Neurotransmitters and

Neuropharmacology
We now focus here:
 Don

A retired accountant developed tremor and slowing of movements and

was diagnosed with Parkinson’s disease at age 67. His neurologist
prescribed levodopa to restore dopamine levels. A couple of years later,
motor symptoms start to fluctuate and the dopamine receptor agonist
ropinirole was added to his treatment.

A few months later, he developed a strong interest in gambling, first

buying lottery tickets and then visiting a casino almost every day. He
concealed his gambling activity until he has lost more than $100,000.

He came for a consultation 5 weeks ago, and ropinirole was replaced with
a monoamine oxidase inhibitor drug. He now reports his interest in
gambling has disappeared.
Two Receptor
Subtypes

ionotropic metabotropic
Two Types of Synapses

Ionotropic receptors open when bound by a

transmitter (called a ligand-gated ion
channel)
Direct

Metabotropic receptors recognize the

transmitter but instead activate G-
proteins
Indirect
Metabotropic receptors
in more detail
An agonist initiates normal
effects of the receptor
An antagonist prevents a
receptor from being
activated by other ligands
Ways Drugs Affect Synaptic Transmission
(AGO = agonist; ANT = antagonist; NT = neurotransmitter)
Amino acids make me gagg
 Glutamate

Most common excitatory neurotransmitter in brain and spinal cord

ionotropic receptors
 Glutamate – metabotropic receptors

Glutamate also acts on mGluRs – slower

metabotropic receptors

Excitotoxicity – neural injury such as stroke or

head trauma causes excess release of
glutamate, which kills neurons

Tre
Summary of glutamate’s actions
 GABA

Most common inhibitory

neurotransmitter in brain
GABAA - ionotropic, produces
fast inhibitory effects

GABA agonists, like Valium and

barbiturates, are potent
tranquilizers
Summary of GABA’s actions
 Glycine
The major inhibitory neurotransmitter in spinal cord

Strychnine blocks glycine:

Symptoms appear within 20 minutes, starting with stiffness of the neck, twitching
muscles, and feeling of suffocation, then violent convulsions in which the body is arched
and the head bent backward. After a minute muscles relax, but a touch or noise causes
convulsions to recur, or they recur spontaneously, every few min.
 Catecholamine Synthesis

Rate-limiting
Case

3 year old identical twins from London had

severely low muscle tone, mental retardation,
and seizures
Biochemical analysis of CSF revealed low activity
of tyrosine hydroxylase
Dopamine infusions temporarily improved their
symptoms

How did this help?

 Dopamine Pathways in the Brain

reward, reinforcement and motor

learning; schizophrenia control
 Norepinephrine Pathways in the Brain
mood, arousal,
sexual behavior
 Serotonin Pathways in the Brain
sleep, mood, sexual
behavior, and anxiety
 Gas
neurotransmitters

Nitric oxide (NO) is produced in

dendrites, and diffuses
immediately

Serves as a retrograde transmitter by

diffusing back into presynaptic neuron

Your result may vary

 Acetylcholine

Two types of ACh receptors: Nicotinic and Muscarinic

 Ach receptors
Nicotinic – most are Muscarinic – most are
• Ionotropic • Metabotropic
• Excitatory • Excitatory or inhibitory
• Peripheral • CNS
Muscles use nicotinic ACh Muscarinic ACh receptors blocked by
receptors – paralysis with an scopolamine alter cognition
antagonist such as curare
Cholinergic Pathways in the Brain
Classes of Neurotransmitters
 Endogenous Opiates

Peptides that bind to opioid receptors and relieve pain (analgesics)

Addictive
Enkephalins
Endorphins endogenous opiates
Dynorphins

Endorphins are produced by the pituitary and hypothalamus during

exercise, excitement, pain, eating spicy food, love and orgasm
Endogenous opiates produce analgesia and a feeling of well-being
 Neuromodulators indirectly affect transmitter release or
receptor response

Adenosine is normally released with

catecholamines
Caffeine blocks the effect of
adenosine, a neuromodulator that During wakefulness
normally inhibits catecholamine adenosine builds up,
release via presynaptic making us sleepy
autoreceptors
Caffeine thus stimulates
catecholamine release, causing
arousal

400 million cups of coffee are consumed every day in America. Mayo Clinic Proceed Aug.
2013: A study of 40,000 individuals found a greater than 50% increased mortality risk in
young men and women who drank more than 4 cups a day
Sites of drug action
 Antipsychotic (neuroleptic) drugs
Class of drugs to treat schizophrenia and aggressive behavior
Typical neuroleptics are dopamine (D2) antagonists
 Antidepressants
Monoamine oxidase inhibitors (MAOIs) prevent breakdown of monoamines at
the synapse
Accumulation of monoamines is the major action of antidepressants
 Antidepressants – Two main modern classes

Tricyclics (older) increase norepinephrine and serotonin at synapses by

blocking their reuptake into presynaptic axon terminals

Selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft cause

serotonin to accumulate in synapses, with fewer side effects than the
tricyclics
 Anxiolytics

Anxiolytics, or tranquilizers, reduce nervous

system activity

Benzodiazepine agonists act on GABAA

receptors and enhance inhibitory effects
of GABA via Cl- influx
• Allopregnanolone is one endogenous
benzodiazepine
Barbiturates are depressing

• Block sodium channels on neurons to prevent inflow of

sodium ions
• Barbiturates also increase flow of chloride ions across
the neuronal membrane

GABAA complex

Main medical use now is for

anesthesia and epilepsy
 Alcohol has complex effects on behavior
In low doses it is a stimulant, turning off cortical inhibition, reducing social
constraints and anxiety

At higher doses alcohol has sedative effect

Alcohol markedly reduces brain metabolism

 Alcohol’s effects are biphasic

Initial stimulant phase followed by a depressant phase

 Alcohol affects several neurotransmitter systems

• Inhibits glutamate (excitatory transmitter)

• Acts at GABAA receptor to increase binding of GABA
• Combined effect at glutamate and GABA receptors is sedation, anxiety
reduction, muscle relaxation, inhibited cognitive and motor skills
• Pleasurable effects from stimulation of dopamine, opiate, serotonin, and
cannabinoid receptors

Seizures during alcohol withdrawal are due in part to compensatory increase

in the number of glutamate receptors over time
• OJ is a 45 yo man who presents to the ED after a seizure during his first day at a
local alcohol/drug rehab center. He was ordered by the court to attend this
center after his second drunk driving violation in one year. The seizure lasted
approximately 1 minute, and resolved spontaneously.
• It has been about 60 hours since his last drink
Healthy man vs. an alcoholic man
Effects of Chronic Alcohol on Adult Brain
Alcohol damages neurons in cerebellum and frontal lobe

Neurons can recover!

Fetal alcohol syndrome

Small head
Opiates
 Opium and Morphine
Opium contains morphine, a potent analgesic

Binds to opioid receptors in the brainstem, especially locus coeruleus and the
periaqueductal gray
 What is the origin of heroin?
Heroin is named for ‘heroic’

Bayer sought a new Aspirin and Codeine replacement

Bayer marketed the drug as a cure for codeine addiction before it was
quickly discovered that it rapidly metabolizes into morphine

Oops.
 Case

53 y/o man is found down in the driveway of a house. EMS arrives and on exam
he is comatose and his pupils are tiny (2mm) and barely react to light. An IV is
inserted and he is given naloxone.
Within a minute he arouses and opens his eyes.

Diagnosis?
• Oxycontin overdose
 Marijuana – active ligand is THC (tetrahydrocannabinoid)
Brain has cannabinoid receptors that bind anandamide and 2-AG (2 arachidonoyl
glycerol) (endocannabinoids) with many effects:

Endocannabinoids are retrograde

signaling molecules released to
activate cannabinoid receptors on
nearby neurons

Lipophilic molecules, so can’t store

in vesicles, thus exist as part of the
membrane

Synthesized 'on-demand‘

5000 BC - Indian medical practice used marijuana to

treat appetite loss
 Marijuana

CB receptors are concentrated in

brain areas that influence:
pleasure, memory, concentration,
time perception, appetite, pain,
coordination
CB

• Impairs short-term memory - making it hard to learn complex tasks

• Slows reaction time - impairing driving skills
• Altered judgment and decision making
• Altered mood - euphoria, calmness; in high doses, anxiety, paranoia
 Nicotine
Primary psychoactive and addictive drug in tobacco

In the periphery, it activates muscles

and causes twitching Nicotine from tobacco: activates nicotinic ACh
receptors in the ventral tegmental area (DA)
Centrally, it increases alertness and
decreases reaction time
 Nicotine

Smoking health risk is mostly due to other compounds in tobacco, not nicotine
But nicotine is the addictive component

Smoking is the primary cause of preventable death in the world

• Kills 493,000 people a year in the US and 4 million worldwide
• (heroin kills 400 people a year in US)

• Withdrawal symptoms are mild, (but there is a 7% increase in workplace

accidents on Britain’s “No Smoking Day”)

• Only 5% of each attempt to stop are successful; about the same statistic for
heroin
 Cocaine
Leaves from coca shrub alleviate hunger, enhance endurance and sense
of well-being. Not addictive.

Cocaine, the purified extract:

• Crack cocaine enters the brain more rapidly, thus highly addictive
 Cocaine

Cocaine blocks monoamine transporters, especially dopamine – blocks

reuptake of catecholamines, enhancing their effects
Cocaine-amphetamine-regulated transcript (CART) - peptide involved in pleasure
sensations from these drugs and in appetite suppression
A Normal Brain and a Brain on Cocaine
 Amphetamine

Amphetamine and
methamphetamine are synthetic
stimulants
They block reuptake and increase
release of catecholamines

Short-term effects include

alertness, euphoria and stamina

Long-term abuse leads to

sleeplessness, weight loss,
schizophrenic symptoms
Stimulants for ADHD

Adderall - dextroamphetamine
Ritalin – methylphenidate
Strattera - atomoxetine

Brain imaging studies show that stimulant medication increases activity in prefrontal
cortex, some subcortical regions, and cerebellum - all centers for executive function.

Cortico-thalamic networks control inhibitory attentional and impulse control systems and
process internal and external stimuli. ADHD medications stimulate these inhibitory
networks to function better.

Hyperactive behavior (leg tapping, fidgeting) stimulates those brain networks to work
better. When the medication stimulates these networks, the hyperactive behavior
becomes unnecessary and is reduced.
 LSD resembles serotonin
Serotonin agonist on receptors in
visual cortex
The effects of LSD are unpredictable. They depend
on amount taken, the user’s personality, mood and
expectations, and surroundings in which the drug is
used. Effects include dilated pupils, higher body
temperature, increased heart rate and blood
pressure, sweating, loss of appetite, sleeplessness,
dry mouth, and tremors.
The user may feel several different emotions at once
or swing rapidly from one emotion to another. The
drug produces delusions and visual illusions. The
sense of time and self changes. Sensations seem to
“cross over,” giving the user the feeling of hearing
colors and seeing sounds.
 Phencyclidine (PCP)
(angel dust)
Glutamate NMDA receptor antagonist

PCP produces feeling of depersonalization and detachment from reality

Its many side effects include combativeness and catatonia
 Ecstasy (MDMA)

Amphetamine analog:
Its primary effects in brain are on
neurons that use serotonin

MDMA blocks the serotonin reuptake transporter (which removes serotonin

from the synapse); thus
• MDMA prolongs the serotonin signal and causes excessive release of serotonin
• MDMA causes oxytocin release
 What's trending?
Khat is a flowering shrub abused for its stimulant-like effect. Khat has two
active ingredients, cathine and cathinones

• Effects are similar to other stimulants, such as cocaine and amphetamine

Khat is native to East Africa/Arabian Peninsula, where its use

is an established cultural tradition for many social situations
 What's trending?
“Bath salts” describes a family of manmade chemicals related to cathinone

Usage is stable at about 1% of

high school juniors and seniors

As governments outlaw each current “bath salt” chemical, chemists

synthesize new ones
 What's trending?
Gamma-hydroxybutyric acid (GHB) is the generic drug oxybate. Xyrem is the
trade name of the FDA-approved prescription medication

• Analogues are available legally as industrial solvents used to produce

polyurethane, pesticides, pharmaceuticals, coatings on metal/plastic
• At bars or rave parties, GHB is sold in liquid by the capful for $5 to $25

• GHB and its analogues increase libido, suggestibility, passivity, and cause
amnesia - users are vulnerable to sexual assault
 What's not trending?

Rohypnol is a trade name for flunitrazepam - not made in US

• The tablet can be swallowed whole, crushed and snorted, or dissolved in

liquid. Adolescents abuse Rohypnol to produce euphoria
• Cocaine addicts use Rohypnol to relieve side effects (irritability and
agitation) from cocaine binges
• Rohypnol is used to physically and psychologically incapacitate women for
sexual assault
Drugs, addiction, and reward

Addiction is a chronic, often relapsing brain disorder that causes

compulsive drug use, despite harmful consequences to the addicted
individual and to those they are near

Although the initial decision to take drugs is voluntary, brain changes that
occur over time challenge a person’s self-control and ability to resist
intense impulses urging them to take drugs
NIDA InfoFacts: Understanding Drug Abuse and Addiction
 Addiction
Tolerance – decreased sensitivity to a drug as a result of taking it
Sensitization - increased sensitivity to a drug as a result taking it

Physical Dependence – caused by withdrawal symptoms (not the reason people

continue to take most drugs)
Psychological Dependence – Compulsive and repetitive use, craving
 Addiction
Addiction is:
• preoccupation with obtaining a drug
• compulsive use of the drug in spite of adverse consequences
• a high chance of relapse after quitting

Withdrawal is a negative reaction when drug use is stopped

 The basis for addiction is reward
Reward is the positive effect any agent (drug, food, sex, lottery win, IMGUR
upvote) has on the user
Mesolimbocortical dopamine system is the major reward system

• Abused drugs increase dopamine in the VTA

• This dopamine system underlies reward effects of drugs, food, sex, gambling, etc.
A Neural Pathway in Addiction

Patient B-19, a 24-year-old man who suffered from

depression and obsessive-compulsive tendencies, was
wheeled into the operating room, where electrodes
were implanted at 9 sites in deep regions of his brain,
and 3 months were allowed to pass.

The electrode implanted near the MFB produced

pleasurable sensations. When B-19 was given free
access to the stimulator, he quickly began mashing
the button ‘like an 8-year-old playing Donkey Kong. ‘

"During these sessions, B-19 stimulated himself to a

point that, behaviorally and introspectively, he was
experiencing an almost overwhelming euphoria and
elation and had to be disconnected despite his
vigorous protests."
 Addiction and withdrawal are independent
Rats will self-inject morphine into the Rats will not work to inject morphine
VTA, indicating the area is involved in into periventricular gray, so it is not
addiction involved in addiction
• But blocking opiate receptors there • But once rats are addicted, blocking
does not produce withdrawal opiate receptors in periventricular
gray produces withdrawal
 Why does drug rehab usually fail?
Craving

Cocaine addicts:

• delta FosB slowly builds up in

neurons with each drug exposure but
remains activated for years after the
last exposure

• delta FosB causes structural changes

in nucleus accumbens, which
perpetuates craving, and perhaps the
high relapse rate in treated addicts

nucleus accumbens
 Addiction: Pharmacologic treatment strategies
1) Agonistic treatments mimic the drug’s effects, but are milder
• Methadone or buprenorphine for opiate addiction
• Nicotine patch
• Chantix stimulates nicotine receptors more weakly than nicotine does
(partial agonist)
These replace the drug, which helps with motivation

Controversy: is it wrong to give an addict another addictive drug as treatment?

"I count him braver who overcomes his desires than him who overcomes his enemies" -
Aristotle
 Addiction: Pharmacologic treatment strategies
2) Antagonistic treatments block drug effects
• Opiate addiction - naltrexone; Alcohol addiction - baclofen interferes
with the dopamine pathway to block craving
• Antagonistic treatments don’t replace the drug, so compliance
depends on addict’s motivation to quit

3) Aversive treatments cause unpleasant reactions when drug is used

• Antabuse for alcohol addiction
 The future?
Anti-drug vaccines
Anti-drug vaccines stimulate immune system to make antibodies that degrade
the drug (nicotine)