Psychopharmacology

The Study of the effects of drugs on the nervous system and behavior

• Drugs: – Exogenous chemical (not produced by the body)

– Not necessary for normal functioning• Not a vitamin, mineral, protein, carbs…

– Alters the functions of certain cells (neurons)– when given in low doses (mg/kg)

Drug influence:Changes in physiological and behavioral processes of the organism

Action sites:Sites where the drug

1. Form of drug administration (how it is taken)

2. Drug fate in body

Principles of psychopharmacology include:

1. Forms of drug administration:

1. Intravenous injection2. Intraperitoneal injection3. Intramuscular injection4. Subcutaneous injection

5. Oral administration6. Sublingual administration

7. Intrarectal administration8. Inhalation9. Topical administration10. Intracereberal administration

Drugs get to the brain usually through the blood

2. Fate of drug

Depot Binding with Blood Albumin ProteinCan influence the rate at which the drug will reach the brain from the blood stream

Drug efficacy

Dose-response curve – describes the influence of a drug as a function of the dose administered

Multiple effects of drugs

(beneficial effects, and side effects)

The separation between the two curves serves as an measure for its safety

Therapeutic Index = LD50/ED50

LD – Lethal doseED – effective dose

Examples:Morphine (muscle relaxant) has a TI of 70Cocaine: 15Heroin: 6

Alcohol: 10 (but you usually vomit/pass out before reaching the lethal dose)

Drug effectiveness depends on:

Site of action

Affinity & kinetics

Number of times it was used:

Tolerance = Decrease in the efficiency of a drug

Sensitization = Increase in the efficiency of a drug

Once a drug enters the brain it may have one of two effects:

• Agonist – mimics/facilitates the post-synaptic effect

• Antagonist – inhibits/blocks the post synaptic effect

for a given neurotransmitter

Drugs can affect any stage in the process of synaptic transmission:

1) Production of neurotransmitter

2) Packing in vesicles and vesicle release

3) Binding to receptors

4) Neurotransmitter degradation and reuptake

Production of neurotransmitter

1. Precursor of neurotransmitter (Agonist):

DopamineL-DOPA serves as a precursor for the production of dopamine (used in Parkinson’s Disease)

GlutamateMSG (monosodium glutamate) – is a precursor of glutamate production

2. Inactivation of an enzyme needed for synthesis (Antagonist)

AMPT (Alpha-methyl-p-tyrosine) – blocks Tyrosine hydroxylase (Antagonist)

serotonin

p-chlorophenylalanine (PCPA) – is an inhibitor of Tryptophan hydroxylase

Storage and release of neurotransmitter

1. Preventing storage by inactivating vesicle transporter (Antagonist)Reserpine (blocks storage of norepinephrine, serotonin, and

dopamine in the presynaptic vesicles)

2. Enhancing storage in vesicles by inhibiting neurotransmitter breakdown

3. Stimulation of release from terminal button (Agonist)

Black widow spider venom (facilitates release of AcH)

4. Inhibition of release from terminal button (Antagonist)

Butulinium toxin (Botox) – blocks release of AcH

http://jama.ama-assn.org/issues/v285n8/images/jst00017f1.jpg

Post-synaptic receptors

• Direct agonists (competitive binding) – bind with receptor and activate it (mimic the effect of the neurotransmitter)– Examples: Nicotine, and Muscarine for AcH, LSD for

serotonin

• Direct antagonist (competitive binding) – bind with the receptor and do not activate it (receptor blockers)– Examples: Curare (blocks the nicotinic AcH receptor)– Atropene (blocks the muscarinic AcH receptor)– Caffeine (blocks adenosine receptors)

Indirect agonist (non-competitive binding): Binds on a different site than the neurotransmitter but mimics its effect

Indirect antagonist (non-competitive binding): Binds on a different site than the neurotransmitter and blocks its effect

A voltage and Neurotransmitter dependent channel

PCP (angel dust): Indirect antagonist

NMDA receptor (glutamate)

PCP (angel dust) – indirect antagonist

GABAa

Neurotransmitter dependent Cl- channel

Indirect Agonists

Reduce anxiety

Neurotransmitter degradation and reuptake

1. Blockers of re-uptake (agonists)Example: Cocaine is a seotonin-norepinephrine-dopamine reuptake inhibitor

Hemicholine – blocks reuptake of choline and serves as an AcH antagonistRitalin – inhibits reuptake of dopamine and norepinephrineAmphetamine (‘speed’) – inhibits reuptake of dopamineFluoxetine (Prozac) – serotonine reuptake inhibitor (SSRI)MDMA (‘Ecstasy’) – NE and Serotonin transporters run backwards

2. Blockers of neurotransmitter degradation (agonist):Example: Neostigmine inhibits AcH-Esterase (the enzyme that breaks AcH to Choline and Acetate) resulting in prolonged presence of AcH in synaptic cleft

Effects on pre-synaptic receptors

• AutoreceptorsStimulation

• Less release of neurotransmitter

Apomorphine (dopamine)