The Central Nervous System
The central nervous system (CNS) controls all bodily functions. It consists of a central part, the brain and spinal cord, linked to a peripheral part, nerve fibres. The sensory nerve fibres carry messages from tissues to the brain or spinal cord, and the motor nerve fibres carry messages from the brain or spinal cord to the tissues
- Cerebral cortex (cerebrum): This is the largest part of the brain which is very rich in nerve cells. It is composed of grey matter (outside) and white matter (inside); it is divided into lobes or regions,each with specific functions. There are two halves or hemispheres to the cerebral cortex withnumerous fibres connecting them. The functions of the cerebral cortex are: sensory and motorcoordination, mental processes, intelligence, memory, vision, judgement, thought, speech, emotions,and consciousness. The cerebral cortex can be stimulated (excited) or depressed (inhibition) by drugs.
- Thalamus: A relay centre; from here impulses are relayed to the cerebral cortex. The thalamus coordinates information. Its function is the coordination and filtration of incoming signals. It is also involved in appreciation of painful sensation.
- Hypothalamus: A very important area; consists of various specialized regions of nuclei located near the base of the skull. The functions are to control the involuntary functions of the body that are necessary for living, e.g. regulation of heart, blood pressure, body temperature, and metabolism. It also controls feeding, drinking, sexual, and emotional responses. The hypothalamus forms a very important part of the limbic system. Neurons in the hypothalamus produce substances called releasing factors which travel to thepituitary gland and modify this gland. A number of drugs can affect the hypothalamus.
- Pituitary: A small gland located at the base of the brain which secretes hormones that control growth, behaviour and metabolism of the body through the action of these hormones on peripheral tissues, e.g. follicle stimulating hormone stimulates follicle maturation in the ovaries. Thyroid stimulating hormone stimulates the thyroid gland to synthesize and release thyroid hormone.
The midbrain is the area the links the forebrain with the hindbrain. It is a relay centre for visual(eye) and auditory (ear) stimuli or signals.
- Medulla (the bulb): This is the site of origin of many cranial nerves. It is where regulation of respiration (breathing centre) and regulation of heart and blood pressure occurs. It also exercises control over some involuntary activity (the autonomic nervous system). A number of drugs whichdepress respiration and blood pressure will do so by depressing the medulla, e.g. barbiturates.
- Cerebellum: The cerebellum is a large, highly convoluted structure connected to the brain stem by large fibre tracts. It is responsible for coordination and posture. It does not initiate movement, butis an organizer of voluntary activity initiated elsewhere. Drugs which affect the cerebellum will cause ataxia (drunkenness), e.g. alcohol.
The Brain Nerve Cell (The Neuron)
- The cell body: or soma contains a nucleus and surrounding cytoplasm which is packed with rough endoplasmic reticulum, a network of smooth endoplasmic reticulum, and abundant vesicles which can be secreted. These are characteristic of cells active in protein synthesis and secretion of substances.
- The dendrites: function as the receiving antennae for incoming information, are usually short, and can have highly complex branching patterns. The incoming information is accepted or picked up through a receptor located on the dendritic membranes. Upon receipt of a "signal" from anothercell, an electric current is generated and transmitted to the axon.
- The axon: a single fibre that extends from the cell body and ends at a synapse. The axon carries signals away from the cell body. The dendrites and cell body receive information in the form of pulses from other neurons. The neuron responds (or it does not respond) by sending its own pulsesthrough its axon to another neuron. Some neurons are activated by other neurons; many neuronscan activate themselves spontaneously.
In order for the brain to function properly, the nerve cells (neurons) must communicate with each other. The neurons are not continuous with each other, but simply touch each other only at certain places or junctions. The junction between two neurons is called the synapse. The synapse is commonly formed by contact of the axon belonging to one neuron with a dendrite or the cell body of another neuron. Each neuron may have thousands of synapses on its cell body or dendrites. An impulse (signal), when it reaches the synapse, has to be communicated to another neuron if it is to produce further effect. The passage of a signal from one neuron to another neuron is called synaptic transmission. Synaptic transmission is usually chemical in nature. Substances mediating synaptic transmission are synaptic transmitters. Synapses are usually unidirectional and one synapse makes one connection between two cells. However, a single cell can make synaptic connections with many other cells. In chemical transmission, the release of a transmitter substance is required in order to activate the other cell or pass on the message.
Concept of Synaptic Transmission
The nerve impulse (electrical activity) passes down a nerve axon and releases a chemical substance into the synaptic cleft. The postsynaptic membrane contains binding sites for the chemical transmitter. These binding sites are called receptors. The binding of the chemical transmitter to the receptor usually provokes a change in the permeability of the membrane and ions (calcium) move across the membrane,causing a change in electrical activity of the membrane and this electrical activity is passed along to the next cell. The continuous presence of a transmitter in the synaptic cleft would prevent other impulses from getting through. To prevent the synapses from becoming non-functional, the chemical transmitter is removed by one of two major mechanisms: broken down by enzymes or taken back up into the presynaptic structure. The process of synaptic transmission is very rapid. The synapses can be a target site for many drugs. Some drugs can interrupt synaptic transmission, where as others can enhance or facilitate it. There are many different ways in which drugs can interfere with this process, thereby modifying the activity of the brain
The Concept of Receptor
As stated above, after release into the synaptic cleft, the neurochemical transmitter or messenger binds to specific molecules known as receptors. Receptors are proteins synthesized in the rough endoplasmic reticulum, transported to different parts of the cell and inserted into the cell membrane of the cell body, dendrites and axons. (Some receptors can be inside the cell). Receptors have specificity for endogenous transmitters and this specificity or differences in the binding properties of receptors has been exploited in drug development. Stated another way, each endogenous transmitter usually has its own specific receptor. When the transmitter binds to the receptor, it elicits a specific response. Drugs can either stimulate a receptor (called agonists) or inhibit action on a receptor (called antagonists).
Cholinergic synapses and receptors are found in both the peripheral nervous system (neuromuscular junction, autonomic ganglia and parasympathetic postganglionic synapses) and in the brain and spinal cord. Cholinergic receptors have two broad classifications. Those that are stimulated by nicotine are called nicotinic receptors. Nicotinic receptors are found in all autonomic ganglia, at theneuromuscular junction, and in certain regions of the brain. Muscarinic receptors are stimulated by the alkaloid, muscarine, and are found in a wide array of the regions of the brain. The normal endogenous transmitter is acetylcholine. Muscarinic receptors in the brain are involved in learning, memory and cognitive function. Drugs which block or antagonize the action of acetylcholine at these receptorsproduce amnesia. Loss of these cholinergic neurons may be associated with Alzheimer's disease.
Serotonin and its receptors are found in the upper brain stem, with significant amounts in the pons and medulla, hypothalamus, hippocampus, and cerebral cortex. Hyperactivity of the serotonergic system is involved in the pathogenesis of anxiety, and hypoactivity has been implicated in depression. Regardless, drugs have been developed which modulate the serotonergic system.
Catecholamines - dopamine
- Dopaminergic pathways occur predominantly in three areas- hypothalamus, basal ganglia and brainstem, and midbrain. Dopaminergic pathways are involved in control of some hormonal systems(hypothalamus), motor coordination (basal ganglia), and motivation and reward. Disturbances in these pathways lead to Parkinson's disease and schizophrenia, depending on the location of the affected neurons.
- There are several subclasses of dopamine receptors. The two most important are D1 and D2. D1 receptors, when activated by dopamine, are excitatory and D2 receptors are inhibitory.
Catecholamines - Norepinephrine
Norepinephrine pathways originate in the brain stem and send projections to the cerebral cortex, hypothalamus, limbic system, and the cerebellum. There are a large number of receptor types fornorepinephrine. The two main classes are alpha and beta. Activation of these receptors usually leads to excitation of the cell, but one of the subclasses of these receptors, when activated, is inhibitory. Some of the antidepressants will function by modulating (enhancing) the norepinephrine system.
Glutamate or glutamic acid is one of the more important amino acid neurotransmitters in the brain. Glutamate is the primary excitatory neurotransmitter in the brain and is found in almost all neurons. Glutamate acts on a family of receptors (glutamatergic receptors). Glutamatergic neurons are involved in learning.
Gamma-aminobutyric acid (GABA):
GABA is the main inhibitory neurotransmitter in the CNS. GABAergic neurons and receptors are found in high concentrations in the cerebral cortex, hippocampusand cerebellum. A number of CNS depressants (e.g. barbiturates and benzodiazepines) bind to theGABA receptor.
- There are three main classes of opioid peptides: enkephalins, endorphins, and dynorphins. They have varying degrees of selectivity for one of the opioid receptors – mu (:), delta (*)or kappa (6)
- The : opioid receptor subtype is most abundant in the cerebral cortex, hypothalamus, brain stem,and part of the spinal cord. This distribution is consistent with their involvement in pain regulation.
- The* opioid receptor is concentrated in the olfactory system and various limbic structures where they play an important role in olfaction, motor integration (coordination), reward, and cognitive (thinking) functions.
- The 6 receptors are abundant in the caudate-putamen and hypothalamic sites and are involved in regulation of food intake, water balance, pain perception, and control of the endocrine system.
The Peripheral Nervous System
- The efferent component of the peripheral nervous system consists of the motor nerves and the autonomic nervous system.
- The motor nerves in nervate the skeletal muscles or those parts of the body that are under voluntary control, primarily the muscles of posture and movement. The transmitter that is released by the motor nerves as they innervate muscle is acetylcholine. The receptor is designated as nicotinic as it is stimulated by nicotine, and the synapse is called the neuromuscular junction.
- The autonomic nervous system (ANS) is involved in maintaining a stable internal environment. It governs vital bodily functions that are normally carried out without conscious effort. For example, the ANS helps to control blood pressure, heart rate, movement of the bowel, urinary output, and sweating. These often are referred to as the visceral or vegetative functions, and because they are controlled without conscious effort, the autonomic nervous system is often called the involuntary nervous system.
General stimulation of this system promotes or increases the vegetative functions of the body. At rest, the parasympathetic type of activity is the predominant activity. The sympathetic activity is largely inhibited.
General stimulation of this system results in the mobilization of resources to prepare the body to meet emergencies. The mass sympathetic discharge results in increased activity of many functions of the body, including increased heart rate, blood pressure, blood supply to the tissues, rate of cell metabolism, and blood glucose. The sum of these effects permits the body to perform physical tasks that otherwise would not be possible. As it is stress that usually excites the sympatheticsystem, it is frequently said that the sympathetic system provides extra energy to the body for a state of stress, and this is often called the sympathetic alarm reaction or stress reaction.
- Acetylcholine is the transmitter at all autonomic ganglia and the receptors are designated as nicotinic.
- The transmitter at the postganglionic parasympathetic nerve ending is acetylcholine and the synapse is cholinergic. The receptors are designated muscarinic as they are stimulated by the alkaloid, muscarine.
- The transmitter at the postganglionic sympathetic nerve ending is norepinephrine and these receptors have been designated adrenergic. The adrenergic receptor has been further classified into several types. It is prudent to consider three of these types of adrenergic receptors.
- Alpha (") receptorsare located predominantly on smooth muscle, e.g. blood vessels, gastro intestinal muscle, and uterus. Activation of " receptors usually leads to activation or contraction of the muscle.
- Beta ($) receptors can be sub-divided into $1 and $2. $1 receptors are found in the heart, and when activated, increase the forceand rate of contraction of the heart. $2 receptors are found in the lungs, blood vessels, gastrointestinalmuscle and uterus, and activation of these receptors leads to muscle relaxation.
four general types of drugs that modify the sympathetic and parasympathetic systems
- 1. Drugs that mimic the effects of the sympathetic system.Example: norepinephrine
- 2. Drugs that block the effects of the sympathetic system.Example: propranolol ($ receptors in the heart)prazosin (" receptors in the blood vessels)
- 3. Drugs that mimic the effects of the parasympathetic system.Example: acetylcholine
- 4. Drugs that block the effects of the parasympathetic system.Example: atropine (belladonna)
Drugs Affecting the ANS through their Action on the Brain
The activity of the autonomic nervous system also can be modified by drugs acting on the brain. Central stimulants can increase sympathetic and parasympathetic activity (excitation), and central depressants can decrease the activity of these two systems (inhibition)
Autonomic Stimulation gives (sympathetic/parasympathetic)
- Eye: Parasympathetic - Constriction of pupil. Sympathetic - Dilation of pupil
- Heart: Parasympathetic - Decreased heart rat Sympathetic - Increased heart rate
- Heart: Parasympathetic - Decreased force ofcontraction Sympathetic - Increased force of contraction
- Lung (Bronchi): Parasympathetic - Constriction Sympathetic - Dilation
- Gut: Parasympathetic - Increased movement Sympathetic - Decreased movement
- Urinary Bladder: Parasympathetic - Contraction (excitation) Sympathetic - Relaxation (inhibition)
- Blood Vessels (in Skeletal Muscle): Parasympathetic - None Sympathetic -Dilation
- Blood Vessels (in Skin): Parasympathetic - Dilation Sympathetic - Constriction
- Blood Vessels (in Heart) : Parasympathetic - Constriction Sympathetic - Dilation
- Adrenal Gland : Parasympathetic - None Sympathetic - Discharge of epinephrine