Transcript Specific NT systems

Pre-synaptic
receptors
Neurotransmitters
Post-synaptic
receptors
--
precursors
NT ‘x’
1. produce
2. pack
AP  Ca++ inflow
3. release
4. Bind
++
5. Post-synaptic
changes
(e.g., epsp)
6.A Recycle
6.B Destroy
Pre-synaptic
Neuron
(axon)
synaptic
cleft
Post-synaptic
neuron
(dendrite)
Pharmacology
• A drug can do only two things, either:
– Increase the effect of neurotransmitter X (agonist)
– Decrease the effect of neurotransmitter X (antagonist)
Thus, in order to understand the action of a ‘drug Y’, we need to
understand the neurochemical system it interacts with.
In other words, we need to understand how Neurotransmitter X
- is produced & released from the pre-synaptic neuron
- acts on the receptors of the post-synaptic neuron
- is removed from the synaptic cleft
Specific Neurotransmitter Systems
(& drugs that affect them)
• Acetylcholine
• Monoamines
– Dopamine
– Noradrenaline & Adrenaline
– Serotonin
• Amino Acids
– Glutamate
– GABA
•
Opioids
•
•
THC
Adenosine (caffeine)
Receptors for Acetylcholine
Cholinergic neurons
(release Acetylcholine)
Nicotine: Stimulates
Nicotinic receptors
- Muscarinic
- Nicotinic
Curare: Blocks nicotinic receptors
1. produce
2. pack
3. release
4. Bind
5. Post-synaptic changes
BOTOX
Ach-E
Atropine: Blocks muscarinic receptors
6.B Destroy
Pre-synaptic
Neuron
(axon)
Alzheimer’s treatment
Inhibits Ach-E
Post-synaptic
neuron
(dendrite)
Belladonna
(atropine)
curare
Acetylcholine (Ach)
• Important for:
–
–
–
–
–
Muscle
Botox prevents release by terminal buttons (Antagonist)
Vigilance Nicotine mimics Ach effect in brain (Agonist)
Memory
Anti-cholinesterase drugs for Alzheimer’s disease (Agonist)
Learning Anticholinergic drugs (to prevent vomit) (Antagonist)
Autonomic Nervous System
• Cholinergic neurons (release Ach)
• Receptors:
– Nicotinic (ionotropic):
stimulated by nicotine, blocked by curare
– Muscarinic (metabotropic): blocked by atropine (belladona)
Dopaminergic neurons
Receptors for dopamine
- D1, D2, D4
(release dopamine)
MAO
inhibitor
L-Dopa
Inactive substance
Mono-amino
Oxidase (MAO)
D2
Antipsychotic drugs for schizophrenia
Blocks D2 receptors
Precursor dopamine
pack
D2
release
Bind
Recycle
Pre-synaptic
Neuron
(axon)
Cocaine, amphetamine,
Methylphenidate (ritalin)
Makes dopamine transporter
work in reverse
Post-synaptic changes
D1
Post-synaptic
neuron
(dendrite)
Dopamine (DA)
• Important in:
– Movement control
– Drug addiction
– Schizophrenia (?)
– ADHD
death of dopaminergic cells in Parkinson’s disease
amphetamine, cocaine (agonist)
anti-psychotic drugs (antagonists)
metylphenidate (ritalin)
• dopaminergic neurons (release DA)
– Substantia nigra:
– Ventral Tegmental Area (VTA):
– VTA to frontal cortex
•
•
movement control
drug addiction
schizophrenia (?)
Receptors: D1, D2, D4
Group Activity:
– Would PD treatment with L-dopa increase or decrease hallucinations? (one of the
symptoms of schizophrenia)
– Would antipsychotic drugs produce PD like symptoms as a side effect (e.g., motor
problems)? Why? Why not?
– Schizophrenic patients often fail to take their medication, despite the benefitial effects.
Can you provide a physiological explanation? (hint: which systems does the drug
block?)
Dopamine
The
Reward
System:
Dopamine
Activities of survival (sex, feed)
activate the reward system
Drugs of abuse similarly
activate the reward system
Electrical stimulation of the
reward system is also addictive
Dopamine release in the nucleus accumbens
during Intracranial self stimulation
- during sexual behavior
- in anticipation of sex
-during ingestion of a preferred food
- to a cue associated with food (CS)
-during IV cocaine self-administration
-to a cue associated with cocaine (CS)
Cocaine and Amphetamine:
administration & distribution
Administration:
intranasal
intravenous
smoke (‘crack’)
Distribution:
‘Crack’: is more liposoluble, thus stronger effect!
Cocaine has a very short half life (40 mins)
Overview- neurotransmitters
• Acetylcholine
• Dopamine
•
•
•
•
•
•
Adrenaline
Serotonine
Glutamate
GABA
Opioids
THC (cannabis)
Noradrenaline & Adrenaline
• Aka: norepinephrine &
epinephrine
• Important for:
– Vigilance (adrenaline
response)
• Noradrenaline acts as a
neurotransmitter
• Adrenaline acts also as a
hormone
• Receptors:
– Alpha
– Beta: beta-blockers are
used for hypertension
Oh no!
my
sympathetic
nervous
system is
overactive
again!
Serotonin (5-HT)
• Important in:
– Depression
• Receptors:
– Way too many!
• Drugs:
– Fluoxetine (prozac): inhibitor of reuptake (recycle) (SSRI)
– LSD: agonist of 5-HT2A
– Ectasy: agonist for serotonin and agonist for noradrenaline
Glutamate
• Is the most pervasive excitatory NT in the brain
• Receptors:
– Four types (remember NMDA):
• Important in:
– Learning (NMDA receptor in the hippocampus)
• Drugs:
– Alcohol: NMDA antagonist
• Sleepy, impaired cognitive performance
• Alcohol withdrawal  seizures
GABA
• Is the most pervasive inhibitory NT in the brain
• Receptors:
– GABAa: opens Cl- channel
– GABAb: opens K+
– Question: does it puzzle you that, being GABA an inhibitory NT, GABAa
and GABAb receptors open channels of different polarity? Justify
• Drugs:
– Benzodiazepines (valium): GABA Agonist
• For reducing anxiety, promoting sleep, anti-convulsant, muscle
relaxant
– Alcohol: GABA agonist
• Anxiolytic
• Don’t drink while taking this medication
• Alcohol withdrawal  seizures
Alcohol
• Alcohol acts on many systems:
– Blocks NMDA: that is why memory is impaired, and
why alcohol withdrawal can trigger seizures
– GABA: That is why at low levels alcohol has an
anxiolytic effect, and at higher levels sedative effect
– Dopamine (mesolimbic system): increases release
of DA in nucleus accumbens, thus the euphoria,
addictive power of alcohol
Opiates:
– Endogenous opiates: secreted in response to survival behaviors
• analgesia
• positive reinforcement (encourages the survival behavior)
– Exogenous opiates;
• Morphine (opium)
• Codeine (opium)
• Heroin (semisynthetic)
•1897 – Mail order advertisement from
Sears, Roebuck & Co. for opium-based drink
•Early 20th century – mothers encouraged
to use opium syrup to soothe teething pain
•
•Narcotic comes from the Greek word, “narke”,
meaning stupor and referred to any drug that
induced sleep
Opiates: administration & distribution
Administration:
smoke (Opium, Heroin)
intranasal (heroin)
intravenous (Heroin)
oral, not very good to get high
(Codeine, morphine, methadone)
Distribution:
Heroin is 10 times more liposoluble than morphine, so
it reaches brain faster and at larger concentrations, and
get transformed into morphine
Opioids
morphine
• Drug Effects:
– Analgesia (morphine)
– Activates Reward system (addictive power)
– Inhibits defensive response (e.g., hiding)
•
Antagonist:
– Naloxone:
• Use in the acute treatment of heroin overdose
• Blocks analgesic effect of placebo
Naloxone
Opiates: Side effects
Most of the risks are secondary to the status as illegal.
– Legal: Jail
– Health: HIV, hepatitis C, overdose
– Financial: loss of employment, cost of drugs
– Few direct problems from chronic use (surprisingly)
• (constipation, bladder cancer, pregnancy)
Cannabis:
• THC is the active ingredient in marijuana.
• THC receptor: CB1
– large concentration in hippocampus (memory effect)
• THC stimulates release of dopamine in the nucleus
accumbens and the ventral tegmental area
– Long-term damage:
• Cognitive impairments from long-term use appear to be subtle.
Cannabinoids (THC)
• There are endogenous & exogenous cannabinoids (marijuana)
• They are lipids:
– They mix well in butter (cookies) & oil (pesto), but not in alcohol or water.
– They depot in fat tissue: thus metabolites can be detected in urine long
after the psychoactive effect
• Drug Effects:
– Analgesia
– Sedation
– Stimulates eating (munchies)
– Reduces concentration & memory
– Distorts time perception
•