Modificazioni cerebrali associate all’utilizzo di droghe

Silvia Mandillo

ELLS LearningLAB“Conoscere il sistema nervoso”

EMBL Monterotondo22-24 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-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

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

Increased risk with early use:The brain is still developing during adolescence

‘Physical vs. psychological dependence?’

Brain > BehaviourDrug

Drug Body

PET images of diseased organs

Cerebral hemisphere lobes

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

Reward system

Natural rewards

FoodWaterSexNurturingMusicArt

…and Drugs!

VTAN.Acc

PfcxDopamineDopamine

Neurons, synapses and neurotransmitters

Drugs act at the synapse

Interfering with major neurotransmitter systems

DopamineDopamineOpioidsSerotoninAChGABAGlutamate

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, relaxationRelieves of anxiety, stress and fatigue, perception changes

Chronic repeated use

Tolerance and dependence

>>> ADDICTION

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.

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

Brain changes in addiction

Dopamine D2 receptors Serotonin neuron axons

Brain regions and functions affected by drugs

Most common drugs of abuse

Nicotine Alcohol Cannabis Opioids (Morphine, Heroin) Hallucinogens and club drugs (LSD, Ecstasy...) Psychostimulants (Amphetamines, Cocaine...)

Parte II

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 tobaccodecreases MAO levels (monoamine oxidase), enzyme for dopamine breakdown

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

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)

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

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

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

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

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

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

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..)

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/

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

Ecstasy acute effects at serotonin synapse

http://www.dancesafe.org/slideshow/index.html

Normal state

Serotonin overflow…. …and depletion

Long term effects

Reduced DAT binding

Neurotoxicity

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

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)

VTAN.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

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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

Effects of Methamphetamine

D2 receptors DAT binding

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

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!

smandillo@ibc.cnr.it