modificazioni cerebrali associate all’utilizzo di droghe
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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) - PowerPoint PPT PresentationTRANSCRIPT
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Modificazioni cerebrali associate all’utilizzo di droghe
Silvia Mandillo
ELLS LearningLAB“Conoscere il sistema nervoso”
EMBL Monterotondo22-24 Ottobre 2008
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Parte I Definizioni Concetti generali Basi biologiche
Parte II Nicotina Alcohol Cannabis Opioidi (Morfina, Eroina) Allucinogeni e club drugs (LSD, Ecstasy...) Psicostimolanti (Anfetamine, Cocaina...)
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What is drug addiction?
Drug addiction is a chronic, relapsing BRAIN disease
that is characterized by COMPULSIVE drug seeking
and use, despite harmful consequences
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Use>Abuse>Addiction
Why do people take drugs:-to feel good-to feel better-to do better-curiosity-imitation-love of risk
Why do people CONTINUE to take drugs:-not to feel sick-to feel ‘normal’-loss of control-habit
Why do people become ADDICTED:-physical changes in the brain-loss of judgment-compulsive behavior
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Risk factorsDoes everybody become addicted to drugs?
VULNERABILTY
Biology/Genes Environment
Repeated DRUG USE
BRAIN changes
Addiction
Stress
Home and familySchool/WorkPeer influence
GeneticsGenderMental disorderAge
Early useAvailabilityCost
Method of administration
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Increased risk with early use:The brain is still developing during adolescence
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‘Physical vs. psychological dependence?’
Brain > BehaviourDrug
Drug Body
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PET images of diseased organs
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Cerebral hemisphere lobes
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Brain regions, cortical areas and the limbic system
Occipital lobe
Parietal lobeFrontal lobe
Temporal lobeMemoryEmotionHearingLanguage
Decision-makingProblem solvingPlanning
Sensory information
Vision
Motor coordination
Heart rate BreathingSleeping
Reward circuit
HippocampusAmygdala
Limbic system
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Reward system
Natural rewards
FoodWaterSexNurturingMusicArt
…and Drugs!
VTAN.Acc
PfcxDopamineDopamine
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Neurons, synapses and neurotransmitters
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Drugs act at the synapse
Interfering with major neurotransmitter systems
DopamineDopamineOpioidsSerotoninAChGABAGlutamate
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Drugs disrupt the reward circuit
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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
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Effects on behavior
Acute single use
Hyperactivity, alertness, intense pleasure, relaxationRelieves of anxiety, stress and fatigue, perception changes
Chronic repeated use
Tolerance and dependence
>>> ADDICTION
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Tolerance and dependence
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.
…are the main components of addiction.
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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 connectionsNeuroplasticityLearning
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Brain changes in addiction
Dopamine D2 receptors Serotonin neuron axons
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Brain regions and functions affected by drugs
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Most common drugs of abuse
Nicotine Alcohol Cannabis Opioids (Morphine, Heroin) Hallucinogens and club drugs (LSD, Ecstasy...) Psychostimulants (Amphetamines, Cocaine...)
Parte II
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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
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Actions in the brain
Nicotine increases dopamine and endorphins levels in the reward pathways.
Another component of tobaccodecreases MAO levels (monoamine oxidase), enzyme for dopamine breakdown
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Nicotine’s effectsChanges 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
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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 smokingSmoking 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)
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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’, anxiolyticDisinhibitory 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
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Action in the brainFrontal 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
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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)
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Cannabis
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 secondsPlasma half-life: about 2 hoursMetabolites 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
Effectseuphoria, relief of anxiety, sedation and drowsiness, changes in perception, mood swings
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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 DreamsHeroinA 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 analgesicTreatment of pain, diarrhea, cough
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HeroinEffects: 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
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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 minTypical Dose 100mg.
Street names: horse, smack, shit, brown
Accidental overdosesInfectious diseases (hepatitis, HIV..)
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Heroin
South-East Asia (China) more common in the ‘70s
White powder, water solubleInjected2004 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/
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Hallucinogens and club drugsLSD, PCP, Ecstasy
Serotonin system (5HT2 receptor, SERT)Glutamate receptor (NMDA receptor)Dopamine system (DAT)
Neurotoxicity
LSD: hallucinations (‘trips’), reality distortion, blend of five senses, perception alteration, fear, euphoria, psychosis, ‘flashbacks’acidPhencyclidine (PCP): hallucinationsangel dust Ecstasy (MDMA): euphoria, increased sensory awareness, socializationAdam, XTC2004 price: 2-16 eu per tablet
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Ecstasy acute effects at serotonin synapse
http://www.dancesafe.org/slideshow/index.html
Normal state
Serotonin overflow…. …and depletion
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Long term effects
Reduced DAT binding
Neurotoxicity
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Psychostimulants
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.
Amphetamine: Synthetic, ingested, Methamphetamine: Synthetic, ingested, smoked. More potentCocaine: Natural, snorted or smoked
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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)
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VTAN.Acc
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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
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% of Population having tried COCAINE at least onceL
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Treatment of addictionMedications
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
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Effects of Methamphetamine
D2 receptors DAT binding
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Websites on drug addiction
http://www.drugabuse.gov/Website of the National Institute on Drug Abuse (NIDA) part of the NIH - National Institutes of HealthThe 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/
United States
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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