Modificazioni cerebrali associate
all’utilizzo di droghe
Silvia Mandillo
ELLS LearningLAB
“Conoscere il sistema nervoso”
EMBL Monterotondo
22-24 Ottobre 2008
Parte I
 Definizioni
 Concetti generali
 Basi biologiche
Parte II
 Nicotina
 Alcohol
 Cannabis
 Opioidi (Morfina, Eroina)
 Allucinogeni e club drugs (LSD, Ecstasy...)
 Psicostimolanti (Anfetamine, Cocaina...)
What is drug addiction?
Drug addiction is a chronic, relapsing BRAIN disease
that is characterized by COMPULSIVE drug seeking
and use, despite harmful consequences
Use>Abuse>Addiction
Why do people take drugs:
-to feel good
-to feel better
-to do better
Why do people CONTINUE to take drugs:
-curiosity
-not to feel sick
-imitation
-to feel ‘normal’
-love of risk
-loss of control
-habit
Why do people become ADDICTED:
-physical changes in the brain
-loss of judgment
-compulsive behavior
Risk factors
Does everybody become addicted to drugs?
VULNERABILTY
Biology/Genes
Genetics
Gender
Mental disorder
Age
Environment
Stress
Repeated DRUG USE
Early use
Availability
Cost
Method of administration
BRAIN changes
Addiction
Home and family
School/Work
Peer influence
Increased risk with early use:
The brain is still developing during adolescence
‘Physical vs. psychological dependence?’
Drug
Drug
Body
Brain > Behaviour
PET images of diseased organs
Cerebral hemisphere lobes
Brain regions, cortical areas and the
limbic system
Parietal lobe
Sensory information
Frontal lobe
Decision-making
Problem solving
Planning
Occipital lobe
Vision
Temporal lobe
Memory
Emotion
Hearing
Language
Hippocampus
Amygdala
Motor coordination
Limbic system
Heart rate
Breathing
Sleeping
Reward circuit
Reward system
Pfcx
N.Acc
Dopamine
VTA
Natural rewards
Food
Water
Sex
Nurturing
Music
Art
…and Drugs!
Neurons, synapses and neurotransmitters
Drugs act at the synapse
Dopamine
Opioids
Serotonin
ACh
GABA
Glutamate
Interfering with major neurotransmitter systems
Drugs disrupt the reward circuit
Methods of administration
How much and for how long a drug acts in the brain depends on
the dose and on the method of administration
The way a drug is administered determines the amount and
permanence in the brain and therefore its effect on behavior
Effects on behavior
Acute
single use
Hyperactivity, alertness, intense pleasure, relaxation
Relieves of anxiety, stress and fatigue, perception changes
Chronic
repeated use
Tolerance and dependence
>>> ADDICTION
Tolerance and dependence
…are the main components of addiction.
Tolerance
decrease of a behavioral response after repeated administration of the
same dose of a drug.
The development of tolerance to the rewarding effect of a drug (e.g.
morphine) leads to administration of the drug at increasing doses in
order to experience the initial effect.
Dependence
is the altered physiological state induced by long-term drug exposure
that leads to a withdrawal syndrome on cessation of drug
administration.
Neural mechanisms of addiction
Long term administration of a drug elicits changes in the neurons of the
central nervous system (CNS) that alter the functioning of neural
circuits.
1. Receptor and transporters level:
Increased or decreased number of binding sites
2. Structural level:
Rearranging of synapses and connections
Neuroplasticity
Learning
Brain changes in addiction
Dopamine D2 receptors
Serotonin neuron axons
Brain regions and functions affected by drugs
Parte II
Most common drugs of abuse
 Nicotine
 Alcohol
 Cannabis
 Opioids (Morphine, Heroin)
 Hallucinogens and club drugs (LSD, Ecstasy...)
 Psychostimulants (Amphetamines, Cocaine...)
Nicotine
Nicotine is a natural alkaloid found in tobacco leaves.
Nicotiana tabacum named after Jean Nicot (1530-1600) who
introduced tobacco to Europe.
Nicotine was first isolated in 1828.
Reinforcing component of tobacco.
When smoked, nicotine reaches the brain in about 10 seconds.
It mimics the action of the neurotransmitter acetylcholine activating
cholinergic nicotinic receptors.
Nicotinic receptor are present in muscles, adrenal glands, heart and
brain
Actions in the brain
Nicotine increases dopamine
and endorphins levels in the
reward pathways.
Another component of
tobacco
decreases MAO levels
(monoamine oxidase),
enzyme for dopamine
breakdown
Nicotine’s effects
Changes in respiration, blood pressure and
vasoconstriction.
Facilitation of task performance, improvement of
memory, reward, reduction of anxiety, appetite
suppression, analgesia
Tolerance and dependence.
Withdrawal syndrome is a major cause of relapse among
people attempting to quit smoking, it produces:
craving, irritability, anxiety, anger, difficulty concentrating,
hunger, and fatigue
Nicotine is highly addictive
Smoking
Tobacco use is the leading preventable cause of death in US
Cancer, respiratory and cardiovascular diseases (stroke, heart attack..)
Women are less successful to quit smoking
Smoking helps to control body weight (appetite suppressant)
Adolescents are more sensitive to reinforcing effects of nicotine
More vulnerable to tobacco addiction
High incidence of smoking in mental illness (e.g. schizophrenia)
Alcohol
Ethyl alcohol (Ethanol) derived in nature
from fermentation of glucose and water
Legal drug widely used as beverages for
social and medical benefits
Sedative, hypnotic, euphoric, ‘social
lubricant’, anxiolytic
Disinhibitory effects, stimulant
At high doses it impairs:
Motor coordination, reaction time,
cognition, sensory processing, judgment
Chronic use:
Addiction (alcoholism), cirrhosis of the
liver, heart disease, pancreatitis
Action in the brain
Frontal lobes, limbic system,
cerebellum, reticular formation
Initial action of ethanol at GABA
and glutamate receptors
It acts on the reward system
increasing dopamine levels
It also disrupt opioid peptides and
serotonin systems
It dysregulates brain stress system
(CRF, NPY)
It interacts into the cell with
second-messenger and CREB
systems
Brain activity during memory task
Cannabis
Natural product of Cannabis sativa L.
It is smoked as herbal (marijuana), resin (hashish)
Psychoactive constituent is tetrahydrocannabinol (Δ9-THC)
THC content and potency is variable
It binds to cannabinoid receptors (anandamide, endogenous ligand)
Analgesic and treatment of nausea from chemotherapy
Fibre production (hemp)
Cannabis
Effects
euphoria, relief of anxiety, sedation and
drowsiness, changes in perception, mood
swings
Most commonly used illicit drug in US
It is usually smoked, often mixed with tobacco or in a smoking device
When smoked can be detected in plasma within seconds
Plasma half-life: about 2 hours
Metabolites can be detected in the urine for up to 2 weeks
Typical dose of average ‘joint’ cigarette 200mg.
Street names: pot, dope, weed, grass, hemp, Mary Jane…
2004 EU price: 5-10 eu per gram
Opioids
(Morphine, Heroin)
Morphine
a natural product of opium: the dried latex of certain poppy species
(e.g. Papaver somniferum L.).
Named after Morpheus the God of Dreams
Heroin
A semi-synthetic product of morphine. Diacetylmorphine is the
psychoactive constituent of heroin
Act as agonists at OPIOID receptors (the μ, κ and δ subtypes) that
normally respond to endogenous peptides known as endorphins.
Limbic system, brain stem, spinal cord.
Narcotic analgesic
Treatment of pain, diarrhea, cough
Heroin
Effects:
Euphoria and a sense of detachment. Subjective effects following
injection are known as ‘the rush’ and are associated with feelings of
warmth and pleasure, followed by well-being and a longer period of
sedation.
Respiratory depression, nausea and vomiting, decreased motility in the
gastrointestinal tract, suppression of the cough reflex and hypothermia.
Withdrawal symptoms:
Yawning, lacrimation, rhinorrea, perspiration, gooseflesh, tremors,
dilated pupils, anorexia, nausea, vomiting, diarrhea, restlessness,
insomnia, weight loss, dehydration, hyperglycemia, high blood pressure
and pulse rate.
Dysphoric state, depression, anxiety, craving
Heroin
Methods of administration
‘Smoked’ by heating the solid on a metal foil above a small flame and
inhaling the vapour.
Injected after solubilisation with citric acid.
When injected it crosses BBB in 20 sec. 1-5 min when smoked.
Plasma half-life: about 3 min
Typical Dose 100mg.
Street names: horse, smack, shit, brown
Accidental overdoses
Infectious diseases (hepatitis, HIV..)
Heroin
South-East Asia (China) more common in the ‘70s
White powder, water soluble
Injected
2004 price range: 31-202 eu per gram
South-West Asia (Afghanistan, Pakistan)
Brown powder, insoluble
‘Smoked’
2004 price range: 12-141 eu per gram
http://www.emcdda.europa.eu/
Hallucinogens and club drugs
LSD, PCP, Ecstasy
LSD: hallucinations (‘trips’), reality distortion,
blend of five senses, perception alteration, fear,
euphoria, psychosis, ‘flashbacks’
acid
Phencyclidine (PCP): hallucinations
angel dust
Ecstasy (MDMA): euphoria, increased sensory
awareness, socialization
Adam, XTC
2004 price: 2-16 eu per tablet
Serotonin system (5HT2 receptor, SERT)
Glutamate receptor (NMDA receptor)
Dopamine system (DAT)
Neurotoxicity
Ecstasy acute effects at serotonin synapse
Normal state
Serotonin overflow….
…and depletion
http://www.dancesafe.org/slideshow/index.html
Long term effects
Reduced DAT binding
Neurotoxicity
Psychostimulants
Amphetamine: Synthetic, ingested,
Methamphetamine: Synthetic, ingested, smoked. More potent
Cocaine: Natural, snorted or smoked
Psychomotor stimulant, euphoria, tachycardia, hypertension and
appetite suppression, increased confidence, sociability and
energy
Cocaine and methamphetamine are strong reinforcers and highly
addictive (tolerance and dependence)
Following oral use, the effects of usually start within 30 minutes and
last for many hours. Later, users may feel irritable, restless, anxious,
depressed and lethargic.
Upon chronic use: deficits in memory and in decision-making and
verbal reasoning. Some of the symptoms resemble those of paranoid
schizophrenia.
Cocaine
Cocaine is a natural product extracted from the
leaves of Erythroxylon coca Lam (South America)
Snorted. Free base form is smoked (Crack)
Typical dose: 100-200mg
Street names: coke, snow, charlie, C
2004 price: 41-100 eu per gram
Medical use as local anesthetic
Psychostimulants increase dopamine levels by blocking
the dopamine transporter or facilitating dopamine release
in the reward pathway (VTA-N.Acc)
VTA
N.Acc
Long term effects
• Irritability and mood disturbances, restlessness, paranoia,
auditory hallucinations
• In animals minimal exposure to cocaine can alter the dopamine
responsiveness for at least a week
•After chronic cocaine abuse, dopamine activate the reward system
even if the abuser encounters a cue associated with the drug
• Craving and relapse
Lifetime prevalence
% of Population having tried COCAINE at least once
Treatment of addiction
Medications
nicotine, bupropion, methadone, naltrexone, acamprosate, disulfiram
Behavioral intervention
enhance the saliency value of natural reinforcers (social support)
strengthen inhibitory control and executive functions
decrease conditioned responses
improve mood if disrupted
Prevention
act on the environmental factors (reduce stress, limit exposure)
more information
prohibition
Effects of Methamphetamine
D2 receptors
DAT binding
Websites on drug addiction
United States
http://www.drugabuse.gov/
Website of the National Institute on Drug Abuse (NIDA) part
of the NIH - National Institutes of Health
The most complete.
A lot of downloadable educational material.
For example:
http://www.nida.nih.gov/MOM/MOMIndex.html
http://www.nida.nih.gov/pubs/Teaching/
Europe
http://www.emcdda.europa.eu/
Site of the European Monitoring Centre for Drugs and Drug
Addiction (EMCDDA). In multiple languages.
EMCDDA was founded in 1993, it is based in Lisbon and it is
the hub of drug-related information in the European Union.
Very good drug profiles
http://www.emcdda.europa.eu/index.cfm?nnodeid=25328
Grazie!
[email protected]
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Brain changes and drug addiction