Pre-synapticNeuron(axon)

Post-synapticneuron

(dendrite)

1. produce

precursors

2. pack 3. release 4. Bind 5. Post-synapticchanges

(e.g., epsp)

6.A Recycle

synapticcleft

6.B Destroy

Post-synaptic receptors

Pre-synaptic receptors

NT ‘x’

AP Ca++ inflow

- -

+ +

Neurotransmitters

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)

Pre-synapticNeuron(axon)

Post-synapticneuron

(dendrite)

1. produce 2. pack 3. release5. Post-synaptic changes

BOTOX

6.B Destroy

Ach-E

Alzheimer’s treatmentInhibits Ach-E

Nicotine: StimulatesNicotinic receptors

Curare: Blocks nicotinic receptors

Atropine: Blocks muscarinic receptors

Cholinergic neurons (release Acetylcholine)

Receptors for Acetylcholine- Muscarinic

- Nicotinic

4. Bind

curare

Belladonna (atropine)

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)

Pre-synapticNeuron(axon)

Post-synapticneuron

(dendrite)

L-Dopa

Post-synaptic changes

Recycle

dopamine

Dopaminergic neurons (release dopamine)

Receptors for dopamine- D1, D2, D4

Cocaine, amphetamine,Methylphenidate (ritalin)

Makes dopamine transporter work in reverse

pack releaseBind

D2

D2

D1

Mono-aminoOxidase (MAO)

Inactive substanceMAO

inhibitor

Antipsychotic drugs for schizophreniaBlocks D2 receptors

Precursor

Dopamine (DA) • Important in:

– Movement control death of dopaminergic cells in Parkinson’s disease– Drug addiction amphetamine, cocaine (agonist) – Schizophrenia (?) anti-psychotic drugs (antagonists) – ADHD metylphenidate (ritalin)

• dopaminergic neurons (release DA)– Substantia nigra: movement control– Ventral Tegmental Area (VTA): drug addiction– VTA to frontal cortex 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?)

Group activity

TheReward

System:

Activities of survival (sex, feed) activate the reward system

Drugs of abuse similarly activate the reward system

Dopamine

Dopamine

Electrical stimulation of the reward system is also addictive

Dopamine release in the nucleus accumbens

-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)- during sexual behavior

- in anticipation of sex

during Intracranial self stimulation

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

• 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

morphine

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

•