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 lipidsoluble 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

 Presynaptic heteroreceptor
A receptor located in the membrane of a terminal button that receives input from another reminal button by means of an axoaxonic synapse; 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 ponsREM 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

Release prevent Botulinum toxin

+ + +
Muscle paralysis

stimulate

Black widow spider venom

Reuptake of choline Deconstructi on enzyme (AChE) Receptor

block

hemicholinium

deactivate

neostigmine

Stimulate nicotinic receptors Block nicotinic receptors Stimulate muscarinic receptors Block muscarinic receptors

nicotine

curare

+ -

Muscarine

atropine

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 (Parkinsons disease) 2. Mesolimbic system ventral tegmental area to limbic system (amygdala and hippocampus) reinforcing and rewarding (drug addiction) 3. Mesocortical system ventral tegmental area to prefrontal cortexshortterm memory, planning and strategy.

Receptors, D1 and D2

Related Drugs of Dopamine

Synthesis facilitate L-DOPA Alleviate Parkinsons disease

+ +

inhibit

AMPT

Storage in vesicles Autoreceptor

inhibit

reserpine

activate

Low dose of apomorphine High dose of apomorphine chlorpromazine Alleviate schizophrenia

Postsynaptic receptor

activate

inhibit

+ +

Reuptake

inhibit

Amphetamine, cocaine, methylphenidate deprenyl

Stimulate release

Deconstructi on enzyme (MAO)

destroy

Norepinephrine (NE)
Autonomic nervous system Final step of synthesis: Domapine norepinephrine occurs 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, 1, 2, 1, 2 Both excitatory and inhibitory effects.

Related Drugs of Norepinephrine

synthesis inhibit Fusaric acid

+ +
Same with Dopamine

Deconstructi on enzyme (MAO-A) Autoreceptor

block

moclobemide

block

idazoxan

Storage in vesicles Reuptake

inhibit

reserpine

inhibit

Amphetamine MDMA

Stimulate release, same as Dopamine

Serotonin
Mood, eating, sleep, arousal, pain, dreaming Originated from Raphe nuclei and projects to basal ganglia and hippocampal formation Released from varicosities rather than terminal buttons At least 9 types of receptors

Related Drugs of Serotonin

Reuptake inhibit Fluoxetine (Prozac) Treatment of depression, anxiety disorder and OCD Treatment of obesity

+ + + +

inhibit

fenfluramine

inhibit

MDMA

Stimulate releasing

synthesis

inhibit

PCPA

Receptor

stimulate

LSD

Storage in vesicles

inhibit

reserpine

Same with Dopamine

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 channelsEPSP and second messenger Required conditions
Glutamate Glycine Removal of magnesium-depolarization

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

Both voltage and neurotransmitterdependent ion channel

Related Drugs of Glutamate

receptor Stimulate AMPA receptor Stimulate kainate receptor Stimulate NMDA receptor Blocks NMDA receptor AMPA

+ + + -

Kainate acid

NMDA

AP5

GABA receptor
5 binding sites Stimulating:
barbiturate, Steroid site, Benzodiazopine Picrotoxin

Inhibiting:

Ionotropic receptor or metabotropic? Voltage or neutrotransmittor dependent Chloride channel? Excitatory or inhibitory?

Related Drugs of GABA

synthesis inhibit allylglycine

direct

receptor

stimulate

muscimol

+ +

block

bicuculline

direct

stimulate

Benzodiazepine Diazepam (Valium) Chlordiazepoxide (Librium) barbiturate

Tranquilizing drugs, reduce anxiety, sleep medication

stimulate

calming effect

+ -

inhibit

Picrotoxin

Glycine
Inhibitory neurotransmitter in the spinal cord Ionotropic receptor controlling a chloride channel Strychnine blocks glycine receptor (-)
Receptor block Stychnine

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)

Receptor

stimulate

Opiates (morphine, heroin, etc) Naloxone

+ -

inhibit

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

receptor

block

Rimonabant

+ + +

stimulate Deconstructi on enzyme (FAAH) reuptake inhibit

THC MAFP

block

AM1172

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

Receptor

block

Caffeine

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, (-)
Synthesis inhibit L-NAME

Type Acetylcholine (ACh) Acetic acid

Postsynaptic effect Excitatory & Inhibitory

Originated location Dorsal lateral pons Basal forebrain Medial septum Substantia nigra Ventral tegmental

Functions muscle movement, REM sleep, Memory, learning Motor reward, planning

Related diseases Paralysis

Dopamine

Amine

Excitatory & Inhibitory

Parkinsons disease, schizophrenia, depression Depression Depression, OCD, anxiety, obesity

Norepinephrine Serotonin

Amine Amine

Excitatory & Inhibitory Excitatory & Inhibitory Excitatory Inhibitory Inhibitory

Locus coeruleus Raphe nuclei

Increase vigilance, heighten mood Mood, sleep, pain, appetite

Glutamate GABA Glycine Enkephalins (Opioids) anandamide adenosine Nitric oxide (NO)

amino acid amino acid amino acid peptides Lipids Nucleosid es Gas

brain brain Spinal cord Painkiller, inhibit defense, reinforcement Analgesia and sedation, perception distortion sleep Dilate blood vessel Caffeine Addiction to opiates Anxiety level Anxiety disorder