Chapter 4

Psychopharmacology

Psychopharmacology• Drug

– Medication?– Heroin or cocaine?– An exogenous chemical not necessary for normal

cellular functioning that significantly alters the function of certain cells of the body when taken in relatively low doses

• Drug effect– Changes of physiological process and behavior

• Site of action– May only have effect on certain neurons at certain

locations

Routes of administration• Intravenous (IV), vein• Intraperitoneal (IP) injection, abdominal wall• Intramuscular (IM) injection• Subcutaneous (SC) injection, beneath the skin• Oral administration• Sublingual administration, beneath the tongue• Intrarectal administration• Inhalation, lung• Topical administration, absorbed by skin• Intracerebral administration• Intracerebroventricular (ICV) administration

• Depot binding– Binding of a drug

with various tissues of the body or with protein in the blood

• Albumin– A protein found in

the blood; serves to transport free fatty acids and can bind with some lipid-soluble drugs

• Dose-response curve• Affinity

– The readiness with which two molecules join together (compare)

• Tolerance– A decrease in the effectiveness of a drug that is

administered repeatedly• Withdrawal symptoms

• Sensitization– An increase in the effectiveness of a drug that is

administered repeatedly• Placebo effects

– An inerr substance that is given to an organism lieu of a physiologically active drug; used experimentally to control for the effects of more administration of a drug

• Antagonists– A drug that opposes or inhibits the effects of a

particular neurotransmitter on the postsynaptic cell

• Agonists– A drug that facilitates the effects of a

particular neurotransmitter on the postsynaptic cell

• Competitive binding: binding of a drug to a site on a receptor interferes with the site for the principal ligand

– Direct agonist• A drug that binds with and

activates a receptor– Direct antagonist / receptor

blocker• A drug binds with a receptor

but does not activate it; prevents the natural ligand from binding with the receptor

• Noncompetitive binding: Binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand

• Indirect antagonist– A drug that attaches to a

binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site for the principal ligand

• Presynapticheteroreceptor– A receptor located in

the membrane of a terminal button that receives input from another reminalbutton by means of an axoaxonicsynapse; binds with the neurotransmitter released by the presynaptic terminal button

Acetylcholine

• Choline acetyltransferase (ChAT)

Functions and sites of effects• A. Muscular

movements and autonomic nervous system

• B. In the brain– 1. Dorsolateral

pons—REM sleep– 2. Basal forebrain—

activating the cerebral cortex and facilitating perceptual learning

– 3. Medial septum—electrical rhythms of the hippocampus and modulate its function

• Acetycholinesterase (AChE)

Two types of ACh receptors

• Nicotinic receptor– Ionotropic, fast, muscle fibers

• Muscarinic receptor– Metabotropic, slow, dominant in CNS

Related Drugs of ACh

+MuscarineStimulate muscarinicreceptors

Muscle paralysis

atropine

curare

nicotine

neostigmine

hemicholinium

Black widow spider venom

Botulinum toxin -preventRelease

+stimulate

Receptor

Deconstruction enzyme (AChE)

Reuptake of choline

-block

-Block muscarinicreceptors

-Block nicotinic receptors

+Stimulate nicotinic receptors

+deactivate

Monoamine• Classification

– Catecholamine• Dopamine, Norepinephrine,

Epinephrine• Catecholamine Synthesis

– L-DOPA---Dopamine---Norepinephrine (NE)

– Indolamines• Serotonin

Dopamine• Both excitatory and

inhibitory– 1. Nigrostriatal system—

substantia nigra to caudate nucleus and putamen—control of movement (Parkinson’s disease)

– 2. Mesolimbic system—ventral tegmental area to limbic system (amygdalaand hippocampus)—reinforcing and rewarding (drug addiction)

– 3. Mesocortical system—ventral tegmental area to prefrontal cortex—short-term memory, planning and strategy.

• Receptors, D1 and D2

Related Drugs of Dopamine

+Stimulate releaseAmphetamine, cocaine, methylphenidate

inhibitReuptake

Alleviate schizophrenia

Alleviate Parkinson’s disease

deprenyl

chlorpromazine

High dose of apomorphine

Low dose of apomorphine

reserpine

AMPT

L-DOPA +facilitateSynthesis

-inhibit

Deconstruction enzyme (MAO)

Post-synaptic receptor

Autoreceptor

Storage in vesicles

-inhibit

+destroy

-inhibit

+activate

-activate

Norepinephrine (NE)• Autonomic nervous

system• Final step of

synthesis: Domapine—norepinephrineoccurs inside the vesicles

• Release through axonal varicosities rather than terminal buttons

• Originating site: Locus coeruleus in dorsal pons—increase in vigilance

• All adrenergic receptors are metabotropic, α1, α2, β1, β2

• Both excitatory and inhibitory effects.

Related Drugs of Norepinephrine

-Same with DopaminereserpineinhibitStorage in vesicles

Stimulate release, same as Dopamine

AmphetamineMDMA

idazoxan

moclobemide

Fusaric acid -inhibitsynthesis

+blockDeconstruction enzyme (MAO-A)

Reuptake

Autoreceptor +block

+inhibit

Serotonin• Mood, eating,

sleep, arousal, pain, dreaming

• Originated from Raphe nuclei and projects to basal ganglia and hippocampalformation

• Released from varicosities rather than terminal buttons

• At least 9 types of receptors

Related Drugs of Serotonin

+LSDstimulateReceptor

-Same with DopaminereserpineinhibitStorage in vesicles

-PCPAinhibitsynthesis

Stimulate releasing

Treatment of obesity

Treatment of depression, anxiety disorder and OCD

MDMA

fenfluramine

Fluoxetine (Prozac) +inhibitReuptake

+inhibit

+inhibit

Amino Acids• The most common

neurotransmitters in CNS– Glutamate (direct excitatory

in brain and spinal cord)– Gamma-aminobutyric acid

(GABA) (direct inhibitory in the brain)

– Glycine (direct inhibitory in spinal cord)

• Direct excitatory/inhibitory role– Independent of receptors,

suggesting a general modulating role before the evolution of receptor molecules.

Glutamate

• Four major receptors• Ionotropic

– NMDA receptor– AMPA receptor– Kainate receptor

• Metabotropic receptor– Metabotropic glutamate receptor

NMDA receptor of Glutamate• 6 binding sites,

sodium and calcium channels—EPSP and second messenger

• Required conditions– Glutamate– Glycine– Removal of

magnesium--depolarization

• Modulations– Zinc ion (-)– Polyamine (+)– PCP (-)

• Both voltage and neurotransmitter-dependent ion channel

Related Drugs of Glutamate

+NMDAStimulate NMDA receptor

+Kainate acidStimulate kainatereceptor

AP5

AMPA +Stimulate AMPA receptor

receptor

-Blocks NMDA receptor

GABA receptor• 5 binding sites• Stimulating:

– barbiturate, – Steroid site, – Benzodiazopine

• Inhibiting: – Picrotoxin

• Ionotropic receptor or metabotropic?

• Voltage or neutrotransmittordependent Chloride channel?

• Excitatory or inhibitory?

Related Drugs of GABA

+calming effectbarbituratestimulate

-allylglycineinhibitsynthesis

+Tranquilizing drugs, reduce anxiety, sleep medication

BenzodiazepineDiazepam (Valium)Chlordiazepoxide(Librium)

stimulate

-directbicucullineblock

direct

Picrotoxin

muscimol +stimulatereceptor

-inhibit

Glycine

• Inhibitory neurotransmitter in the spinal cord• Ionotropic receptor controlling a chloride

channel• Strychnine blocks glycine receptor (-)

-StychnineblockReceptor

Neuropeptides and meuromodulators

• General characteristics of neuropeptides and neuromodulators

• 1. Larger molecular weight

• 2. Slower-acting (minutes, hours)

• 3. Can act in concert with a neurotransmitter

• 4. Like neurotransmitters, there is more than one receptor subtype, and the response is tissue-specific

Peptides• Neurotransmitter: Endogenous opiods• Receptor: Opiate receptor• Effects

– Analgesia– Inhibits defensive response such as fleeing and hiding– Reinforcement (addiction)

-Naloxoneinhibit

+Opiates (morphine, heroin, etc)

stimulateReceptor

Lipids• Neurotransmitter: anandamide• Metabotropic receptors• Effects

– Analgesia and sedation, stimulate appetite, reduce nausea, reduce symptom of motor disorder

– Interferes with concentration and memory, alter visual and auditory perception and perception of the passage of time

+MAFPinhibitDeconstruction enzyme (FAAH)

+AM1172blockreuptake

+THCstimulate

-Rimonabantblockreceptor

Nucleosides• Sugar molecule bound with a

purine or pyrimidine base• Neuromodulator: adenosine• Metabotropic receptors with

potassium channels • Effects:

– Dilate blood vessel and bring oxygen to cells

– Inhibitory, control of sleep, increase during wakefulness and decrease during sleep

• Caffeine, block receptor (-), excitatory effects

-CaffeineblockReceptor

Soluble gases• Nitric oxide (NO) one nitrogen and one oxygen atom• Control of muscle of intestine wall; Dilate blood vessel

to become metabolically active• Produced in several regions of a nerve cell, including

dendrites, release as soon as produced, no vesicles/impulse involved

• L-NAME deactivate the enzyme that involves in the synthesis of NO, (-)

-L-NAMEinhibitSynthesis

brainExcitatoryamino acid

Glutamate

Spinal cordInhibitoryamino acid

Glycine

CaffeinesleepNucleosides

adenosine

Analgesia and sedation, perception distortion

Lipidsanandamide

Addiction to opiates

Painkiller, inhibit defense, reinforcement

peptidesEnkephalins(Opioids)

Inhibitory

Excitatory & Inhibitory

Excitatory & Inhibitory

Excitatory & Inhibitory

Excitatory & Inhibitory

Postsynaptic effect

Related diseasesFunctionsOriginated locationType

Paralysismuscle movement, REM sleep, Memory, learning

Dorsal lateral ponsBasal forebrainMedial septum

Acetic acid

Acetylcholine (ACh)

Parkinson’s disease, schizophrenia, depression

Motorreward, planning

Substantia nigraVentral tegmental

AmineDopamine

Dilate blood vesselGasNitric oxide (NO)

Anxiety disorderAnxiety levelbrainamino acid

GABA

Depression, OCD, anxiety, obesity

Mood, sleep, pain, appetite

Raphe nucleiAmineSerotonin

DepressionIncrease vigilance, heighten mood

Locus coeruleusAmineNorepinephrine