligand-gated cation channels (pre- and post-synaptic)
Enhance transmitter release and neuronal excitability icluding opioid peptides
Cortex & hippocampus (cognitive function) and ventral tegmental area (DA release and reward)
alertness, irritability (dependent on dose and situation)
What are withdrawal symptoms
Physical, characterised by abstinence syndrome (LC)
Sweating, gooseflesh (cold turkey), irritability, aggression
Psychological, craving to avoid withdrawal effects
Psychostimulants: deep sleep, lethargy, depression, anxiety & hunger
MDMA (ecstacy):Depression, anxiety,
irritability, aggression
Heroin: Sweating, gooseflesh (cold turkey), irritability, aggression
Nicotine: Irritability, hunger, weight gain, impaired cognitive and motor performance, craving (persisting many years)
Alcohol: Tremor, nausea, sweating, fever, hallucinations
Seizures, confusion, agitation, aggression
Chronic effects of drugs- mechanism of dependence and tolerance
Chronic drug administration – homeostatic adaptive changes to oppose the drug action. Withdrawal of the drug can cause a rebound effect e.g alcohol can cause convulsions, amphetamine can cause sedation.
Chronic drug administration results in neuroadaptive changes. Depressants can induce ↑ in Ca2+ channels, stimulants e.g. amphetamine can lead to depletion of NT, hallucinogens that act via 5-HT2 receptors can lead to down-regulation of the 5-HT2 receptor and opioids lead to an increase in activity of adenylyl cyclase and increase in cAMP
Homeostastic compensatory neuroadaptation: Chronic drug administration – homeostatic adaptive changes to oppose the drug action. Withdrawal of the drug can cause a rebound effect
Increase in cAMP increase noradrenaline in the brain, causing some of those withdrawal symptoms
ie. most withdrawal symptoms occur as a result of homeostasis compensatory mechanisms
Mechanism of dependence shown in imaging scans
Dopamine D2 images of Drug Addiction
cocaine users put in fMRI scanners, brain activity is recorded
reduction in brain activity in pre-frontal cortex or hypo frontality stops people from making decisions-often why people continue taking drugs
PET scan- lets you visualise localisation or density of receptors in living brain. Inject radiotracer into circulation, enter through blood brain barrier. Put person in PET scan, emits any radioactivity emitted by radiotracer. If you compare the control the abuser, you notice the reduction in dopamine D2 receptors in abuser compared to control- present in also alcoholics and gamblers- a BIOMARKER of addiction
people with lower availability of D2 receptors are more vulnerable to developing addiction
upregulation of a4b2 to show dependence
Studies where rats were treated with nicotine for long period of time
Nicotonic receptors were analysed with qualitative radiographic binding
brains above show saline vs nicotine treated
Nicotine treated brain shows upregulation of specific receptor called alpha4 beta 2 nicotnic receptor
