CNS ReceptorsMade 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).

is composed of three parts: the brainIn the CNS the , and cerebellum(seat of consciousness), the cerebrum

(these latter two are "part of medulla oblongatathe 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

(often acetylcholinechemical compound*Thein both neurotransmitter) is aAChabbreviated

central (PNS) andperipheral nervous systemthe(CNS) in many organisms nervous system

including humans.

*Ach receptors:

, also known nAChR()Nicotinic acetylcholine receptors1" acetylcholine receptors) are ionotropicas "

nicotineparticularly responsive to

, also mAChR()Muscarinic acetylcholine receptors2" acetylcholine receptors) metabotropicknown as "

.muscarineare particularly responsive to

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’:

Aricept ® : Donepezil

Galantamine

: Rivaxel®, Exelon ®Rivastigmine

Cognex ®: Tacrine

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 (a 2αcoupled receptor) andqG(a1αsubtypes

is Phenylephrinecoupled receptor).iG

of the α receptor.selective agonista

. 3βand2β,1β) β receptors have the subtypes2All three are linked to Gs proteins

also couples to Gi), which in turn 2β(although

.adenylate cyclaseare linked to

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:

SNRIsnorepinephrine reuptake inhibitors-Serotonin

: Effexor®, Safemood®Venlafaxine

B) Dopamine

types:2 Dopamine receptors are of

*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).

following systems:3 Dopamine is the major neurotransmitter of the

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.

’Parkinson’s diseaseDeficiency of dopamine in this system causes ‘

*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.

types of receptors:2 GABA acts on

- 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?APPLICATION_NAME=drugportal

*Drug Bank

http://www.drugbank.ca/

*Book: Basic Neurochemistry:Molecular, Cellular, and Medical Aspects (Volume1)