Advanced neuropharmacology

Sharmeen Asad
 Neuropharmacology
• Neuropharmacology is the study of drugs affecting cellular
function in the nervous system.
• There are two main branches of neuropharmacology: behavioral
and molecular.
• Behavioral neuropharmacology focuses on the study of how
drugs affect human behavior including the study of how drug
dependence and addiction affect the human brain.
• Molecular neuropharmacology involves the study of neurons
and their neurochemical interactions, with the overall goal of
developing drugs that have beneficial effects on neurological
function.
• Both of these fields are closely connected, since both are
concerned with the interactions of neurotransmitters,
neuropeptides, neurohormones, neuromodulators, enzymes,
second messengers, co-transporters, ion channels, and receptor
proteins in the central and peripheral nervous systems.
 Glial cells
• Glial cells, the astrocytes, are the main non-neuronal
cells in the CNS surronded by neurones 10 to 1.
 Existence of blood brain barrier
• BBB is the another important factor for neuropharmacology.
• It is a highly selective permeability barrier that separates the
circulating blood from the brain extracellular fluid (BECF) in
the central nervous system (CNS).
• It is formed by capillary endothelial cells, which are
connected by tight junctions.
• It allows the passage of water, some gases, and lipid soluble
molecules by passive diffusion, as well as the selective
transport of molecules such as glucose and amino acids that
are crucial to neural function.
• Astrocytes are necessary to create the blood–brain barrier.
• A small number of regions in the brain, including the
circumventricular organs (CVOs), do not have a blood–brain
barrier.
Blood brain barrier
 Neurochemical Interactions
General process
• Depolarization of neuron
leading to an action
potential.
• Transmission of impulse
down axon.
• Release of
neurotransmitter from
axon terminal .
• Binding of
neurotransmitter to
receptor on post-synaptic
cell.

•Post-synaptic cell changes action

•Muscle relaxes or contracts
•Glands secrete or stop secreting
•Neurons fire more often or less often
• Transmitter synthesis
• Transmitter Storage (vesicles)
• Release of Transmitter
• Receptor Binding (reversible)
• Termination of Transmission: Reuptake, Enzymatic degradation, Diffusion
 Ligand-gated ion channels
• Ligand-gated ion channels (LGICs) mediate intercellular
communication by converting the binding of a neurotransmitter
that is released from the presynaptic terminal into an ion flux in
the postsynaptic membrane.
• They are integral membrane proteins that carry an orthosteric-
binding site for the neurotransmitter and an ion channel that
spans the membrane.
• Under resting conditions, the channel is closed, and binding of
the agonist triggers a conformational change that opens the
gate.
• Once the channel is opened, cations or anions diffuse through
the pore at rates approaching tens to hundreds of millions of
ions per second.
• In addition to their well-established role in neurotransmission, it
is now recognized that some LGICs are critical in nonexcitable
cells, such as endothelial cells, suggestive of a wider functional
role of these receptors outside the peripheral and central
nervous system.
• LGICs thus represent attractive targets for new therapeutic agents.
• LGICs have been shown to be involved in several diseases including
neurodegenerative disorders. Among those are Alzheimer’s Disease
and Parkinson’s Disease, as well as with epilepsy, hyperekplexia, and
neuropathic pain because they are characterized by major LGIC
dysfunctions.
 G protein coupled receptors
• Transmembrane receptor or heptahelical receptor, protein located in
the cell membrane that binds extracellular substances and transmits
signals from these substances to an intracellular molecule called a G
protein (guanine nucleotide-binding protein).
• GPCRs are found in the cell membranes of a wide range of organisms,
including mammals, plants, microorganisms, and invertebrates.
• There are numerous different types of GPCRs (some 1,000 types are
encoded by the human genome alone) and as a group they respond to
a diverse range of substances,
including light, hormones, amines, neurotransmitters, and lipids.
• Some examples of GPCRs include
– beta-adrenergic receptors, which bind epinephrine;
– prostaglandin E2 receptors, which bind inflammatory substances
called prostaglandins;
– and rhodopsin, which contains a photoreactive chemical called
retinal that responds to light signals received by rod cells in
the eye.
 G protein coupled receptors

Epinephrine binds to a type of G protein-coupled receptor known as a beta-adrenergic receptor.

When stimulated by epinephrine, this receptor activates a G protein that subsequently
activates production of a molecule called cAMP (cyclic adenosine monophosphate). This
results in the stimulation of cell-signaling pathways that act to increase heart rate, to dilate
blood vessels in skeletal muscle, and to break down glycogen to glucose in the liver.
 Drugs and Neural Transmission
• Most psychoactive drugs produce their effects by action at the
synapse. Drugs effects can be produced by altering the following
neurochemical systems:
• Neurotransmitter synthesis – A drug may increase or decrease the
synthesis or production of neurotransmitters.
• Neurotransmitter transport – A drug may interfere with the
transport of neurotransmitter molecules to the axon terminals. If
the substance is manufactured in the cell body it must still be
transported to the terminal before it is functional.
• Neurotransmitter storage - A drug may interfere with the storage of
neurotransmitters in the vesicles of the axon terminal. For example,
the drug reserpine, causes certain vesicles to become leaky and then
the transmitters involved are not effectively released into the
synapse
*Vesicles – Tiny sacs in axon terminals that store neurotransmitters.
 Drugs and Neural Transmission
• Neurotransmitter release - A drug may cause the axon terminals to
release neurotransmitter molecules into the synapse prematurely.
Stimulant drugs such as amphetamines are thought to act this way.
• Neurotransmitter degradation – A drug may influence the breakdown
of neurotransmitters by enzymes. It can alter neural transmission by
affecting enzyme activity. Some antidepressant drugs alter brain levels
of the neurotransmitters norepinephrine, dopamine, and serotonin by
inhibiting the activity of monoamine oxidase, the enzyme that breaks
down these compounds .
*Enzyme Breakdown – One process by which neurotransmitters are
inactivated. Chemicals called enzymes interact with the transmitter
molecule and change its structure so that it no longer is capable of
occupying receptor sites.
• Neurotransmitter reuptake - A drug may block the reuptake of
neurotransmitters into the axon terminals. Cocaine exerts some of its
action by blocking the reuptake process
*Reuptake – One process by which neurotransmitters are inactivated.
Neurotransmitter molecules are taken back up into the axon terminal that
released them.
 Drugs and Neural Transmission
• Receptor activation – A drug may activate a receptor site by
mimicking a neurotransmitter, similar to a duplicate key that fits into
and opens the locks. Morphine and heroin mimic natural
neurotransmitters called endorphins.
• Receptor blocking – A drug may cause a receptor to become inactive
by blocking it.
• Some drugs act as if they fit into the lock but then jam it and prevent it
from firing. Such a drug is called a blocking agent . Any chemical,
natural or otherwise, that fits a receptor lock and activates it is said to
be an agonist of that receptor. Any compound that occupies a receptor
and does not activate it, but prevents other compounds from activating
it, is said to be an antagonist .
• Agonist (Enhance) – A substance that occupies a neural receptor and
causes some change in the conductance of the neuron
• Antagonist (Inhibit) – A substance that occupies a neural receptor and
blocks normal synaptic transmission. Naloxone is an antagonist of the
receptors on which opiate drugs such as heroin work
 Roles of glutamatergic system in disease
• Glutamate – Among the most abundant of the excitatory amino
acid neurotransmitters. Some hallucinogenic drugs (Ketamine) act
on glutamate receptors in parts of the brain.
• Distinct subpopulations of the N-methyl-d-aspartate, NMDA
receptor (NMDAR) mediate neuronal death and survival.
• (a) Under normal conditions, synaptic activity maintains neuronal
survival via activation of the synaptic NMDAR. This pro-survival
effect is dependent on the calcium influx through the receptors.
• (b) During cerebral ischemia (one kind of stroke), excessive release
of glutamate into the synapses and extrasynaptic sites causes
global stimulation of NMDAR at both locations. The C-terminal
domain of the GluN2B subunit acts as a major hub for recruiting
death-signaling proteins, which in turn is activated by calcium influx
through the receptors to induce neuronal death.
• However, excessive NMDAR activity causes excitotoxicity and
promotes cell death, underlying a potential mechanism of
neurodegeneration occurred in Alzheimer's disease (AD).
 Glutamate antagonists
• Drugs acting on glutamate
receptors
– Piracetam, aniracetam
– used in dementia
• Potential therapeutic
targets of glutamate
antagonists
– Reduction in brain damage
following strokes and head
injury
Drawbacks
– Treatment of epilepsy
Hallucinations
– Alzheimer’s disease Currently using
– Schizophrenia Ketamine – (anaesthesia and analgesia)
Memantine (Alzheimer’s disease)
 GABA and its receptors
• Gamma Amino Butyric Acid (GABA) - major inhibitory neurotransmitter
of the mammalian brain.
• Mechanism of action: Activation of GABAA receptor (Endogenous –
GABA, Inositol; Exogenous - Drugs)  Opening of central pore  ↑
influx of Cl- ions through the pore  Hyperpolarization of the neuronal
membrane  ↓ occurrence of action potential  Inhibition of
neurotransmition (early part of IPSP)
• Drugs that act on the GABA system are the depressant drugs such as
barbiturates, tranquilizers such as Valium and Librium, and alcohol.
 GABA and anxiety
• GABA inhibits postsynaptic neurons from firing – stops them passing
on the neural impulse.
• It gets in the synapse to block transmission.
• One of it’s role is it helps fine tune brain activity, keeps neural
transmission maintained at an optimal or “best possible” level.
• Without GABA, activation of postsynaptic neurons might get out of
control and spread throughout the brain, causing seizures similar to
those of epilepsy.
• Lack of the neurotransmitter GABA might lead to over stimulation,
and thus heightened anxiety.
• Role of a group of drugs known as benzodiazepines in the
management of phobic anxiety provide evidence for the role of
GABA in anxiety.
• Benzodiazepines – a class of drugs that ‘calm down’ neural activity.
Valiam, Xanax, Rohypnol, Serepax etc. commonly referred to as
“minor tranquillisers”.
• Benzodiazepines reduce physiological arousal and promote
relaxation, but induce drowsiness and are highly addictive.
 Benzodiazepines are GABA agonists
• Inhibitory or agonist - a substance that
stops or slows a chemical reaction.
Benzodiazepines are GABA agonists. They
imitate GABA and stimulate activity at the
site of a postsynaptic neuron where GABA
is received from a presynaptic neuron. By
doing this, benzodiazepines have
inhibitory effects on postsynaptic
neurons and reduce symptoms of
anxiety by imitating GABA’s inhibitory
effects.
• Ethyl alcohol (type people drink) has
similar effects on GABA receptors which is
why alcohol is typically experienced as
relaxing.
• Agonist is the opposite to antagonist.
Antagonist reduce GABA function and
therefore produce anxiety symptoms.
 West’s syndrome
• West syndrome is a constellation of symptoms
characterized by epileptic/infantile spasms, abnormal
brain wave patterns called hypsarrhythmia and intellectual
disability. The spasms that occur may range from violent
jackknife or "salaam" movements where the whole body
bends in half, or they may be no more than a mild twitching
of the shoulder or eye changes. These spasms usually begin
in the early months after birth and can sometimes be
helped with medication.
• Infantile spasm is an epileptic syndrome consist of:
– Sudden forward flexion of head
– Bending of knees
– Flexion of arms (salaam seizures)
– Occasionally this spasm is an extension resembling of Moro
Response and occur in 3-9 months of age.
– These spasm last for few seconds but recur several times.
 West’s syndrome
• Symptomatic infantile spasm occurs in patient with:
– Brain damage from prenatal insult
– Birth asphyxia
– Brain malformation
– Postnatal insult
– Tuberous sclerosis.
• Prognosis is poor and there is a risk of 80-90% mental retardation.
• Cryptogenic: 10-20% of infantile spams are classified as cryptogenic as
children have normal development, normal physical examination and no
associated risk factors.
• Prognosis in infants with cryptogenic infants spasm is good.
• On EEG: EEG shows hypsarrhythmia, a chaotic pattern of high amplitude slow
waves and spikes.
• Treatment:
– Nitrazepam
– Clonazepam
– ACTH
– Prednisone.
 Monoamines
• A class of chemicals characterized by a single amine group; includes the
neurotransmitters: norepinephrine (noradrenaline), dopamine, and
serotonin.
– Norepinephrine – A neurotransmitter that is involved in activity of the of the
sympathetic branch of the autonomic nervous system. Outside the brain it
mediates physical changes that accompany emotional arousal; inside it is
important in the regulation of hunger, alertness, and arousal.
– Serotonin – A neurotransmitter found throughout the brain that is involved with
sleep, mood, depression and pain regulation.
– Dopamine – A neurotransmitter in the brain that is involved with coordinated
movement and reward.
• As the monoamine neurotransmitters are closely linked to mood states and
emotional disorders, drugs that influence them have revolutionized
modern psychiatry.
• It is proposed that clinical depression is associated with disregulation of
monoamines, particularly norepinephrine and serotonin.
• Theory originated with the finding that certain drugs that depleted
monoamines seemed to produce depression and drugs that are useful in
treating depression (e.g., Prozac) influence either norepinephrine or
serotonin transmission or both.
• Evidence of abnormal monoamine activity in clients who suffer from
depression has been reported.
 Dopamine
• Mesolimbic Dopaminergic Pathway – Pathway that is rewarding when
stimulated and thus referred to as the “pleasure center”.
• Many pleasurable events result in the release of dopamine in this pathway
– good tasting food (especially chocolate),
– and drugs such as cocaine, heroin, and nicotine
is oversimplification to say that dopamine release always translates into
pleasure since events such as electric shock also release dopamine.
• Synthesis, storage and release
– synthesized from tyrosine by tyrosine hydroxylase
– stored in presynaptic vesicles by active transport mechanism (blocked by
reserpine)
– Released by calcium ion-dependent exocytosis
• Termination of action
– reuptake (blocked by cocaine, amphetamine)
• Dopamine Involved in movement, attention, learning, motivation, reward
– Overactive Dopamine Schizopherina (Drug- Antipsychotics)
– Loss of Dopamine Parkinson Disease (Drug- Levodopa)
 Parkinson’s Disease
• Parkinson’s Disease – A disease that primarily
afflicts the elderly and involves a progressive
deterioration of motor control. Symptoms
include loss of fine motor movements, muscle
rigidity, and tremor.
• Pathologically, PD is characterized by a loss of
dopaminergic neurons from a part of mid brain.
• L-Dopa – A chemical precursor of dopamine used
in the treatment of Parkinson’s disease
• Blood-brain Barrier – The system that “filters”
the blood before it can enter the brain protecting
it from toxic chemicals. L-Dopa is able to
penetrate this barrier and is converted into
dopamine.
• Cardinal signs of PD are:
– rest tremor
– bradykinesia
– rigidity
– impairment of postural reflexes.
 Treatment of Parkinson’s disease
Levodopa
• Most effective agent for the treatment of the symptoms of PD .
• Metabolic precursor of dopamine.
• It is converted to dopamine by L-aromatic acid decarboxylase.
• Almost always administered in combination with carbidopa, an inhibitor of the
decarboxylase which does not cross the blood-brain barrier.
• Onset of action is rapid - 30 - 60 min, but affected by gastric pH and emptying.
• Duration of action is variable, and is greatly affected by extent of disease.
Declining duration of effect is the primary limitation of long-term levodopa
therapy.
• Available in both standard and controlled-release formulation.
• Adverse effects:
• peripheral:
– nausea and vomiting
– hypotension (reduced by carbidopa)
• central:
– psychosis
 Schizophrenia
• It involves a major loss of contact
with reality and is characterized by
false beliefs or delusions,
hallucinations, social withdrawal,
and distortions of emotionality.
• Strong evidence ties these
symptoms to high levels of
monoamine activity.
• Drugs that are effective in treating
schizophrenia block monoamine
transmission, specifically dopamine
receptors.
• Stimulant drugs such as cocaine and
amphetamines increase
monoamine activity in the brain and
in high doses often lead to paranoid
delusions and a loss of reality
contact that strongly resembles
some symptoms of schizophrenia.
 Acetylcholine
• Acetylcholine is the neurotransmitter used at the neuromuscular junction.
• Neuromuscular Junction – Junction or space similar to the synapse, between
neuron and muscle fibers where release of acetylcholine by neurons causes
muscles to contract.
• It is found both in the brain and in the parasympathetic branch of the
autonomic nervous system that is linked with memory processes.
• One of the first neurotransmitters to be discovered because it is found in the
neurons outside the brain.
• There are two main classes of acetylcholine receptor, nicotinic and muscarinic.
• 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
Note: If the name of a neurotransmitter is to be used as an adjective, take the stem
of the name (i.e., choline ) and add the suffix “ ergic ”. Thus neurons that
contain acetylcholine are cholinergic neurons and drugs that block
acetylcholine, such as atropine, are anticholinergic drugs. Nicotine is an
example of a cholinergic drug: it is an agonist at acetylcholine receptors in some
parts of the brain.
 Acetylcholine
• Myasthenia gravis, an autoimmune disease characterized by severe
muscle weakness and fatigue is caused by a blockage of acetylcholine
at the neuromuscular junction.
• Botulinum, one of the deadliest toxins known, which also blocks the
release of acetylcholine at the neuromuscular junction results in
muscle paralysis, and in sufficient doses, death by asphyxiation.
• Alzheimer’s disease may be related to loss of neural function in some
of the brain’s cholinergic pathways, and thus, drugs that reduce it’s
symptoms are thought to elevate acetylcholine in the brain
• Alzheimer's, is a chronic neurodegenerative disease that usually starts
slowly and worsens over time. It is the cause of 60% to 70% of cases
of dementia. The most common early symptom is difficulty in
remembering recent events (short-term memory loss). As the disease
advances, symptoms can include problems with language,
disorientation (including easily getting lost), mood swings, loss of
motivation, not managing self care, and behavioural issues.
 Drugs acting on the acetylcholine system
• Drugs acting on the
acetylcholine system are either
agonists to the receptors,
stimulating the system, or
antagonists, inhibiting it.
• Acetylcholine receptor agonists
and antagonists can either have
an effect directly on the
receptors or exert their effects
indirectly, e.g., by affecting the
enzyme acetylcholinesterase,
which degrades the receptor
ligand.
• Agonists increase the level of
receptor activation, antagonists
reduce it. Examples of drugs * Pilocarpine is a cholinergic drug, that is, a drug
agonists that mimics the effects of the chemical,
• Direct acting agonist: acting acetylcholine which is produced by nerve cells.
directly on cholinoceptors. E.g. *Pilocarpine eye drops have been used for many
Pilocarpine. years to treat glaucoma, a condition in which
pressure within the fluid of the eye is abnormally
elevated and ultimately damages the eye and
impares vision.
 Serotonin
• Serotonin or 5-Hydroxytryptamine (5-HT) is a monoamine
neurotransmitter, biochemically derived from tryptophan.
• Present in Intestine (90%) along with platelets and brain (10%)
– 90% in EC cells and 10% in neurones of different plexuses
• Stored in granules like catecholamine
• Also present in plants and insects
– Plants like tomato, banana & pineapple
– Lower animals - mollusks, arthropods, snake and bee venom/sting
• Biochemically, the indoleamine molecule derives from the amino
acid tryptophan, via the (rate-limiting) hydroxylation of the 5 position
on the ring (forming the intermediate 5-hydroxytryptophan), and
then decarboxylation to produce serotonin.
• In humans, serotonin is a neurotransmitter used throughout the body
having action of 14 variants of the serotonin receptor to have diverse
effects on mood, anxiety, sleep, appetite, temperature, eating
behaviour, sexual behaviour, movements, and gastrointestinal motility.
• High dose 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”)
damages 5-HT axons.
 Serotonin
Antagonists of serotonin
• Ergot derivatives: Ergotamine, ergonovine
and methysergide (Carcinoid) etc.
• Alpha-blockers: Phenoxybenzamine
• Antihistaminics: Cyproheptadine,
cinnarizine
• Phenothiazines: Chlorpromazine
• Ketanserin: used as antihypertensive
• Clozapine: for schizophrenia
• Metoclopramide, Ondansetron and
Granisetron are currently available as
anti-emetic for chemotherapeutic
induced nausea and vomiting (5-HT3
antagonists)

You Are Never Too Old to Make New Neurons:

*Research now shows that in the hippocampus and some areas of the cerebral cortex, neurogenesis
(new brain cell development) may occur throughout adulthood.
*A link between neurogenesis and depression is suspected since studies show that various types of
stress can suppress production of new neurons and stress is linked to depression.
*Elevated serotonin levels increase neurogenesis and antidepressant medication generally elevates
serotonin.
 Migraine
• Severe, throbbing, pulsating headache usually unilateral headache
(few hours to a few days in duration)
• Associated with nausea, vomiting, sensitivity to light and sound,
flashes of light, loose motion and others
Types:
• Classical with aura
• Without aura (common)
Pathophysiology:
• Pulsatile dilatation of temporal or certain cranial vessels
• Vascular theory: initial vasoconstriction or shunting of blood through
carotid arterio-venous anastomosis causing cerebral ischaemia
• Neurogenic theory: depression of cortical electrical activity followed
by depression
• Migraine attack associated with (based on histological studies):
– sterile neurogenic perivascular edema
– inflammation (clinically effective antimigraine medication reduce
perivascular inflammation)
 Migraine
• Pharmacotherapy of Migraine
Three types: Mild, Moderate and Severe
Mild: NSAIDS and Antiemetics (optional)
– Ibuprofen (400 mg 8 hrly)
– Paracetamol (500 mg 8 hrly)
– Naproxen (250 mg 8 hrly)
– Mefenamic acid (500 mg 8 Hrly)
– Diclofenac (50 mg 8 Hrly)
– Antiemetics: Metoclopramide (10 mg oral or IV), Domperidone (10 mg oral)

Moderate Migraine –
Intense throbbing headache
lasting for 6 – 24 Hrs, nausea
and vomiting
NSAIDs
Antiemetics
Specific drugs like ergots
and others (sumatriptan)
Severe Migraine
More than 2-3 attacks per
month lasting for 12 – 48
hrs, often vertigo and
vomiting and patient is
completely incapacitated
– NSAIDS cannot relieve
symptoms
– Specific antimigraine
drugs like ergot
alkaloids and triptans
– Also prophylactic
regimens
 Hallucinogen
• A hallucinogen is a psychoactive agent that often or ordinarily
causes hallucinations, perceptual anomalies, and other substantial
subjective changes in thought, emotion, and consciousness that are
not typically experienced to such degrees with other drug
classifications.
• The common classifications for hallucinogens
are psychedelics, dissociatives and deliriants.
• The classical hallucinogens are considered to be the representative
psychedelics and LSD is generally considered the prototypical
psychedelic.
• Tryptamine-Related Hallucinogens: LSD
– naturally-occurring plant alkaloids (ex ergot alkaloids, Claviceps
purpurea)
– chemically synthesized derivatives (LSD) lysergic acid diethylamide
– acts primarily through 5-HT receptor subtypes
 Opiate receptor
• Opioids:
– a type of pain medicine that is man made (oxycodone, Percocet).
– Mordern- Molecule that interact with opioid receptor
– Compound with morphine-like activity
• Opiates:
– a type of pain medicine that is naturally occurring (morphine, heroin).
– All Naturally Occurring Opioids Come From the Opium Poppy (Papaver
somniferum)
• Opioid compound:
– Opioid receptor agoninsts, antagonists, agonists-antagonists
– Natural products, synthetic and semisynthetic compounds
– peptides synthesized by neurone and other cell
Synthetic opioids:
Natural opium alkaloids: Semisynthetic opiates:
• Morphine Diacetylmorphine (Heroin) Pethidine (Meperidine)
Pholcodeine Fentanyl, Alfentanil,
• Codeine
Sufentanil, Remifentanil
Methadone
Dextropropoxyphene
Tramadol
 Opiate receptor
Pain
– is an ill-defined, unpleasant sensation, evoked by an external or internal
noxious stimulus.
– Analgesic relieves pain without significantly altering consciousness.
Medical Uses of Opioids
– Prescribed Indication: Important and essential medications for pain
relief
– Other Uses: anesthesia, cough suppression, and diarrhea
– Toxic Effects: lethargy, respiratory depression, overdose, death
Why Do Some Drugs Lead to Abuse/Dependence?
– Because of their effect on the brain
– Many drugs have no abuse potential
• Examples include aspirin, antibiotics and high blood pressure
medicine
– Others can lead to abuse and dependence including opioids and
sedatives (like benzodiazepines)
 What Happens in the Brain that can Lead to Addiction?
• Endorphins are a group of peptides that are produced by your
pituitary gland and central nervous system and that act on the
opiate receptors in your brain.
• Natural Pain and Stress Fighters.
• The human brain is stimulated by everything you do. When you do
something you enjoy (such as eating delicious food), your brain
releases chemicals called endorphins, also known as endogenous
opioids.
• They work similarly to a class of drugs called opioids.
 What Happens in the Brain that can Lead to Addiction?
• Endorphins attach to opioid receptors in the brain causing them to
release a chemical called dopamine.
• Dopamine gives you a good feeling to reward you for doing something,
which makes you want to repeat these behaviors.
• Opioids relieve pain and can produce a feeling of euphoria.
• Illicit opioids (such as heroin) and opioid pain medications attach to
some of the same receptors as endorphins, or endogenous opioids. (It
interrupts the release of endorphins and dependency grows).
• However, opioids cause the release of more dopamine than normal
enjoyable activities do, causing a “high.”
• When the high ends, the brain craves this feeling again.
• They are sometimes prescribed for short-term use after surgery or for
pain-relief.

ROBERT DOWNEY JR.

ALCOHOL, COCAINE, HEROIN,
BENZODIAZEPINES, MARIJUANA
Addiction
 Huntington's disease
• Huntington's disease is slowly progressive, rapidly growing hereditary brain disease
that causes abnormal motor coordination, thinking, behavior and ultimately leads
to dementia.
• No drug therapy is available s disease,
• Symptoms of Huntington’s Disease
– Chorea (dance like movement)
– Gait abnormality (disturbance in walking pattern)
– Impaired cognitive function (memory loss)
– Mood Swings (depression, anxiety)
– Disturbance in energy metabolism (weight loss)
Pathological mechanisms involved in Huntington's disease
• The loss of neurons in HD patients is widely linked with mitochondrial failure and
elevated oxidative stress dependent breakdown of macromolecules including DNA,
proteins and lipids.
• MITOCHONDRIAL DYSFUNCTION
– Mitochondria are normally present in all the cells and their chief function is to generate
energy like ATP through the process of oxidative phosphorylation.
– During the process of ATP production in ETC some of the electrons are leak from the
chain mainly during complex- I and III functioning, react with oxygen to form free
radicals.
– These free radical species like ROS formed after oxidative phosphorylation act like a
signaling molecules and cause lipid peroxidation, endorse excitotoxicity, and finally
leading to protein modification and eventual neuronal death.
 Huntington's disease
Treatment of HD
• Presently there is no successful or target therapy available which can be used to cure the HD
because of unknown pathophysiology.
• It is believed that 70 – 80 % of HD is of genetic predispotion.
• The present target for HD includes:
– To improve motor coordination
– To reduce psychiatric disturbances
– Speech therapy
– Physical therapy &
– Use of some antioxidants.
Drugs used for HD
• Use of neuropleptic drugs (Tetrabenazine) to reduce choreic movements.
• Anti-psychotic (Olanzapine or sulpiride, Haloperidol, chlorpromazine) to reduce psychiatric
disturbances.
• Benzodiazepines (clonazepam) to maintain muscle tonicity neuronal signalling centrally.
• Neurosteroid therapy
– Neurosteroids are released from the neurons in the brain & having neuroprotective role.
– PROTECTIVE MECHANISMS
• ANTIOXIDANT
• PREVENT GABA NEURONS DAMAGE
• ANTI GLUTAMATE (ANTI EXCITATORY)
• ANTI-INFLAMMATORY
 Imaging the Human Brain
• Electroencephalography (EEG ) -Technique used to measure electrical activity
in the brain. Brain waves change in predictable ways and abnormalities in EEG
patterns can reveal gross brain damage.
• Computerized Axial Tomography (CT or CAT scan ) -Technique that produces a
three-dimensional X-ray image of the brain. Focus can be changed to different
depths of the brain to detect internal tumors, enlarged spaces or ventricles,
and other internal abnormalities.
• Positron Emission Transaxial Tomography (PET) -Technique used to measure
activity/functioning in selected brain regions. The PET and the closely related
SPECT (single photon emission computed tomography) scan promise to greatly
increase our ability to detect subtle brain damage that drugs may induce.
• Magnetic Resonance Imaging (MRI) – Technique that creates a high-
resolution, three-dimensional image of the brain that may improve our ability
to detect and understand brain dysfunction. A modification of the MRI called
functional MRI (fMRI) permits very rapid imaging and enables us to measure
oxygen levels in blood vessels of the brain.
 CNS Drug: Case study
• 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.
• 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.
• 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.
• 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 effects from a particular treatment paradigm.
 Sample Questions
• Explain- ‘Astrocytes are necessary to create the blood–brain barrier’.
• Discuss the neurochemical interactions. Mention the name of some
neurotransmitters.
• How ligand gated ion channels represent attractive targets for new
therapeutic agents?
• What is GPCR? How G protein activates production cAMP?
• Explain- ‘Excessive NMDAR activity causes excitotoxicity and
promotes cell death (neurodegeneration).’
• Illustrate- ‘Benzodiazepines are GABA agonists’.
• How L-Dopa treat the parkinson’s disease ?
• Discuss the drugs acting on the acetylcholine system.
• How opioid affect our brain?
• What are pathological mechanisms involved in Huntington's
disease?
• Write a short note on the imaging the human brain.
 Sample MCQ
1. Precursor of serotonin is _______.
a. tyrosine b. tryptophan
c. alanine d. phenylalanine

2. Endorphins act on________.

a. GABAa receptor b. glutamate receptor
c. opiate receptor d. 5-HT 3 receptor