CNS Receptors

Made By: Dr. Rowan Mohamed Ahmed

Faculty of Pharmacy
University of Alexandria – Egypt
 The Central Nervous System
The nervous system monitors and controls almost every
organ system through a series of positive and negative
feedback loops. The Central Nervous System (CNS)
includes the brain and spinal cord. The Peripheral
Nervous System (PNS) connects the CNS to other parts
of the body, and is composed of nerves (bundles of
neurons).

In the CNS the brain is composed of three parts: the

cerebrum (seat of consciousness), the cerebellum, and
the medulla oblongata (these latter two are "part of
the unconscious brain").

The spinal cord runs along the dorsal side of the body and
links the brain to the rest of the body.
Parts of The CNS
 Systems of the CNS
These systems are pathways formed
of specific parts of the brain and
the neurons connecting them
1. The Pyramidal system
2. The Extra Pyramidal system
3. The Limbic system
4. The reticular formation
5. The tuberohypophyseal system
 Chemical Transmission
Chemical transmission is the major means by
which nerves communicate with one another
in the Nervous System.
Chemical transmission requires the following
steps:
1 - Synthesis of the neurotransmitter in the
presynaptic nerve terminal
2- Storage of the NT in the secretory vesicle
3- Regulated release of the NT into the synaptic
space between the pre and post synaptic
neurons
Chemical Transmission
Neurotransmitters and Receptors
 1) Acetylcholine
*The chemical compound acetylcholine (often
abbreviated ACh) is a neurotransmitter in both
the peripheral nervous system (PNS) and central
nervous system (CNS) in many organisms
including humans.
*Ach receptors:
1)Nicotinic acetylcholine receptors (nAChR, also known
as "ionotropic" acetylcholine receptors) are
particularly responsive to nicotine
2)Muscarinic acetylcholine receptors (mAChR, also
known as "metabotropic" acetylcholine receptors)
are particularly responsive to muscarine.
 Acetylcholine
*Cholinergic pathways play an important role in ‘arousal’,
‘learning’, ‘motor control’, ‘short term memory’.
*Hyperactivity if Cholinergic neurons in the corpus striatum
leads to ‘Parkinson’s disease’
*Loss of Cholinergic neurons in the hippocampus is
associated with ‘Alzheimer’s Disease’
*Drugs used for Treatment of ‘Alzheimer’s disease’:
Donepezil: Aricept ®
Galantamine
Rivastigmine : Rivaxel®, Exelon ®
Tacrine: Cognex ®
They reversibly inhibit the enzyme Acetycholinesterase.
 2)Catecholamines
*The catecholamines dopamine,
norepinephrine and epinephrine are
neurotransmitters and/or hormones in the
periphery and in the CNS.
a)Norepinephrine is the neurotransmitter in the
brain as well as in postganglionic,
sympathetic neurons.
b)Dopamine, the precursor of norepinephrine,
has biological activity in the periphery, nost
particularly in the kidney, and serves as a
neurotransmitter in several important
pathways in the CNS.
 A) Norepinephrine
There are two main groups of adrenergic
receptors, α and β, with several subtypes:
1) α receptors have the
subtypes α1 (a Gq coupled receptor) and α2 (a
Gi coupled receptor). Phenylephrine is
a selective agonist of the α receptor.

2) β receptors have the subtypes β1, β2 and β3.

All three are linked to Gs proteins
(although β2 also couples to Gi), which in turn
are linked to adenylate cyclase.
 A) Norepinephrine
*Norepinephrine plays an important role in the
regulation of both ‘arousal’ and ‘mood’.
*Increased release in the brain is responsible for
wakefulness and alertness.
*Deficiency of Norepinephrine in certain parts of the
brain is thought to be the main cause of
‘Depression’.
*Treatment of Depression:
Serotonin-norepinephrine reuptake inhibitors SNRIs
Venlafaxine : Effexor®, Safemood®
 B) Dopamine
Dopamine receptors are of 2 types:
*D1-type(including D1&D5 subtypes)
*D2-type (including D2, D3, D4 subtypes)
**Both types are G-protein coupled receptors that involve
‘adenylate cyclase/cAMP’ as a signal transduction mechanism
(D1-receptors activate, while D2-receptors inhibit adenylate
cyclase).
Dopamine is the major neurotransmitter of the 3 following systems:
1- The nigrostriatal system.
2- The limbic system.
3- The tuberohypophyseal system.
 B) Dopamine
*In the nigrostriatal system, dopamine is involved in the control of
motor function.
Deficiency of dopamine in this system causes ‘Parkinson’s disease’
*In the limbic system, dopamine is involved in the control of
behavior and emotion.
Increased dopaminergic activity in this system is believed to cause
‘Schizophrenia’
Treatment of Parkinson’s:
*Levodopa and Carbidopa (dopamine precursor): Sinemet®
*Piribedil (dopaminergic agonist): Trivastal®
Treatment of Schizophrenia:
*Typical antipsychotics: Haloperidol® , Chlorpromazine: Neurazine®,
Largactil®(blocking DA receptors)
 3) Serotonin (5-HT)
*5-HT is an important CNS transmitter although the brain accounts
for only 1% of its total body content.
*5-HT receptors in the CNS include 5-HT1, 5-HT2 and 5-HT3
receptors.
*5-HT pathways in the CNS are involved in behavioral changes,
mood, hallucinations, sleep, wakefulness, and control of sensory
transmission.
*5-HT receptors appear to play a role in depressive illnesses and
the negative symptoms of schizophrenia.
 3) Serotonin (5-HT)
*Treatment of Depression:
-Buspirone (Buspar®) partial agonist of 5-HT1 R
-Selective Serotonin Reuptake inhibitors (SSRIs):
Fluoxetine: Prozac®, Fluoxetine®
Hypericum perforatum: Safemood®
Paroxetine: Seroxat®, Xandol®, Paxetin®
Trazodone: Trittico®
Sertraline: Lustral®, Moodapex®, Serlift®, Serpass®, Sertral®
 3) Serotonin (5-HT)
*Treatment of schizophrenia:
-Atypical antipsychotics (blocking serotonergic receptors 5-HT2
in addition to D2 receptors)
Risperidone: Psychodal®, Schizodal®, Risperidal®, Apexidone®
Quetiapine: Seroquel®, Quitapex®
Aripiperazole: Schizofy®, Abilify®, Aripiprex®
Clozapine: Leponex®, Clozapex®, Clozapine®
Olanzapine: Zyprexa®, Olapex®
 4) Histamine
*Histamine is present in the brain in much smaller amounts •
than in other tissues (skin & Lung).
*Histaminergic neurons arise from a small region in the •
hypothalamus and extend to the forebrain and midbrain.
*Histamine receptors in the brain include H1, H2, H3- receptors,
which are all G-protein coupled receptors.
*Histamine in the CNS is thought to function in the regulation of
arousal, body temperature and vascular dynamics.
*Blocking central H1 receptors is associated with both sedative
and antiemetic effects.
 5) Glutamate
It’s an excitatory amino acid widely distributed in the CNS and
have important metabolic and neurotransmitter roles.
Glutamate receptors are classified into:
1)Ionotropic glutamate receptors:
Channel-linked receptors which include:
NMDA(N-methyl D-aspartate) receptors … slow excitatory
response
AMPA (amino methyl propionic acid) receptors & Kainate
receptors …. Fast transmission
2)Metabotropic glutamate receptors:
G-protein coupled receptors which are linked to second
messenger systems.
 5) Glutamate and Aspartate
*Glutamate and aspartate exert an extremely powerful excitatory
effect on neurons in every region of the CNS.
*Glutamate antagonists have a potential therapeutic role in the
treatment of ‘epilepsy’ & ‘Schizophrenia’ as well as reduction of
‘Brain cell death’ (anoxia, stroke, ischemia, trauma) caused by
excessive NMDA receptor activation (excitotoxicity)
*Memantine, a weak nonselective NMDA receptor antagonist, was
used as an add-on to clozapine therapy in a clinical trial for
treatment of Schizophrenia.
*A well known anesthetic as ‘Ketamine’ are selective blocking agents
of NMDA-operated channels.
6) Gamma amino Butyric acid (GABA)
GABA is an inhibitory neurotransmitter amino acid that is
synthesized by decarboxylation of the excitatory amino acid
glutamate.
It occurs only in brain tissues and is abundant in the nigrostriatal
system.

GABA acts on 2 types of receptors:

- GABA a-Receptor
- GABA b-Receptor
 6) GABA
- GABA a- receptors: channel-linked receptors, which are
stimulated by GABA leading to increased chloride permeability,
hyperpolarization, and reduction of excitability.
Abnormalities with GABA system is associated with “Anxiety
Disorders”
- GABA b- receptors: G-protein coupled receptors, inhibit
calcium channels and open potassium channels reducing
excitability.
 6) GABA
Treatment of Anxiety:
Benzodiazepines (binding to the GABA a-Receptor accessory site
as the ‘benzodiazepine receptor’
-Diazepam: Valinil®, Neuril®, Valium®, Farcozepam®, Epival®
-Alprazolam: Xanax®, Zolam®, Prazolam®, Alprax®, Restolam®
-Oxazepam: Oxazin®, Comedormir®
-Lorazepam: Ativan®
-Midazolam: Dormicum®, Midathetic®

Antiepileptics:
Clonazepam: Rivotril®, Apetryl®, Amotril®, Clopam®
 7) Glycine
*Glycine is an inhibitory amino acid which is present in high
concentrations in the spinal cord.
*The Spinal stimulant ‘Strychnine’ produces convulsions by
competitive antagonism of the inhibitory response to
glycine in the spinal cord.
*In addition, ‘tetanus toxin’ acts selectively to prevent
glycine release from inhibitory neurons of the spinal cord
causing excessive reflex hyperexcitability and violent
muscle spasms.
 8) Adenosine
*Adenosine is a purine acting A1, A2 and A3 receptors (G-
protein coupled).
*Adenosine is mainly inhibitory producing drowsiness,
analgesia and anticonvulsant activity.
*Therefore, synthetic adenosine agonists could be useful in
treating sleep disturbance, pain, epilepsy.
*On the other hand, Xanthines, such as Caffeine, produce
arousal and alertness by acting as antagonists at the A2-
receptors.
Stopain®, Panadol Extra®, Alertin®
 9) Melatonin
*Melatonin is a mediator that is synthesized from the 5-HT in
the pineal gland.
*Melatonin receptors are G-protein coupled, and are mainly
found in the retina and brain.
*Melatonin secretion is controlled by an input from the retina
to a structure in the hypothalamus termed as ‘the biological
clock’
*Melatonin secretion is high at night and low by day, therefore
it’s important in the regulation of the ‘Circadian rhythm’
*Melatonin is medicinally used to control ‘Jet-lag’ and in
improving the performance of night-shift workers.
References:
*National Institute of Mental Health:
http://www.nimh.nih.gov/index.shtml
*Drug Information Portal
http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp?APPLICA
TION_NAME=drugportal
*Drug Bank
http://www.drugbank.ca/
*Book: Basic Neurochemistry:Molecular, Cellular, and Medical
Aspects (Volume1)