Overview of Drug Abuse Basic Considerations. M. Imad Damaj, Ph.D. Associate Professor Dept. of Pharmacology/Toxicology, Virginia Commonwealth University America is a drugged society 90% of all drugs manufactured in the world are consumed by 10% of the American population. Today there are an estimated 30 million chronic drug users in America Most chronic abusers (addicts) started by using marijuana, alcohol, and tobacco in their youth icotine & Tobacco Impact of Drug Abuse on Society Up until the 1960 s, it was definitely cool to smoke! 1 Million /Year! 1
Impact of Drug Abuse on Society $246 Billion dollars/year! Why People Use Drugs 1 st take drugs out of curiosity Peer pressure eed to belong and be accepted Makes one "feel good Thrill seeking behavior Experience new things Amphetamine d-amphetamine: Euphoria (ARCI MBG) Mean (sem) 7 6 5 4 3 2 1 0 1 2 3 Placebo 10 mg d-amphetamine Hour 20 mg d-amphetamine Brauer and de Wit, 1997 Mean (sem) Mean (sem) 75 60 45 30 15 "Feel Drug" (VAS) 0 pre 0.5 1.0 1.5 3.0 "Euphoria" (MBG) 6 5 4 3 2 1 pre 0.5 1.0 1.5 3.0 Hours Ethanol Ethanol "Like Drug" (VAS) 25 20 15 10 5 0-5 pre 0.5 1.0 1.5 3.0 Hours Placebo 0.2 g/kg Ethanol 0.4 g/kg Ethanol 0.8 g/kg Ethanol Holdstock and de Wit, 1998 Transition to Addiction Good to Bad Stages of Drug Use & Increased Energy It sustains and refreshes both body and brain... in the same space of time more than double the amount of work could be undergone... Sears, Roebuck, and Co. Consumers Guide, 1900 Replace atural Reward "A coke shot...it's like... injectable sex, an orgasm in every cell. Craving I found I was taking money meant to buy presents for my children. Paranoia He thought he was being forcibly electrocuted and could see electric wires leading to his body. 1. Initial use, experimentation 2. Repeated or regular use 3. Abuse 4. Dependence 5. Relapse 2
How to understand DSM- IV DIAGOSES FOR DRUG ABUSE & Clinical classifications of drug abuse phenomena DSM IV IDC10 & & Experimental animal models of drug abuse Operant behaviour Mechanism(s) At the cellular or systemlevel use resulting in failure to fulfill major role obligations, or in legal problems use despite adverse consequences (social, physical, legal) tolerance,dependence drug taken in larger amount than intended persistent desire to cut down much time spent obtaining the drug The Triangle of Dependence Drug Tolerance Psychological Dependence Physical Tolerance Dependence F F E ormal Drug Dose Tolerance After repeated use, the same amount of drug is insufficient to cause the desired effect and thus, more drug is used. A compensatory response: adaptation E C T Drug tolerance Causes of Tolerance 1. Pharmacokinetic or metabolic 2. Pharmacodynamic or functional 3. Learned or behavioral Drug tolerance Metabolic tolerance arises from an increase in the rate at which the body is able to metabolise and get rid of a drug. Repeated drug may increase the action of an enzyme the body uses to destroy the drug. Pharmacodynamic tolerance arises from an adaptation in receptor function, number or messengers Behavioural tolerance arises when an animal, through experience with a drug, learns to decrease the effect that the drug is having. This learning can involve both instrumental learning and conditioning processes. 3
Physical Dependence Predictable group of signs and symptoms resulting from abrupt removal of a drug. The body needs the drug for normal physiological function. Signs are usually the opposite to the original effects of the drug Physical withdrawal symptoms serve as negative reinforcement Importance of drug kinetics and elimination rate Does not occur with all drugs of abuse Psychological Dependence A drug-seeking behavior Motivational component: great subjective need, compulsion, drive to get the drug. Drug craving. Drug effects serve as positive reinforcers. Major factor in relapse Animal models of reward and reinforcements Animal Studies A) Drug-self administration & Drugs as reinforcers in animals. & High correlation with human dependence liability. Morphine/Heroin Self-Administration Stages of Drug Use 1. Initial use, experimentation 2. Repeated or regular use 3. Abuse 4. Dependence 5. Relapse 4
Factors and Determinants of Drug Abuse Most Common Drugs of Abuse Genetic Biological & Genetic factors Psychological Traits Drugs Environment Reinforcing Properties of Drugs Social Factors Cocaine in Commercial Products Ecstasy (pill) Rohypnol O CH3 H C 3 O CH3 Caffeine H3C COOCH3 H O O C H Routes of Administration Cocaine CH3 icotine 5
DRUG ADDICTIO IS A COMPLEX ILLESS All Drugs of Abuse Exert Effects through Mesolimbic and Prefrontal Cortical etworks 6
THE MESOLIMBIC DOPAMIERGIC REWARD PATHWAY Brain Reward System Changes in brain function => Reward=> Craving Involve the Dopaminergic System Mesolimbic pathway :Ventral tegmental area (VTA), medial forebrain bundle, nucleus accumbens and the prefrontal cortex. Positron Emission Tomography (PET) igrostriatal pathway: Sustantia nigra, striatum. Mesocortical pathway: VTA, cingulate and frontal CTX. Tubero-Infundibular: Arcuate. in hypothalamus. ormal Drug Use Addiction Challenge: Treatment MRI of Functioning Brain Skull Eye Socket & ose ucleus Accumbens 7
C Activation of the ucleus Accumbens The Synapse as an Electrochemical Machine Amphetamine* Phencyclidine Cocaine icotine Alcohol neurotransmitter transporters agonist-activated channels GPCRs enzymes α Caffeine G protein-activated channels ucleus Accumbens LSD Morphine-heroin Tetrahydrocannabinol Morphine-heroin Caffeine* (*= intracellular target) eurotransmitter systems implicated in drug reward & Dopamine (cocaine, heroin, nicotine, alcohol, cannabinoids) & Opioid peptides (heroin, morphine) & Acetylcholine (nicotine) & Cannabinoid (marijuana) & GABAA (barbiturates, benzodiazepines, alcohol) & Glutamate (phencyclidine, alcohol) & Serotonin (cocaine, hallucinogens, alcohol) icotine Opioid Caffeine ETOH PCP Drugs of Abuse Stimulate Mesoaccumbens Dopamine VTA DA GABA MDMA Cocaine Amphetamine Accumbens GABA Reward Well Being Motor Stimulation Opioid DA Release Release of Dopamine in the Rat ucleus Accumbens: Acute Administration How Drugs Become Addictive 300 Kalivas, P. 2002 Dopamine (% Change) 250 200 150 100 50 0 60 120 180 240 Time (min) Footshock Sucrose Cocaine icotine Alcohol 8
Tyrosine Tyrosine Dopamine Synapse L-DOPA DA Cocaine inhibits the re-uptake of dopamine DA and 5HT levels in nucleus accumbens after cocaine 9
PET/fMRI of Cocaine Craving Childress et al., 1999; Am.J.Psychiat Darker areas = lower density of serotonin use User: 1.5 yrs, at least 70 doses (none for 3 wks). ational Institute on Drug Abuse, 2002; Monkey Brain 10
Acute Drug State Chronic Drug State Chronic Drug State Short-term Abstinence Long-term Abstinence Reinforcement, reward Increase: & Mesolimbic DA? Other (e.g., 5-HT) Minutes to hours Tolerance Sensitization Dependence Receptor adaptations Increase: & camp pathway & CREB & FosB Days to years Withdrawal Increase: & Glutamatergic & oradrenergic & CRF Decrease: & DA, 5-HT Hours to days Synaptic remodeling (learning & modeling) & CRF Craving Stress-induced relapse & glucocorticoids Days to years euroadaptation see alsocellular mechanisms 11