Neuropharmacology, 2009

John Schriefer, Ph.D.

Introduction to Neuropharmacology

Objectives

The student shall be able to:

1. explain why most mechanisms of action given the neuropharmacologic drugs are
approximations.

2. define what is meant by specific mechanism of action.

3. describe the various events in synaptic transmission which might be altered by drugs.

4. describe the consequences of drug-induced alteration of membrane potential.

5. differentiate between a neurotransmitter and a neuromodulator.

6. recognize the substances which have been proposed to act as CNS neurotransmitters.

7. differentiate between ionotropic and metabotrophic receptors.

8. describe the blood brain barrier and its implications in drug therapy.

9. describe the function of, and the disorders affecting, the various CNS neuronal
systems.

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 INTRODUCTION TO NEUROPHARMACOLOGY

I. Neuropharmacology is the study of drugs specifically employed to affect the nervous

system.

II. Mechanism of action

A. Entire mechanism is generally unknown. Approximations of CNS mechanism

made from information regarding effects of drugs in isolated systems.

CNS as a “Black Box”

Extrapolation from biochemical events to behavior is difficult.

B. Specific Mechanism of Action. A specific drug action affects a recognized

protein target, i.e., a receptor, an ion channel, an enzyme, or a transporter.

III. Site of action

A. Most neuropharmacologic agents produce effects by altering synaptic events

Central nervous system (CNS) neurotransmission and sites of drug action. CNS drugs
act primarily by affecting the synthesis, storage, release, reuptake, or degradation of
neurotransmitters (NT) or by activating receptors. NT are synthesized from precursors
accumulated or synthesized in the neurons. The NT are stored in vesicles whose membranes
contain proteins involved in NT release (synaptobrevin and synaptotagmin). The NT are
released when an action potential-mediated calcium influx initiates interaction of
synaptobrevin and synaptotagmin with neuronal membrane-docking proteins (syntaxin and
neurexin). This leads to docking and exocytosis. Synaptic NT may activate presynaptic or
post-synaptic receptors (R1, R2, and R3). The action of NT is terminated by reuptake into the
presynaptic neuron or by enzymatic degradation.
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 Present research concentrates on long-term consequences of alteration of
synaptic transmissions.

B. Alteration of synaptic transmission leads to excitation or inhibition of post-

synaptic nerves.

IV. Neurotransmitters

A. Neurotransmitter – a substance which is released locally and causes a change

in post-synaptic potential.

B. Neuromodulator – a substance which acts to modify the response of the

synapse to a neurotransmitter.

C. Substances identified as neurotransmitters.

• Acetylcholine
• Amino acids
• Biogenic amines
• Peptides
• Purines (ATP, adenosine)
• Nitric acid
• Endocanabinoids

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TABLE 18-1. Major Neurotransmitters in the Central Nervous System*
Neurotransmitter Receptors Mechanisms of Signal Neuronal Tracts Functions
Transduction
Acetylcholine Muscarinic Basal ganglia, Excitatory (M1, M3, M5, and
M1, M3, and M5 ↑ IP3 and DAG. basal nucleus of nicotinic) or inhibitory (M2 and
M2 and M4 ↓ cAMP; ↑ gK+. Meynert to cerebral M4) NT: memory, motor
Nicotinic ↑ gCa2+, gK+, and gNa+. cortex; septal area coordination and sensory
to hippocampus processing
Amino Acids
Gamma- GABAA ↑ gC1- Ubiquitous Major inhibitory NT in CNS;
aminobutyric GABAB ↑ gCa2+ and gK+ motor coordination and neuronal
Acid (GABA) (metabotropic) excitability
Glutamate and Ionotropic Widely distributed Major excitatory NT in CNS,
aspartate AMPA and KA ↑ gK+ and gNa+ throughout CNS long-term potentiation
NMDA ↑ gCa2+, gK+, and gNa+ (memory), neuronal toxicity and
Metab. (MGluR) ↓ cAMP; ↑ IP3 and DAG apoptosis, and pain processing
Glycine Strychnine- ↑ gCl- Spinal cord; brain Major inhibitory NT in spinal
insensitive stem cord; also found in brain stem;
Strychnine- Modulate NMDA motor coordination and neuronal
sensitive Receptors excitability
Biogenic amines
Dopamine D1 and D5 ↑ cAMP Nigrostriatal, Inhibitory NT; behavioral and
D2, D3, and D4 ↓ cAMP nucleus drug reinforcement, emesis,
accumbens, hormone release, mood, motor
mesolimbic, and coordination, and olfaction.
tuberoinfundibular;
chemoreceptor
trigger zone
Histamine H1 ↑ IP3 and DAG. Hypothalamic Excitatory NT; sedation, sleep,
H2 ↑ cAMP tracts to entire CNS temperature regulation, and
H3 Unknown vasomotor function
Norepinephrine Adrenergic Locus ceruleus Excitatory (α1 and β1) or
α1 ↑ IP3 and DAG (pons) to thalamus, inhibitory (α2 and β2) NT;
α2 ↓ cAMP cerebral cortex, anxiety, cerebellar function,
β1 and β2 ↑ cAMP cerebellum, and learning, memory, mood,
spinal cord; sensory processing and sleep
midbrain to
hypothalamus
Serotonin (5- 5-HT1 ↓ cAMP; ↑ gK+ Raphe nuclei Excitary (5-HT2, 5-HT3, and 5-
hydroxy-tryptamine, 5-HT2 ↑ IP3 and DAG (Central brain HT4) or inhibitory (5-HT1) NT;
or 5-HT) 5-HT3 ↑ gK- and gNa+ stem) to forebrain appetite, emotional processing,
5-HT4 ↓ cAMP and spinal cord hallucinations, mood, pain
processing, and sleep
Peptides
Opioid peptides δ, κ, and μ ↓ cAMP and gCa2+; ↑ gK+ Widely distributed, Inhibitory NT, emotions,
especially in brain hearing, motor coordination,
stem, spinal cord, neurohormone secretion, pain
and thalamus processing, taste, and vision
Tachykinins Excitatory NT; neuromodulation
Neurokinins NK1, NK2, and NK3 ↓ gK+; ↑ IP3 and DAG Primary sensory and pain processing
Substance P NK1, NK2, and NK3 ↓ gK+; ↑ IP3 and DAG neurons; cell
bodies at all levels
Hypocretin 1 and 2 involved in sleep/wakefulness

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*AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; cAMP = cyclic adenosine monophosphate;
CNS = central nervous system; DAG = diacylglycerol, g = conductance; IP3 = inositol triphosphate; KA =
kainate; NK = neurokinin; NMDA = N-methyl-o-aspartate; and NT = neurotransmitter
V. Neurotransmitter receptors

A. Ionotropic receptors (also known as ligand-gated channels) are associated

with ion channels, and change ionic conductance.

B. Metabotropic receptors are coupled with enzymes via G-proteins and other
intermediates.

VI. Signal transduction

A. Activation of ionotropic receptors may increase chloride, sodium, potassium,

or calcium conductance and cause excitatory or inhibitory membrane
potentials.

B. Activation of metabotropic receptors can lead to synthesis of cAMP, IP3, and

DAG which can alter a variety of intracellular pathways. Activation of
metabotropic receptors can also modulate voltage gated ion channels.

VII. Blood Brain Barrier

A term used to describe diffusional barriers retarding the passage of substances from
the central circulation to nerve cells.

Characteristics which regulate diffusion of substances through capillaries are

1. molecular weight
2. lipid solubility
3. ionization at physiological pH

Barrier is a consequence of anatomical differences in CNS capillaries.

• less permeable
• tight junctions
• fewer pinocytotic sites
• surrounded by pericytes and astroglial processes
• carrier mediated transport

VIII. Neuronal systems in the CNS

A. Cognitive processing – interpretation of sensory information

1. results in motor activity, reasoning, forethought

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 2. disorders referred to as delirium
3. altered by antipsychotics, CNS stimulants, hallucinogens

B. Memory – ability to recall events

1. involves many brain structures

2. disorders referred to as dementia
3. altered by cholinesterase inhibitors and benzodiazepines

C. Emotional processing – the conscious perception of neuronal activity

1. involves limbic structures and frontal lobe cortex

2. disorders include anxiety, mood disorders, and schizophrenia
3. altered by anxiolytics, antidepressants, antipsychotics, and all drugs
causing drug dependence

D. Sensory processing

1. vision, hearing, olfaction, touch, pain

2. disorders include sleep disorders, chronic pain
3. altered by antidepressants, hallucinogens, anesthetics, analgesics

E. Motor processing

1. control of motion and posture

2. disorders include Parkinson’s disease, and degenerating and
demyelization diseases
3. altered by antiparkinsonian drugs, CNS stimulants, sedative-hypnotics

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 Norepinephrine in the CNS

• Mechanisms for synthesis, storage, release, and

reuptake of noradrenaline in the CNS are
essentially the same as in the periphery, as are
the receptors.
• Noradrenergic cell bodies occur in descrete
clusters, mainly in the pons and medulla, one
important such cell group being the locus
ceruleus.
• Noradrenergic pathways, running mainly in the
medial forebrain bundle, and descending spinal
tracts, terminate diffusely in the cortex,
hippocampus, hypothalamus, cerebellum, and
spinal cord.
• The actions of noradrenaline are mainly
inhibitory (β-adrenoceptors), but some are
excitatory (α- or β- adrenoceptors).
• Noradrenergic transmission is believed to be
important in
o the ‘arousal’ system, controlling
wakefulness and alertness
o blood pressure regulation
o control of mood (functional deficiency
contributing to depression).
o psychotropic drugs that act partly or
mainly on noradrenergic transmission in
the CNS include antidepressants, cocaine,
amphetamine. Some antihypertensive
drugs (e.g., clonidine, methyldopa) act
mainly on noradrenergic transmission in
the CNS.

Dopamine in the CNS

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• Dopamine is a neurotransmitter as well as being
the precursor for noradrenaline. It is degraded in a
similar fashion to noradrenaline, giving rise mainly
to DOPAC and HVA, which are excreted in the urine.
• There are three main dopaminergic pathways.
o nigrostriatal pathway, important in motor
control
o mesolimbic/mesocortical pathways, running
from groups of cells in the midbrain to parts
of the limbic system, especially the nucleus
accumbens, and to the cortex; they are
involved in emotion and drug-induced reward
systems.
o tuberohypophyseal neurons running
from the hypothalamus to the pituitary
gland, the secretions of which they
regulate.
• There are five dopamine receptor subtypes. D1-
and D5-receptors are linked to stimulation of
adenylate cyclase. D2-, D3- and D4-receptors are
linked to inhibition of adenylate cyclase. Most
known functions of dopamine appear to be
mediated mainly by receptors of the D2 family.
• Receptors of the D2 family may be implicated in
schizophrenia. The D4-receptor shows marked
polymorphism in humans.
• Parkinson’s disease is associated with a deficiency
of nigrostriatal dopaminergic neurons.
• Behavioural effects of an excess of dopamine
activity consist of stereotyped behaviour patterns
and can be produced by dopamine-releasing agents
(e.g., amphetamine) and dopamine agonists (e.g.,
apomorphine).
• Hormone release from the anterior pituitary gland
is regulated by dopamine, especially prolactin
release (inhibited) and growth hormone release
(stimulated).
• Dopamine acts on the chemoreceptor trigger zone
to cause nausea and vomiting.

5-Hydroxytryptamine (5-HT in the CNS)

• The processes of synthesis, storage, release,

reuptake, and degradation of 5-HT in the brain are
very similar to events in the periphery.

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• Availability of tryptophan is the main
factor regulating synthesis.
• Urinary excretion of 5-HIAA (see text)
provides a measure of 5-HT turnover.
• 5-HT neurons are concentrated in the
midline raphe nuclei in the pons and
medulla, projecting diffusely to the
cortex, limbic system, hypothalamus,
and spinal cord, similar to the
noradrenergic projections.
• Functions associated with 5-HT pathways
include :
o various behavioural responses
(e.g., hallucinatory behaviour, ‘wet-
dog shakes’)
o feeding behaviour
o control of mood and emotion
o control of sleep-wakefulness
o control of sensory pathways,
including nociception
o vomiting.
• 5-HT can exert inhibitory or excitatory
effects on individual neurons, acting
either presynaptically or postsynaptically.
• The main receptor subtypes in the CNS
are 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT3.
Associations of behavioural and
physiological functions with these
receptors have been partly worked out.
Other receptor types (5-HT4-7) also occur
in the CNS, but less is known about their
function.

Acetylcholine in the CNS

• Synthesis, storage, and release of

acetylcholine in the CNS are essentially the
same as in the periphery.
• Acetylcholine is widely distributed in the
CNS, important pathways being:
o basal forebrain (magnocellular) nuclei,
which send a diffuse projection to most
forebrain structures, including the cortex
o septohippocampal projection

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 o short interneurons in the striatum and
nucleus accumbens.
• Certain neurodegenerative diseases,
especially dementia and Parkinson’s
disease, are associated with abnormalities
in cholinergic pathways.
• Both nicotinic and muscarinic acetylcholine
receptors occur in the CNS. The former
mediate the central effects of nicotine.
Nicotinic receptors are mainly located
presynaptically; there are few examples of
transmission mediated by postsynaptic
nicotinic receptors.
• Muscarinic receptors appear to mediate the
main behavioural effects associated with
acetylcholine, namely effects on arousal,
and on learning and short-term memory
• Muscarinic antagonists (e.g., hyoscine)
cause amnesia.
• Acetylcholinesterase released from neurons
may have functional effects distinct from
cholinergic transmission.

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Excitatory amino acids (EAAs)

• EAAs, namely glutamate, aspartate, and possibly homocysteate,

are the main fast excitatory transmitters in the CNS.
• Glutamate is formed mainly from the tricarboxylic acid cycle
intermediate α-oxoglutarate, by the action of GABA
aminotransferase.
• There are four main EAA receptor subtypes:
o NMDA
o AMPA
o kainate
o metabotropic.
• NMDA-, AMPA-, and kainate-receptors are ionotropic receptors
regulating cation channels; metabotropic receptors are G-
protein-coupled receptors and act through intracellular second
messengers. There are many molecular subtypes within each
class.
• The channels controlled by NMDA-receptors are highly
permeable to Ca2+ and are blocked by Mg2+.
• AMPA- and kainate-receptors are involved in fast excitatory
transmission; NMDA-receptors mediate slower excitatory
responses and, through their effect in controlling Ca2+ entry, play
a more complex role in controlling synaptic plasticity (e.g., long-
term potentiation).
• Competitive NMDA-receptor antagonists include APS and other
experimental compounds; the NMDA-operated ion channel is
blocked by dizocilpine, as well as by the psychotomimetic drugs
ketamine and phencyclidine.
• CNQX is a selective AMPA receptor antagonist.
• NMDA-receptors require low concentrations of glycine as a co-
agonist, in addition to glutamate; 7-chlorokynurenate blocks this
action of glycine.
• NMDA-receptor activation is increased by endogenous
polyamines, such as spermine, acting on a modulatory site that
is blocked by ifenprodil.
• The entry of excessive amounts of CA2+ produced by NMDA-
receptor activation can result in cell death; excitotoxicity.
• Metabotropic receptors are G-protein-coupled receptors, linked
to inositol trisphosphate formation and intracellular Ca2+ release.
They play a part in glutamate-mediated synaptic plasticity and
excitotoxicity. Specific agonists and antagonists are known.
• EAA receptor antagonists are being developed for clinical use.

Inhibitory amino acids: GABA and glycine

• GABA is the main inhibitory transmitter in the brain.

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• It is present fairly uniformly throughout the brain; there
is very little in peripheral tissues.
• GABA is formed from glutamate, by the action of GAD
(glutamic acid decarboxylase). Its action is terminated
mainly by reuptake, but also by deamination, catalysed
by GABA transaminase.
• There are two types of GABA receptor, GABAA and
GABAB.
• GABAA-receptors, which occur mainly postsynaptically,
are directly coupled to chloride channels, opening of
which reduces membrane excitability. Muscimol is a
specific GABA agonist, and the convulsant bicuculline is
an antagonist.
• Other drugs that interact with GABAA-receptors and
channels include:
o benzodiazepine tranquillizers, which act at an
accessory binding site to facilitate the action of
GABA
o convulsants such as picrotoxin, which block the
anion channel
o neurosteroids, including endogenous progesterone
metabolites, and other CNS depressants, such as
barbiturates, which facilitate the action of GABA.
• GABAB receptors are G-protein-coupled receptors, linked
to inhibition of cAMP formation. They cause pre- and
postsynaptic inhibition by inhibiting calcium channel
opening and increasing K+ conductance. Baclofen is a
GABAB-receptor agonist used to treat spasticity. GABAB
antagonists are not yet in clinical use.
• Glycine is an inhibitory transmitter mainly in the spinal
cord, acting on its own receptor, structurally and
functionally similar to the GABAA-receptor.
• The convulsant drug strychnine is a competitive
glycine antagonist. Tetanus toxin acts mainly by
interfering with glycine release.

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