Introduction to CNS Pharmacology

Faraza JavedPhD Pharmacology

The Nervous System

The Nervous system is the master controlling and communicating system of the body.

The Nervous system controls and coordinates all essential functions of the human body.

Functions of Nervous System Sensory Function: Nervous system uses its millions of

sensory receptors to monitor changes occurring both inside and outside the body. Those changes are called stimuli and gathered information is called sensory input.

Integrative Function: The Nervous system process and interprets the sensory input and make decisions about what should be done at each moment - a process called integration.

Motor Function: The Nervous system the send signals to muscle, glands and organs so that they can respond correctly such as muscular contraction or glandular secretion.

Structural Classification of the Nervous System

Central Nervous System: consist of brain and spinal cord, which act as integrating and command centers of the nervous system.

Peripheral Nervous System: it is the part of nervous system outside the CNS. They link all parts of the body by carrying impulses from sensory receptors to CNS and from the CNS to appropriate glands or muscles.

Central Nervous System

THE BRAIN Brain is located within the

cranial cavity of the skull and consists of the cerebral Hemisphere, brain stem and Cerebellum.

Cerebral Hemisphere The two cerebral hemispheres (the left

and the right side) form the largest part of the brain, called cerebrum.

Its surface called cerebral cortex, is convoluted and exhibits elevated ridges called gyri which are separated by shallow grooves called sulci. It also has deeper grooves called fissures which separates large regions of the brain.

Each cerebral hemisphere is divided by some fissure and sulci into number of lobes which are named for the cranial bones that lie over them.

The cerebral hemisphere are involved in logical reasoning, moral conduct, sensory interpretation and initiation of voluntary muscle activity.

The outer surface of the cerebrum is called the cerebral cortex or grey matter. It is the area of the brain where nerve cells make connections, called synapses, that control brain activity. The inner area of the cerebrum contains the insulated (myelinated) bodies of the nerve cells (axons) that relay information between the brain and spinal cord. This inner area is called the white matter because the insulation around the axons gives it a whitish appearance.

The cerebrum is further divided into 4 sections called lobes. These include the frontal (front), parietal (top), temporal (side) and occipital (back) lobes.

Each lobe has different functions: The frontal lobe controls movement, speech, behaviour,

memory, emotions and intellectual functioning, such as thought processes, reasoning, problem solving, decision making and planning.

The parietal lobe controls sensations, such as touch, pressure, pain and temperature. It also controls spatial orientation (understanding of size, shape and direction).

The temporal lobe controls hearing, memory and emotions. The left temporal lobe also controls speech.

The occipital lobe controls vision.

Brain Lateralization

Cerebellum The cerebellum is the next largest part of the brain. It is

located under the cerebrum at the back of the brain. It is divided into 2 parts or hemispheres and has grey and white matter, much like the cerebrum.

The cerebellum is responsible for: Fine coordinated movement posture balance reflexes complex actions (walking, talking) collecting sensory information from the body

Brain Stem The brain stem is a bundle of nerve tissue at the base of

the brain. It connects the cerebrum to the spinal cord and sends messages between different parts of the body and the brain.

The brain stem has 3 areas: midbrain pons medulla oblongata

The brain stem controls: breathing body temperature blood pressure heart rate hunger and thirst Cranial nerves emerge from the brainstem. These

nerves control facial sensation, eye movement, hearing, swallowing, taste and speech.

The Spinal Cord The spinal cord is a reflex

center and conduction pathway which is found in the vertebral canal.

It extends from the foramen magnum to L1 or L2.

31 pairs of spinal nerves arise along the spinal cord. These are "mixed" nerves because each contain both sensory and motor axons.

The spinal cord carries out two main functions: It connects a large part of the peripheral nervous system

to the brain. Information (nerve impulses) reaching the spinal cord through sensory neurons are transmitted up into the brain. Signals arising in the motor areas of the brain travel back down the cord and leave in the motor neurons.

The spinal cord also acts as a minor coordinating center responsible for some simple reflexes.

Neurotransmission by Action Potential

Nerve signals are transmitted by action potentials that are abrupt, pulse like changes in the membrane potential that last a few ten thousandths of a second.

Action potential can be divided into 3 phases. Resting, depolarization and repolarization.

Terminology Associated with Changes in Membrane Potential

Depolarization- a decrease in the potential difference between the inside and outside of the cell.

Hyperpolarization- an increase in the potential difference between the inside and outside of the cell.

Repolarization- returning to the RMP from either direction.

In the nervous system, different channel types are responsible for transmitting electrical signals over long and short distances: K+ slow leaky channels; mechanically operated Na+ channelsVoltage gated Na+ & K+ channels.

A) Graded potentials travel over short distances and are activated by the opening of mechanically or chemically gated channels.

B) Action potentials travel over long distances and they are generated by the opening of voltage-gated channels.

Gated Channels Are Involved in Neuronal Signalling

Action Potential Conduction

Movement of the AP along the axon at high speed is called conduction. A wave of action potentials travel down the axon.

Each section of the axon is experiencing a different phase of the AP (see figure).

Factors Influencing Conduction Speed of APs

The resistance of the membrane to current leak out of the cell and the diameter of the axon determine the speed of AP conduction.

Large diameter axons provide a low resistance to current flow within the axon and this in turn, speeds up conduction.

Myelin sheath which wraps around vertebrate axons prevents current leak out of the cells. Acts like an insulator, for example, plastic coating surrounding electric wires.

However, portions of the axons lack the myelin sheath and these are called Nodes of Ranvier. High concentration of Na+ channels are found at these nodes.

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Saltatory Conduction• When depolarization reaches a node, Na+ enters the axon through open channels. • At the nodes, Na+ entry reinforces the depolarization to keep the amplitude of the AP constant, but slows the current flow due to a loss of charge to the extracellular fluid.

• However, it speeds up again when the depolarization encounters the next node. •The apparent leapfrogging of APs from node to node along the axon is called saltatory conduction.•Diseases which destroy the myelin sheath (demyelinating disorders) can cause paralysis or other problems.

Synaptic Transmission

Excitatory postsynaptic potentials (EPSP) and Inhibitory postsynaptic potentials (IPSP) are inputs that depolarize/hyperpolarize the postsynaptic cell bringing it closer/away from firing an action potential.

EPSP are caused by opening of channels that are permeable to Na and K.

Neurotransmitters: Ach, Dopamine, Serotonin IPSP are caused by opening of Cl channels Neurotransmitters: GABA and Glycine

Neurotransmitters

Acetylcholine Serotonin Norepinephrine Dopamine GABA Glutamate Most drugs that affect the central nervous system (CNS)

act by altering some step in the neurotransmitters mediating the physiological and pathological responses in neuropharmacology.

Acetylcholine

Myasthenia gravis is characterized by skeletal muscle weakness and fatigability resulting from a reduced number of Ach receptors on muscle end plate (due to autoimmune antibodies against acetylcholine receptors at neuromuscular junction). Diagnosis and treatment invloves acetylcholine esterase inhibitors (neostigmine)- prolong the action of acetylcholine at muscle end plate.

Ach esterase inhibitors (Tacrine)-Alzheimer’s Disease Anticholinergic (Benztropine) in Parkinson’s Disese

Serotonin

Involved in mood, depression and pain regulation.Activities modified by: Antidepressants CNS Stimulants

Dopamine

Involved in movement, attention, learning, motivation, reward

Overactive DopamineSchizopherina (Antipsychotics) Loss of DopamineParkinson Disease (Levodopa)

GABA

Main inhibitory neurotransmitter in CNS Anxiety Disorders (Benzodiazepine) Huntington’s Chorea that involves loss of neurons that

utilize GABA.

Glutamate

High concentrations of glutamate lead to neuronal cell death by mechanisms that have only recently begun to be clarified. The cascade of events leading to neuronal death is thought to be triggered by excessive activation of NMDA or AMPA/kinase receptors, allowing significant influx of Ca2+ into neurons. Because of their widespread distribution in the CNS, glutamate receptors have become targets for diverse therapeutic interventions. For example, a role for disordered glutamatergic transmission in theetiology of chronic neurodegenerative diseases and in schizophrenia has been postulated.

CNS Drug Design Pharmacology

As is evident from the previous literature, a large number of agents have been developed to treat neuropsychiatric diseases. With few exceptions these agents offer primarily symptomatic improvement; few are truly disease modifying. For example, the use of L-dopa to treat Parkinson disease alleviates the symptoms effectively but the disease continues to progress. Similarly, although antipsychotics and antidepressants are often efficacious, the symptoms tend to recur. Moreover, many drugs developed to treat CNS diseases are not uniformly effective: Approximately one-third of patients with severe depression are “treatment-resistant.

Furthermore, the complexity of the brain and its neuronal pathways results in significant risk of side effects, even when the most biochemically selective agent is administered. Studies of treatments for neurodegenerative disease are even more difficult. With current diagnostic capabilities, it is difficult to detect a significant change in the rate of progression of cognitive decline in patients with Alzheimer’s disease in less than a year. One way to circumvent the long time necessary to detect a biological meaningful result is through the use of surrogate markers (e.g., a decrease in serum cholesterol for improved cardiovascular morbidity and mortality). Regrettably, there are relatively few useful surrogate markers for CNS diseases.

Impact of Genomics on CNS Drug Discovery

The sequencing of the human genome has the potential to significantly change drug discovery in the CNS. Thus,genetic testing may predict the likelihood that a given individual will develop a particular disease, will respond to a particular therapy, or will suffer side effectsfrom a particular treatment paradigm. Genetic testing may be particularly important in the case of CNS diseases, where the etiology is likely to be multigenic.Molecular approaches will likely speed development of more and improved animal models that better mimic humandisease.

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