Introduction to Neuropharmacology

Neuropharmacology: is the science that studies the effect of the pharmacological agent on the
nervous system.
There are four major anatomical systems in the brain: cortex, thalamus, the basal ganglia and
the medial temporal lobes.
The thalamus: is the gateway to the cortical processing of all incoming sensory information.
The association cortex: integrate information from primary cortical areas, from subcortical
structures and from brain areas involved with memory to create an internal representation of
the sensory information.
The medial temporal lobes (hippocampus, amygdala): integrate multimodal sensory
information for storage and retrieval from memory and attachment of emotions to sensory
information.
The basal ganglia: integration of motor input from cortical areas (coordination).
Therefore the basic function of the brain includes the following:
 Reception of sensory information.
 The creation of internal representation.
 Creation of response.
The function of the above systems is modulated by several groups of neurons located within the
CNS and includes: cholinergic (basal forebrain, brainstem); dopaminergic (substantia nigra,
ventral tegmental area); noradrenergic (locus cerulous); serotoninergic (raphi nuclei).
Most of the therapeutic agents used in the current medical practice aimed at strengthening or
inhibiting these modulatory systems.
The basic unit of the CNS which produces all the above actions is the neuron; the key function of
the neuron is to communicate with other neurons or with other target cells (glands, muscles).
The communication of neurons is done either:
 Electrically, this is simple and stereotyped.
 Chemical transmission (neurotransmission) describes the process by which information is
transferred from one neuron to another across synapses. This transmission is variable
involving slow and rapid release of different neurotransmitters, therefore its complex.
This complexity of chemical transmission include also time and amount of transmitter release is
the basis of synaptic plasticity; and the synaptic plasticity is the backbone of all the higher
mental functions for example learning and memory.
Neurotransmitter is a substance found or secreted by a neuron and producing effect on the
target cell, the effect either excitation (depolarizing Na + or Ca2+ channels) or inhibition
(hyperpolarizing K+ channels or blocking receptors).
Neuromodulators: is a substance originated from one neuron to act on receptors of other
neurons to modulate its excitability (synaptic plasticity) like nitric oxide, carbon monoxide,
arachidonic acid.
The synaptic plasticity include short-term physiological events such as regulation of pre and
postsynaptic excitability like no, arachidonic acid or longer term neurotrophic effects are
involved in the regulation of the growth, morphology and functional properties of the neurons
like (neurotrophins, neurosteroids, cytokines, and growth factors).
Receptor: are proteins expressed on the surface of neurons that allow the binding of
neurotransmitter or hormone.
Postsynaptic receptor: it’s the typical receptors that mediate the actions of the released
neurotransmitters, these receptors either excitatory or inhibitory.
Presynaptic autoreceptor: they are located on the same neuron; they detect the
neurotransmitter released from the parent neuron to act as brake on the further release of
neurotransmitter.
Presynaptic heteroreceptor: these receptors are the target of neurotransmitters secreted from
another neurons to modulate the action of the neurons containing that receptor for example
noradrenalin act on α-2 receptors which found on serotoninergic neurons to inhibit serotonin
release.
Receptor subtypes that are important in the CNS include:
 Ionotropic receptors: directly coupled to an ion channel, therefore concerned with fast
neurotransmission (NMDA, GABAA).
 Metabotropic receptors: coupled with G-protein produce intracellular effect through a
second messenger (dopamine, noradrenalin, 5HT).
Neurotransmitters:
Include the following which highly distributed and commonly modulated in clinical practice:
1. Glutamate:
Is the most widely distributed excitatory neurotransmitter in the CNS, Glutamate in the CNS
comes either from Krebs cycle intermediate or glutamine that is stored within glial cells.
Glutamate stored within synaptic vesicles and released in response to increase intracellular Ca 2+;
the action of the transmitter ended by reuptake into neuronal terminals or by nearby astrocytes.
Glutamate receptors: highly concentrated within the cortex, basal ganglia, and sensory
pathways, there are four types of receptors NMDA, AMPA, Kainate, and metabotropic receptor.
NMDA receptor:
 Highly permeable to Ca2+, activation of these receptors leads to calcium entry.
 When the cell is polarized its channels is blocked by Mg 2+, but when the cell depolarized
the block is released.
 Activation of NMDA receptors requires the presence of both glutamate and glycine.
 Competitive glycine antagonist indirectly inhibits glutamate action.
 NMDA receptors also blocked with ketamine,phencyclidine, dizocilpine and memantine.
Other glutamate receptors:
 Kainate receptors are fast excitatory transmitter located both pre and post-synaptic.
 AMPA receptors are also fast excitatory, found on neurons as well as astrocytes.
 Metabotropic receptors are G-protein coupled receptors they act either by raising
intracellular Ca2+ or inhibit adenylate cyclase.

Function of Glutamate receptors in the CNS:

  NMDA and metabotropic receptors are important in long-term adaptive changes in the
brain (neuronal plasticity), and also involved in many pathological conditions in the
brain like ischemia, epilepsy and neurodegenerative diseases.
 AMPA and kainate receptors are responsible for fast excitatory transmission in the CNS
and if they are fully blocked brain function shutdown completely.
Synaptic plasticity: is a long-term change in synaptic connectivity and efficacy either following
physiological alteration in neuronal activity (learning and memory) or result from pathological
disturbances (epilepsy, chronic pain, drug dependence).
Long-term potentiation: long lasting enhancement of synaptic transmission that occur at
various CNS synapses following a short (conditional) burst of high frequency presynaptic
stimulation.
Therapeutic application of glutamate receptors:
 Antagonists:
 Lowering brain damage after stroke or head injury.
 Epilepsy treatment.
 Alzheimer’s disease.
 Schizophrenia.
 Drug dependence.
 Agonists:
 AMPA receptor agonist may improve memory and cognitive performance (piracetam).
2. γ-aminobutyric acid (GABA):
 Is the main inhibitory transmitter in the CNS, while in the peripheral nervous system, glycine
has the same function.
 GABA is formed from glutamate by the action of the enzyme glutamic acid decarboxylase,
function of the amino acid GABA teminated by reuptake mechanism or by GABA
transaminase enzyme.
 Most of the GABA neurons are short interneurons for modulating neuronal functions, but
some long GABA neurons may be found between cerebellum and stratum.
GABA receptors:
 GABAA receptors: postsynaptic, ionotropic receptors mediate fast chloride channel opening
causing hyperpolarization of the cells (inhibition). Drugs act on GABA A receptors include
benzodiazepines, barbiturates, and general anesthetics.
 GABAB receptors: G-protein coupled receptors, on the presynapses it inhibit Ca 2+ entry and
prevent neurotransmitter release; on post-synapses it open K + channels causing reduction in
the excitability of the neurons. Drugs acting on GABA B receptors include baclofen (selective
agonist used in the treatment of spasticity of motor related diseases). Saclofen is a
competitive antagonist may enhance cognitive performances.
3. Dopamine:
 Dopamine is important neurotransmitter, its deficiency or excess, may cause many diseases
like parkinson’s disease, schizophrenia, attention deficit disorders, drug dependence, and
endocrine disorders.
 The synthesis of dopamine from the amino acid tyrosine by the enzyme dopamine
decarboxylase, the action of the transmitter ended by either amine reuptake or by enzyme
metabolism (MAO, COMT).
Dopamine receptors:
 D1 group (D1,D5): metabotropic receptors that activate adenylate cyclase enzyme. D1
receptor widely distributed in the striatum, limbic system, thalamus, and hypothalamus.
 D2 group (D2,D3,D4): metabotropic receptors that inhibit adenylate cyclase. D2 receptors
distribution is similar to D1 receptors in addition to the pituitary gland. D3 receptors
occur in the limbic system but not in the striatum. D4 receptors weakly expressed in the
cortex and limbic system have important relation with drug dependence and
schizophrenia.
Dopamine functions in the CNS:
 The nigrostriatal pathway: represent 75% of the dopamine neurons, it consists of cell
bodies in the substantia nigra whose axons terminate in the corpus striatum. Disorder in this
pathway may occur in Parkinson’s disease (disease of motor control), or by the
administration of D2 receptor antagonist (extrapyramidal symptoms).
 Mesolimbic/mesocortical pathway: the cell bodies found in the midbrain and the fibers
project to the limbic system (nucleus accumbens, amygdala) and the frontal cortex.
Dopaminregic hyperactivity occurs in cases of schizophrenia. The mesocortical dopaminergic
reward pathway play a key role in drug dependence.
 Tuberohypophysial system: is a group of short neurons running from the ventral
hypothalamus to the pituitary gland to regulate the secretion of prolactin. Blocking
dopamine receptors increase the level of prolactin leading to breast enlargement and
galectorrhea. Dopamine agonist drugs used in cases of hyperprolactinemia.
 Vomiting centre: dopamine stimulates vomiting.
4. Noradrenaline:
 The cell bodies of noradrenergic neurons occur in small clusters in the pons and medulla,
and they have extensive connection with many parts of the brain and spinal cord.
 Noradrenergic neurons may have excitatory effect mediated by α and β-receptors or
inhibitory effect mediated by β-receptors.
 About half of the noradrenaline of the brain located within the pontine nucleus called locus
ceruleus. Activation of this nucleus leads to alertness and arousal (RAS).
 Deficiency of noradrenaline in the brain may cause mental depression, while excess of the
transmitter can cause mania.
 Other effect includes autonomic control of blood pressure.
5. 5-hydroxytryptamine (serotonin):
 5-HT containing cell bodies are grouped in the pons and upper medulla (raphe nuclei). The
rostrally situated nuclei project to the cortex, hippocampus, basal ganglia, limbic system and
hypothalamus. The caudally situated cells project to the cerebellum, medulla and spinal
cord.
 5-HT synthesized from the amino acid tryptophan (should be supplied from diet). Action
terminated by the amine reuptake and/or metabolism with monoamine oxidase.
5-HT receptors in the CNS:
 All are metabotropic receptors, except 5-HT3, which is ionotropic receptor.
 5-HT1 receptors: these receptors are predominantly inhibitory in their effects.
 5-HT1A is usually presynaptic autoreceptors, they tend to limit the rate of firing of
these cells. Widely distributed in the limbic system, considered as the main targets
of drugs used in the treatment of anxiety and depression.
 5-HT1B and 5-HT1D: they are presynaptic inhibitory receptors in the basal ganglia. 5-
HT1D receptor agonist used in the treatment of migraine.
 5-HT2 receptors: mostly 5-HT2A in the brain, which exert an excitatory postsynaptic effect,
and are abundant in the cortex and the limbic system. They are the target of many
hallucinogenic drugs. 5-HT2 antagonist used in the treatment of migraine.
 5-HT3 receptors: found chiefly in the area postrema (involved in vomiting).
 5-HT4 receptors: they are expressed in areas of the brain (striatum), have presynaptic
stimulatory effect on the acetylcholine release, and therefore may enhance cognitive
performance. Present in the GIT (modulate GIT movement).
 5-HT6 and 5-HT7 receptors: present mainly in the CNS (hippocampus, cortex and limbic
system), considered as targets for drugs that improve cognition and relieve symptoms of
schizophrenia. Also 5-HT7 receptors may regulate mood and sleep cycles.
 Other effects of 5-HT receptors: regulation of food intake, pain transmission; regulate body
temperature, blood pressure and sexual function.
6. Acetylcholine:
 Ach is widely distributed in the brain (cortex, midbrain, brain stem, and cerebellum).
Degeneration of the nucleus basalis of meynert, which projects mainly to cortex, is
associated with alzheimer’s disease. The septohippocampal nucleus provides the main
cholinergic input to the hippocampus and is involved in memory.
 Local cholinergic interneurons in the corpus striatum are important in relation to
Parkinson’s disease and Huntington’s chorea.
 The main receptors in the CNS are M1, which are presynaptic receptors that inhibit Ach
release. Nicotine Ach are presynaptic receptors widely distributed in the brain, they
facilitate release of other transmitters, such as glutamate and dopamine.
7. Histamine:
 Histaminergic neurons are restricted to a small part of the hypothalamus and project to all
parts of the brain.
 Histamine has many functions in the CNS include: arousal, food and water intake; nausea
and vomiting; and thermoregulation.
8. Adenosine:
Adenosine act mainly as inhibitory neuromdulator; leading to effects such as drowsiness, motor
incoordination, analgesia, and anticonvulsant activity. Adenosine agonist may be used to treat
epilepsy, pain and sleep disorder.