Central Nervous System

Neurotransmitters found in the CNS

HO
O Me HO NH2
Me HO NH2 (Small Peptides)
Drugs that affect the CNS can: H3C O
N
Me
 Selectively relieve pain HO HO
Acetylcholine Endorphins
 Reduce fever Noradrenaline Dopamine
 Suppress disordered movement
 Induce sleep or arousal NH2 HN
O O
HO HO
 Reduce appetite NH2
HO OH
 Allay the tendency to vomit N
N NH2 O
NH2
 Be used to treat anxiety, depression, schizophrenia, Parkinson’s Disease, Alzheimer’s H
gamma-aminobutyric acid
Serotonin Histamine Glutamate
Disease, epilepsy, migraine, etc. (GABA)
(5-Hydroxytryptamine)
5-HT
How do drugs work in the CNS?
“A central underlying concept of neuropharmacology is that drugs that influence behavior and It’s a balancing act!!
improve the functional status of patients with neurological or psychiatric diseases act by enhancing or Current models of CNS diseases often attribute the physiological cause of the disease to an imbalance
blunting the effectiveness of specific combinations of synaptic transmitter actions.” of neurotransmitters.

Blood Brain Barrier (BBB) Neurotransmitters

A physiological mechanism that alters the permeability of brain capillaries, so that some substances, a chemical substance that is released at the
such as certain drugs, are prevented from entering brain tissue, while other substances are allowed end of a nerve fiber by the arrival of a nerve
to enter freely. impulse and, by diffusing across the synapse
or junction, causes the transfer of the
The blood-brain barrier (abbreviated BBB) is composed of endothelial cells packed tightly in brain impulse to another nerve fiber, a muscle
capillaries that more greatly restrict passage of substances from the bloodstream than do endothelial fiber, or some other structure.
cells in capillaries elsewhere in the body.

What is the purpose of the BBB?

The blood-brain barrier protects the brain from the many chemicals flowing around the body. Many
bodily functions are controlled by hormones, which are detected by receptors on the plasma
membranes of targeted cells throughout the body.

The blood-brain barrier is an effective way to protect the brain from common infections. Thus
infections of the brain are very rare; however, as antibodies are too large to cross the blood-brain
barrier, when infections of the brain do occur they can be very serious and difficult to treat.
Acetylcholine
Acetylcholine ﾔ acts ﾕ or ﾔ is transmitted ﾕ within cholinergic pathways that are concentrated mainly
in specific regions of the brainstem and are thought to be involved in cognitive functions, especially
memory.
Severe damage to these pathways is the probable cause of Alzheimer ﾕ s disease.

Norepinephrine
These neurons send their axons to the limbic system (appetite inhibition), the subcortical centers and
the cerebral cortex (arousal).
Noradrenaline is classed as a monoamine neurotransmitter and These neurons provide projections HO NH3+
to the cortex, hippocampus ﾊ, thalamus ﾊ and midbrain. Polar groups Mostly protonated
The release of noradrenaline tends to increase the level of excitatory activity within the brain, and
HO
to the
noradrenergic pathways are thought to be particularly involved in the control of functions such as corresponding
attention and arousal. Dopamine ammonium salt
Answer!
 hippocampus  L-DOPA is transported across the BBB by an amino acid transport system (same one used for
tyrosine and phenylalanine)
 Once across, L-DOPA is decarboxylated to dopamine by Dopa Decarboxylase.
 This is an example of a “prodrug”, that is, a molecule that is a precursor to the drug and is
converted to the actual drug at an appropriate place in the body.

Serotonin
Although the CNS contains less than 2% of the total serotonin in the body, serotonin plays a very
important role in a range of brain functions. It is synthesised from the amino acid tryptophan.Within
the brain, serotonin is localised mainly in nerve pathways emerging from the raphe nuclei, a group of
 Thalamus nuclei at the centre of the reticular formation in theMidbrain ﾊ , pons ﾊ and medulla. These
serotonergic pathways spread extensively throughout the brainstem ﾊ, the cerebral cortex ﾊ and the
spinal cord ﾊ. In addition to mood control, serotonin has been linked with a wide variety of functions,
including the regulation of sleep, pain perception, body temperature, blood pressure and hormonal
activity.Outside the brain, serotonin exerts a number of important effects, particularly involving the
gastrointestinal and cardiovascular systems.

What is serotonin?
NH2
 Dopamine is also classed as a monoamine neurotransmitter and is concentrated in very
specific groups of neurons collectively called the basal ganglia.
HO
 Dopaminergic neurons are widely distributed throughout the brain in three important
5-Hydroxytryptamine, or 5-HT
dopamine systems (pathways):
N
H
A decreased brain dopamine concentration is a contributing factor in Parkinson ﾕ s disease
Understanding Serotonin
while an increase in dopamine concentration has a role in the development of schizophrenia.
The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and
diverse range of 5-HT receptors. At least seven different receptor "families" are known to exist, each
Treatment of Parkinson’s Disease
located in different parts of the body and triggering different responses. As with all
 Since PD is related to a deficiency of dopamine, it would be appropriate to administer
neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in
dopamine
consciousness, are very difficult to ascertain.
 Problem: Dopamine does not cross BBB, since it is too polar
Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the
specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron.
Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), cocaine, tricyclic antidepressants
(TCAs) and selective serotonin reuptake inhibitors (SSRIs).Recent research suggests that serotonin completely stop firing during REM and non-REM sleep. Histaminergic cells can be recorded firing just
plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout before an animal shows signs of waking.
the body.[6]
Disorders involving histamine:
The action of drugs to treat mental illness Histapenia (deficiency of histamine) and histadelia (abundance of histamine) can cause both
 Serotonin, noradrenaline and dopamine are neurological and physical disorders. Histapenia may be caused by excess copper levels, as this
involved in the control of many of our mental decreases blood histamine.
states, sometimes acting on their own and at
other times acting together (illustrated in the Sexual response:
following diagram). These and other Research has shown that histamine is released as part of the human orgasm from mast cells in the
neurotransmitters are likely to play a pivotal role genitals, and the histamine release has been connected to the sex flush among women. If this
in the pathological basis of mental illness and response is lacking while a woman also has trouble achieving orgasm, this may be a sign of
diseases of the brain. Much of the evidence for histapenia. In such cases, a doctor may prescribe diet supplements with folic acid and niacin (which
this stems from the fact that most of the effective used in conjunction can increase blood histamine levels and histamine release), or L-histidine.
antidepressant drugs are thought to work by Conversely, men with high histamine levels may suffer from premature ejaculations.
changing either serotonin and/or noradrenaline
metabolism, or receptor sensitivity to these Antibodies and the Immune Response
neurotransmitters Antibodies are manufactured by the lymph system. Antibodies are specialized proteins that the body
produces in response to invasion by a foreign substance. The process of antibody formation begins
when an antigen stimulates specialized lymphocytes, called B cells, into action. Antibodies then
counteract invading antigens by combining with the antigen to render it harmless to the body.
Definitions:
 Ergotropic: Energy expending systems (sympathetic division of the PNS) “Fight or flight” Production of white blood cells and antibodies in reaction to an invading disease organism is called an
immune response. This response is one of the body's primary and most efficient lines of defense. In
 Trophotropic: Nutrient accumulating systems (parasympathetic division of the PNS) “Rest most cases, once antibodies have been produced to fight a certain organism, it no longer poses a
and digest” great threat to the body. That is why one attack of a disease often prevents that same disease from
infecting the body again -- the first attack causes production of antibodies that protect the body
against subsequent attacks. With measles, for example, antibodies are produced as a result of having
HN
Histamine is a biogenic amine chemical involved in local immune the disease or of being immunized with the measles vaccine. These antibodies are able to resist a
responses as well as regulating physiological function in the gut and acting second attack of the disease.
as a neurotransmitter (Marieb, 2001, p.414). New evidence also indicates N NH2
that histamine plays a role in chemotaxis of white blood cells.
Histamine Antibodies are not always beneficial. For example, when tissue from another body, such as a
transplanted heart, is introduced, antibodies are produced to destroy the "invader." Transplants
Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are usually are made possible only by means of drugs that act against the body's natural immune
found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these response. Also, when blood is transfused from one person to another, it must be of a matching type;
histaminergic neurons project throughout the brain, to the cortex through the medial forebrain otherwise, the recipient's immune system will manufacture antibodies to destroy the transfused
bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine blood.
receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or
inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor Sometimes, the immune system causes reactions that make the body unusually sensitive to foreign
antagonists (which stimulate histamine release) increase wakefulness.It has been shown that material. When the immune response is disruptive to the body in this way, it is called an allergic
histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far reaction. Let's look at this important mechanism, and the types of allergens, in the next section.
recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and
Allergic Reaction In common use, the term antihistamine refers only to H1-receptor antagonists, also known as H1-
An allergy is a state of special sensitivity to a particular environmental substance, or allergen. An antihistamines. It has been discovered that these H 1-antihistamines are actually inverse agonists at
allergic reaction is the body's response to exposure to an allergen. the histamine H1-receptor, rather than antagonists per se.

Although an allergy can be present almost immediately after exposure to an allergen, it usually
develops over time, as the immune system forms antibodies against the foreign substance. Under In the late 1930s, Paul Charpentier had synthesized the first tricyclic antihistamine, promethazine,
normal conditions, such antibodies work to protect the body from further attack. In the case of an which had a strong sedative effect. He then synthesized a variety of promethazine analogues,
allergy, however, the antibodies and other specialized cells involved in this protective function trigger including chiorpromazine.
an unusual sensitivity, or overreaction, to the foreign substance.

S
The antibodies stimulate specialized cells to produce histamine, a powerful chemical. Histamine S
causes the small blood vessels to enlarge and the smooth muscles (such as those in the airways and N
N
the digestive tract) to constrict. Histamine release can also cause other reactions, such as hives.
H3C NMe2
No one knows why allergies develop, but it is known that an allergy can appear, disappear, or Cl NMe2

reappear at any time and at any age. Allergic reactions rarely occur during the first encounter with Promethazine
(Phenargan) Chlorpromazine
the troublesome allergen because the body needs time to accumulate the antibodies. Also, an (currently used as an anti-emetic)
individual's sensitivity to certain allergens seems to be related to a family history of allergies. People
who have a tendency to develop allergies are referred to as atopic.
Chlorpromazine
An allergic reaction can be so mild that it is barely noticeable or so severe that it is life-threatening. was the first antipsychotic drug, used during the 1950s and 1960s. Used as chlorpromazine
An extremely severe allergic reaction, called anaphylactic shock, is marked by breathing difficulties hydrochloride and sold under the tradenames Largactil ｨ and Thorazine ｨ , it has sedative,
(from swelling of the throat and larynx and narrowing of the bronchial tubes), itching skin, hives, and hypotensive and antiemetic properties as well as anticholinergic and antidopaminergic effects. It also
collapse of the blood vessels, as well as by vomiting, diarrhea, and cramps. This condition can be fatal has anxiolytic (alleviation of anxiety) properties. Today, chlorpromazine is considered a typical
if not treated immediately. antipsychotic.

 Allergic reaction: Histamine and Antihistamines The drug had been developed by Laboratoires Rh 冢 e-Poulenc in 1950 but they sold the rights in
1952 to Smith-Kline & French (today's GlaxoSmithKline). The drug was being sold as an antiemetic
Antihistamines to Antipsychotics? when its other use was noted. Smith-Kline was quick to encourage clinical trials and in 1954 the drug
was approved in the US for psychiatric treatment. The effect of this drug in emptying psychiatric
hospitals has been compared to that of penicillin and infectious diseases.[1] Over 100 million people
N were treated but the popularity of the drug fell from the late 1960s as the severe extrapyramidal side
H3C NMe2 effects and tardive dyskinesia became more of a concern. From chlorpromazine a number of other
O CH2 N O
CH2 N similar neuroleptics were developed (e.g. triflupromazine, trifluoperazine).
NMe2 NMe2
Previously used as an antihistamine and antiemetic its effects on mental state were first reported by
Phenbenzamine Mepyramine Diphenhydramine
the French doctor Henri Laborit in 1951 or 1952 (different sources) as sedation without narcosis. It
became possible to cause 'artificial hibernation' in patients, if used as a cocktail together with
In the late 1930s, such dicyclic antihistamines as phenbenzamine, diphenhydramine, and mepyramine pethidine and hydergine. Patients with shock, severe trauma or burns, become, if treated so,
were in wide clinical use. The antihistamines' most striking clinical side-effect was CNS depression -- sedated, without anxiety and unresponsive/indifferent to painful external stimuli like minor surgical
drowsiness. interventions. The first published clinical trial was that of Jean Delay and Pierre Deniker at Ste. Anne
H 冱 pital in Paris in 1952, in which they treated 38 psychotic patients with daily injections of
chlorpromazine.[1] Drug treatment with chlorpromazine went beyond simple sedation with patients
showing improvements in thinking and emotional behaviour. Ironically, the antipsychotic properties
of chlorpromazine appear to be unrelated to its sedative properties. During long term therapy some Norepinephrin Reuptake Inhibitors for Depression
tolerance to the sedative effect develops. Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved for use in children,
adolescents, and adults.
H3C
Chlorpromazine substituted and eclipsed the old therapies of electro and insulin shocks and other
methods such as psychosurgical means (lobotomy) causing permanent brain injury. Before the era of OH
O
neuroleptics, starting with chlorpromazine, positive long-term results for psychotic patients were only HO NHCH3
CH3
20%. N
H
HO

Definitions: Atomoxetine Epinephrine

Neuroleptic: A term that refers to the effects of antipsychotic drugs on a patient, especially on his or (Strattera, Eli Lilly & Co.)
her cognition and behavior.
Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit
Neuroleptic drugs may produce a state of apathy, lack of initiative and limited range of emotion. In hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. It is
psychotic patients, neuroleptic drugs cause a reduction in confusion and agitation and tend to manufactured and marketed under the brand name Strattera ｨ by Eli Lilly and Company as a generic
normalize psychomotor activity.The term comes from the Greek "lepsis" meaning a taking hold. Attentin by Torrent Pharmaceuticals. There is currently no generic available within the United States
due to patent restrictions.
Extrapyramidal side effects: Physical symptoms, including tremor, slurred speech, akathesia,
dystonia, anxiety, distress, paranoia, and bradyphrenia, that are primarily associated with improper Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such
dosing of or unusual reactions to neuroleptic (anti-psychotic) medications. benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was
tested and subsequently approved as an ADHD treatment.
Reward pathways in the CNS
The most important reward pathway in brain is the mesolimbic dopamine system. This circuit (VTA- Reboxetine is an antidepressant drug used in the treatment of clinical depression, panic disorder and
NAc) is a key detector of a rewarding stimulus. Under normal conditions, the circuit controls an ADD/ADHD. Its mesilate (i.e. methanesulfonate) salt is sold under tradenames including Edronax ｨ,
individual ﾕ s responses to natural rewards, such as food, sex, and social interactions, and is therefore Norebox ｨ, Prolift ｨ, Solvex ｨ or Vestra ｨ.
an important determinant of motivation and incentive drive. In simplistic terms, activation of the O
pathway tells the individual to repeat what it just did to get that reward. It also tells the memory OH
HO NHMe
centers in the brain to pay particular attention to all features of that rewarding experience, so it can O
be repeated in the future. Not surprisingly, it is a very old pathway from an evolutionary point of O

view. The use of dopamine neurons to mediate behavioral responses to natural rewards is seen in HO
worms and flies, which evolved 1-2 billion years ago. N
H
Epinephrine
(Adrenaline) Reboxetine
Norepinephrine Reuptake Inhibitors as Antidepressants
Norepinephrine reuptake inhibitors (NRIs), also known as noradrenaline reuptake inhibitors
(NARIs), are compounds that elevate the extracellular level of the neurotransmitter norepinephrine
in the central nervous system by inhibiting its reuptake from the synaptic cleft into the presynaptic Unlike most antidepressants on the market, reboxetine is a noradrenaline reuptake inhibitor (NARI);
neuronal terminal. The drugs inhibit the class of neurotransmitter transporters known as it does not inhibit the reuptake of serotonin, therefore it can be safely combined with an SSRI.
norepinephrine transporters. They have virtually no action at other monoamine transporters.
Viloxazine (Emovit, Vivalan, Vivarint, Vicilan) is a bicyclic antidepressant morpholine derivative that
inhibits the reuptake of norepinephrine.
A

H Single or double bond Nitrogen or carbon

OH N
O
HO NHMe

O O
HO
N N
Cl
Epinephrine
(Adrenaline) Viloxazine
Clomipramine Me Desipramine H
Me N
Amitriptyline (Novartis) N
(Elavil, etc.) N
Me Me
In 1976, Lippman and Pugsley reported that viloxazine, like imipramine, inhibited norepinephrine Me
reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine or amitriptyline, for that
matter) it did not block reuptake of norepinephrine in neither the medullae nor the hypothalami of
rats. N

Imipramine Me Nortryptyline Me
Further ‘tinkering’ with the structure of the S
N N
N Me Me
antipsychotic drugs led to a drug which was useful in N
treating depression
Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. They are named
NMe2
Cl NMe2 after the drugs' molecular structure, which contains three rings of atoms (compare tetracyclic
Chlorpromazine Imipramine antidepressant). The term 'tricyclic antidepressant' is sometimes abbreviated to TCA.
(anti-psychotic) (anti-depressant)
Historical The exact mechanism of action is not well understood, however it is generally thought that tricylic
Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba-Geigy). antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine,
Initially, it was tried against psychotic disorders (e.g. schizophrenia), but proved insufficient. dopamine, or serotonin by nerve cells. Tricyclics may also possess an affinity for muscarinic and
histamine H1 receptors to varying degrees. Although the pharmacologic effect occurs immediately,
During the clinical studies its antidepressant qualities, unsurpassed until the advent of SSRIs, became often the patient's symptoms do not respond for 2 to 4 weeks.[1]
evident. Subsequently it was extensively used as standard antidepressant and later served as a
prototypical drug for the development of the later released tricyclics. Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of
clinical depression, pain, nocturnal enuresis, and ADHD, but they have also been used successfully for
It is not as commonly used today but sometimes used to treat major depression as a second-line headache, bulimia nervosa, interstitial cystitis, irritable bowel syndrome, narcolepsy, persistent
treatment. hiccups, pathological crying or laughing, smoking cessation, as an adjunct in schizophrenia, and in
ciguatera poisoning.[1]
“Tricyclic” Antidepressants
The ‘tricyclic’ antidepressants share the common structural feature of fused 6-7-6 membered rings, Definitions:
as shown below. Narcolepsy is a neurological condition most characterized by Excessive Daytime Sleepiness (EDS). A
narcoleptic will most likely experience disturbed nocturnal sleep, confused with insomnia, and
disorder of REM or rapid eye movement sleep. It is a type of dyssomnia. A person with narcolepsy is
A
likely to become drowsy or to fall asleep, often at inappropriate times and places.

While the cause of narcolepsy has not yet been determined, scientists have discovered conditions
Single or double bond Nitrogen or carbon that may increase an individual's risk of having the disorder. Specifically, there appears to be a strong
link between narcoleptic individuals and certain genetic conditions. One factor that may predispose
an individual to narcolepsy involves an area of Chromosome 6 known as the HLA (human leukocyte
antigen) complex.

Certain variations in the HLA complex are thought to increase the risk of an auto-immune response to
protein producing neurons in the brain. The protein produced, called hypocretin or orexin, is
responsible for controlling appetite and sleep patterns. Individuals with narcolepsy often have
reduced numbers of these protein-producing neurons in their brains.

Attention Deficit Hyperactivity Disorder (ADHD)

Attention-Deficit/Hyperactivity Disorder (ADHD) (sometimes referred to as ADD when only
inattentiveness and distractibility are problematic) is a neurological disorder initially appearing in
childhood which manifests itself with symptoms such as hyperactivity, forgetfulness, poor impulse
control, and distractibility.

Research suggests that ADHD arises from a combination of various genes, many of which affect
dopamine transporters.[27] Suspect genes include the 10-repeat allele of the DAT1 gene,[28] the 7-
repeat allele of the DRD4 gene,[28] and the dopamine beta hydroxylase gene (DBH TaqI).[29]
Additionally, SPECT scans found people with ADHD to have reduced blood circulation,[30] and a
significantly higher concentration of dopamine transporters in the striatum which is in charge of
planning ahead.