Copyright © Allyn & Bacon 2010 Drug Abuse Chapter 18

 ALCOHOL Copyright © Allyn & Bacon

 Among Canadians 15 years and older, the prevalence of past-year cannabis use is 10.7% in  Among Canadians 15 years and older, the prevalence of past-year cocaine or crack is 1.2% in 2010, past-year use of hallucinogens (0.9%), ecstasy (0.7%) and speed (0.5%)  The rates of psychoactive pharmaceutical use and abuse: 26.0% of respondents aged 15 years and older indicated that they had used an opioid pain reliever, a stimulant, or a sedative or tranquilizer in the past year while 0.3% reported that they used any of these drugs to get high in the past year.  Among Canadians 15 years and older, the prevalence of past-year alcohol use was 77.0%  Cost – over 40 billion dollars! DRUG STATS IN CANADA Copyright © Allyn & Bacon

 10% abstain from all alcohol use  One of the highest rates of alcohol and drug addiction than anywhere else in Canada.  More then 13% are struggling with drug addiction, alcoholism or both. These numbers work out to approximately two hundred thousand people at any one time are addicted to something.  Police report that the number one cause of all domestic abuse cases in NL can be linked back to alcoholism and/or drug addiction. DRUG ABUSE IN NEWFOUNDLAND Copyright © Allyn & Bacon

 Common Features of Addiction  Commonly Abused Drugs  Heredity and Drug Abuse  Therapy for Drug Abuse Lecture Preview

 A Little Background Recreational Drugs – historically these are drugs discovered that produce pleasurable effects. One of the earliest recreational drugs was ethyl alcohol. Others include: Opium Cannabis Coca Coffee Tobacco COMMON FEATURES OF ADDICTION

Copyright © Allyn & Bacon DrugSites of Action Ethyl alcoholNMDA receptor (indirect antagonist), GABAa receptor (indirect agonist) barbituratesGABAa receptor (indirect agonist) Benzodiazepines (tranquilizers)GABAa receptor (indirect agonist) CannabisCB1 cannabinoid receptor (agonist) NicotineNicotinic ACh receptor (agonist) Opiates (heroin, morphine, etc) μ and δ Opiate receptor agonist Phencyclidine (PCP) and ketamineNMDA receptor (indirect antagonist) CocaineBlocks reuptake of dopamine (and 5-HT and NE) amphetamineCauses release of dopamine (running DA transporters in reverse)

Cocaine Blocks DA Re-Uptake in the Pre-Synaptic Cell: a DA Agonist

Consumption Reward Drug effects Withdrawal Come-down Desire to alleviate withdrawal symptoms

 Positive Reinforcement Addictive drugs have reinforcing effects Effectiveness of a reinforcing stimulus is greatest if it occurs immediately after a response occurs Most addictive drugs are those that have immediate effects Drug users prefer heroin to morphine not because effects are different, effects are faster Only a small percentage of people that try addictive drugs become dependent Cocaine is one of the most addictive drugs currently available, ~ 15% of people who use it become addicted COMMON FEATURES OF ADDICTION

Neural Mechanisms Natural reinforcers (food, water, sex) – cause release of dopamine (DA) in the nucleus accumbens (NAC) – mesolimbic pathway Amphetamine, cocaine, opiates, alcohol, PCP, cannabis all trigger release of DA in NAC as measured by microdialysis COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Neural Mechanisms Drugs “hijack” brain mechanisms that normally help us adapt to our environment Addiction begins in mesolimbic DA system, produces long-term changes in brain regions that receive input from these neurons COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

DA Pathway

 Neural Mechanisms Ventral tegmental area (VTA) Single injection of addictive drug increased strength of excitatory synapses on DA neurons in VTA in mice Insertion of additional AMPA receptors into the postsynaptic membrane of DA neurons Single injection of drug produces synaptic strengthening in the VTA lasting 5 days, if drug given longer (2 weeks), changes in VTA persist COMMON MECHANISMS OF ADDICTION Copyright © Allyn & Bacon

 Neural Mechanisms Due to changes in VTA, increased activation in regions that receive DA input from VTA Ventral striatum Nucleus accumbens Dorsal striatum Caudate nucleus and putamen COMMON MECHANISMS OF ADDICTION Copyright © Allyn & Bacon

 Neural Mechanisms  At 1 st, addict experiences the pleasurable effects of drug, reinforcing behaviors (getting the drug, preparing it, swallowing, injecting, sniffing, smoking it, etc)  Ventral striatum: nucleus accumbens Early reinforcing effects that take place in NAC encourage drug- taking behavior COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Neural Mechanisms  Subsequent compulsive behaviors in addiction occur only after continued use of addictive drug  Dorsal striatum: caudate nucleus and putamen Infusion of DA antagonist into dorsal striatum suppressed lever presses that had been reinforced by light that had been paired with cocaine Presence of a light that had previously been paired with IV cocaine increased DA release in the dorsal striatum, not ventral (NAC) COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Neural mechanisms In humans… When cocaine addicts are given an injection of methylphenidate, they show a much smaller release of DA in NAC or dorsal striatum than controls When people who were addicted to cocaine watched a video of people smoking cocaine Increased release of DA was seen in dorsal striatum, not ventral striatum  The response to the drug itself is diminished in addicts, but the response to cues associated with the drug is augmented – in the dorsal striatum COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Neural mechanisms Orexin and MCH play a critical role in the reinforcing effects of drugs Orexin (synthesized in LH) is released in VTA, NAC, dorsal striatum Administration of addicted drugs or stimuli associated with them activate orexin neurons Infusion of orexin into VTA causes relapse Block of orexin in VTA blocks cocaine seeking elicited by drug- related cues and prevents CPP (place where morphine was previously administered) COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Neural mechanisms Orexin and MCH play a critical role in the reinforcing effects of drugs MCH (synthesized in LH) – receptors in NAC MCH neurons also contain DA receptors in NAC Stimulating both DA receptors and MCH receptors increased firing of NAC neurons Block of MCH receptors decreased the effectiveness of cocaine or cocaine-related cues of the animals’ behavior Mutant MCH receptor had same effect COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Negative reinforcement A behavior that turns off (or reduces) an aversive stimulus will be reinforced Not punishment – makes behavior less likely Tolerance – decrease in sensitivity to a drug that comes from repeated use Withdrawal symptoms – primarily the opposite of the effects of the drug Effects of heroin – euphoria, constipation, relaxation Withdrawal effects of heroin – dysphoria, cramping and diarrhea, and agitation COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Negative Reinforcement Tolerance – body’s attempt to compensate for unusual condition Drug disturbs normal homeostatic mechanisms in the brain – compensatory responses Because of this compensation, user must take increasing amounts to achieve the original effects of the drug Mechanisms also cause withdrawal When the person stops taking the drug, compensatory mechanisms make themselves felt – unopposed by drug COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Positive reinforcement seems to be what provokes drug taking in the first place  Reduction in withdrawal symptoms may play a role in maintaining drug addiction  Negative reinforcement may also explain acquisition of drug addictions under some conditions Alcohol to relieve feelings of anxiety COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Cravings and Relapse When an addictive drug activates the mesolimbic DA system, it gives incentive salience to stimuli present at that time Stimuli associated with drug become exciting and motivating Increases cravings  Animal model of cravings Reinstatement Animals are first trained to make a response (press a lever), that is reinforced by iv injections of drug (cocaine) Response is extinguished – injections of saline instead of cocaine Once the animal stops responding (pressing the lever), experimenter administers a “free” injection of drug In response, animals begin pressing lever again COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Cravings and Relapse Animal model – reinstatement Relapses produced by unexpected dose of drug activate mesolimbic DA system If the NAC or VTA of rats is temporarily inactivated, free shot of cocaine fails to reinstate responding COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Cravings and Relapse Extinction – new form of learning, animal does not forget to make a particular response, it learns not to Ventromedial prefrontal cortex (vmPFC) Stimulation of vmPFC with infusion of AMPA blocked reinstatement produced by free shot of cocaine Dorsal anterior cingulate cortex (dACC) Reinstatement of lever pressing for infusions of cocaine was abolished by injecting a GABA agonist into dACC – region of dorsal PFC that has excitatory connections with NAC dACC plays a role in craving, vmPFC plays a role in suppression COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Craving and Relapse In humans… Drugs of abuse or cues associated with them activate several brain regions Anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), insula, dorsolateral PFC (dlPFC) COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 PFC Activity in mPFC of cocaine abusers was less active than that of normal subjects When addicts perform tasks that normally activate mPFC, mPFC is less activated than that of healthy controls Amount of activation of mPFC was inversely related to amount of cocaine that cocaine abusers normally took each week lower brain activity, more cocaine Drug abusers show the same deficits on tasks that involved PFC as do people with lesions of PFC Structural abnormalities of PFC in drug abusers 5-11% decrease in gray matter volume in PFC in chronic cocaine abusers Abnormalities a result of drug use/addiction, or predisposing factor? COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 PFC Negative and cognitive symptoms of schizophrenia result from hypofrontality Similar to symptoms of long term drug abuse High level of comorbidity of schizophrenia and drug abuse ~50% of schizophrenics have a substance abuse disorder 70-90% are addicted to nicotine Prefrontal gray matter volumes were 10.1% lower in alcoholic patients, 9% lower in schizophrenics, 15.6% lower in patient with both disorders COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 PFC – judgment, risk taking, control of inappropriate behaviors  Adolescents are more vulnerable to drug addiction than adults  During adolescents, rapid increase in maturation of neuronal circuits in brain – PFC  Before maturation, adolescents display risky behaviors, impulsive behaviors, experimentation with drugs ~50% of cases of addiction begin between ages 15 and 18, very few begin after age 20 Early onset of drug-taking is associated with more severe addiction COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Craving and relapse Stress! Stressful situations can cause former drug addicts to relapse Socially defeated mice become more sensitive to the effects of cocaine Stress that occurs early in life can have long-lasting effects Stressed infant rats, as adults acquired a drug habit and took more drug than controls (non-stressed) CRH can reinstate drug-taking behavior Block of CRH receptors can reduce the likelihood of relapse from drugs or drug cues CRH receptors in VTA – infusion of CRH in VTA causes relapse, CRH antagonist in VTA prevents reinstatement of drug-taking by a stressful stimulus COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Craving and relapse Stress! CRH can reinstate drug-taking behavior Block of CRH receptors can reduce the likelihood of relapse from drugs or drug cues CRH receptors in VTA Infusion of CRH in VTA causes relapse CRH antagonist in VTA prevents reinstatement of drug-taking by a stressful stimulus COMMON FEATURES OF ADDICTION Copyright © Allyn & Bacon

 Opiates  Stimulant drugs Cocaine Amphetamine  Nicotine  Alcohol  Cannabis COMMONLY ABUSED DRUGS Copyright © Allyn & Bacon

1.Heroin is illegal in most countries 2.Because of tolerance, people must take more and more of the drug to produce the same “high” 3.Use of unsanitary needles – hepatitis/AIDS 4.If addict is pregnant, her infant will also become dependent on the drug (crosses the placental barrier). Infant must be given opiates right after birth and then weaned gradually 5.Uncertainty of strength of batch OPIATES Copyright © Allyn & Bacon

 Neural Basis of Reinforcing Effects Analgesia, hypothermia, sedation, reinforcement Opiate receptors in PAG - analgesia Opiate receptors in preoptic area – hypothermia Opiate receptors in reticular formation – sedation Opiate receptors in NAC and VTA – reinforcement Rats will injection heroin directly into NAC and VTA % increase in levels of DA in NAC while a rat pressed a lever that delivered IV heroin OPIATES Copyright © Allyn & Bacon Endogenous opioids are involved in the behavioral effects of natural reinforcers Naloxone (blocks opiate receptors) reduce the reinforcing effects of alcohol in humans and rats

 Neural Basis of Tolerance and Withdrawal Antagonist-precipitated withdrawal – sudden withdrawal from long- term administration of a drug caused administration of an antagonistic drug Rats physically dependent on morphine and injected with naloxone in brain Most sensitive sites: LC, PAG Amygdala - Weak withdrawal LC Lesions reduce severity of antagonist-precipitated withdrawal Antagonist-precipitated withdrawal increases glutamate and aspartate in LC OPIATES Copyright © Allyn & Bacon

 Potent DA agonists, sites of action are different  Cocaine deactivates DA transporters, blocks reuptake  Freebase cocaine (crack) is smoked - enters brain very quickly, very potent Probably the most effective reinforcer of all available drugs  Amphetamine stimulates release of DA  Metamphetamine – related to amphetamine, more potent STIMULANT DRUGS: COCAINE & AMPHETAMINE Copyright © Allyn & Bacon

 If rats or monkeys are allowed to self- administer cocaine, they often self-inject so much cocaine that they die  Rats that self-administer cocaine were almost 3 times more likely to die than were rats that self-administered heroin  IV injections of cocaine or amphetamine increase DA in NAC STIMULANT DRUGS: COCAINE & AMPHETAMINE Copyright © Allyn & Bacon

 Side effects of cocaine and amphetamine Psychotic behavior: hallucinations, delusions of persecution, mood disturbances, repetitive behaviors Symptoms resemble paranoid schizophrenia Increased activity of DA is responsible for positive symptoms of schizophrenia  Long-term addicts Decreased # of DA transporters, decreased number of DA terminals People may have increased risk of PD STIMULANT DRUGS: COCAINE & AMPHETAMINE Copyright © Allyn & Bacon

 Accounts for more deaths than “hard” drugs  Combination of nicotine and other chemicals in smoke is carcinogenic – leads to cancer of the lung, mouth, throat, esophagus  World Health Organization (WHO) 1/3 of people in the world smoke 50% of people who begin to smoke as adolescents and continue smoking throughout their lives will die from smoke-related disease  2015 – tobacco will be the largest single health problem worldwide  6.4 million deaths/year  Deleterious effects on fetus (worse than cocaine?) 25% of pregnant women in US expose their fetuses to nicotine NICOTINE Copyright © Allyn & Bacon

 In humans - highly addictive  In animals – highly addictive  Nicotine stimulates nicotinic ACH receptors  Increases activity of DA neurons of the mesolimbic system and causes DA to be released in NAC Injection of a nicotinic agonist into VTA will reinforce a conditioned place preference (CPP) Injection of nicotinic antagonist into VTA will reduce the reinforcing effect of iv injections of nicotine  Insula may be involved in smoking cessation. NICOTINE Copyright © Allyn & Bacon

 Endogenous cannabinoids play a role in reinforcing effects of nicotine Rimonabant - blocks CB1 receptors Reduces nicotine self-administration, by reducing release of DA in NAC Decreases reinforcing effects of nicotine Help prevent relapse  Withdrawal symptoms Anxiety, restlessness, insomnia, inability to concentrate  Overeating and weight gain Nicotinic receptors are located on the terminals of GABAergic neurons in LH that form synapses with MCH neurons When nicotine activates these terminals, the release of GABA in increased, which inhibits MCH neurons, suppressing appetite NICOTINE Copyright © Allyn & Bacon

 Fetal Alcohol Syndrome (FAS) – one of the leading causes of mental retardation in the Western world  Fetal development Effects are most serious during last trimester and several years after birth  Exposure of the immature rat brain caused widespread apoptosis  Acts as a GABAa agonist, NMDA antagonist ALCOHOL Copyright © Allyn & Bacon

 Low doses Mild euphoria and anxiolytic effect  High doses In-coordination and sedation  Produces both positive (euphoria) and negative reinforcement (anxiolytic)  Increases activity of DA neurons in mesolimbic system, increases release of DA in NAC DA release is related to positive reinforcement DA antagonists reduce the euphoria produced by alcohol ALCOHOL Copyright © Allyn & Bacon

 Role on NMDA receptors Due to blocking NMDA receptors, alcohol disrupts long term potentiation (LTP) May account for the deleterious effects of alcohol on memory and other cognitive functions ALCOHOL Copyright © Allyn & Bacon

 Withdrawal Decreases activity of mesolimbic neurons and their release of DA in NAC If NMDA indirect antagonist is administered, DA secretion in NAC recovers Long-term suppression of NMDA receptors causes upregulation (compensatory increase). When alcohol stops, increased activity of NMDA receptors inhibits the activity of VTA and release of DA in NAC Can trigger seizures and convulsions, death ALCOHOL Copyright © Allyn & Bacon

 Role on GABAa receptors Alcohol binds to one of many binding sites to increase effectiveness of GABA in opening Cl- channel Anxiolytic effect Sedative effect  Reinforcing effect of alcohol is partly caused by its ability to trigger release of opioids Opiate blockers (naloxone/naltrexone) block the reinforcing effects of alcohol Opioids play a role in cravings 1-3 weeks of abstinence increased the # of opiate receptors in NAC Greater the # of receptors, more intense the craving ALCOHOL Copyright © Allyn & Bacon

 THC – active ingredient in marijuana  Site of action of endogenous cannabinoids in brain is the CB1 receptor Anandamide and 2-AG  Administration of a drug that blocks CB1 abolishes the “high” produced by smoking marijuana  Injections of THC increase DA release in NAC  Lab animals will self-administer CB1 agonists CANNABIS Copyright © Allyn & Bacon

 Mutation that blocks CB1 receptor production Abolishes reinforcing effects of THC, morphine, heroin Decreases reinforcing effects of alcohol and acquisition of self-administration of cocaine  Rimonabant – blocks CB1 receptors) Decreases reinforcing effects of nicotine CANNABIS Copyright © Allyn & Bacon

 Hippocampus contains a high concentration of THC receptors  Marijuana affects memory Impairs ability to keep track of a particular topic  Drug disrupts normal functions of the hippocampus Endogenous cannabinoids facilitate activity of CA1 pyramidal cells and LTP Effects of exogenous cannabinoids disrupts spatial memory, similar to hippocampal lesions  Early cannabis use can increase your risk of developing a psychotic illness later in life CANNABIS Copyright © Allyn & Bacon

 Both genetic and environmental factors play a role in determining a person’s likelihood of consuming drugs and becoming dependent Environment plays a stronger role in influencing a person to try a drug (recreational) Genetics play a stronger role in determining whether the person becomes addicted HEREDITY AND DRUG ABUSE Copyright © Allyn & Bacon

 Treatment of Opiate Addiction  Most common treatment is methadone.  Potent opiate  Liquid - oral administration increases opiate level in brain slowly, does not produce the same high (as injection of heroin)  Long-lasting, opiate receptors remain occupied, injection of heroin has little effect – limited  Buprenorphine  Partial agonist for the μ opiate receptor  Drug has high affinity for receptor but activates it less than ligand  Reduces effects of ligand in regions of high concentration and increases it in regions of low concentration  Blocks effects of opiates, produces weak opiate effect  Combination with naloxone THERAPY FOR DRUG ABUSE

 Treatment of Cocaine Addiction Immunotherapy Conjugated cocaine to a foreign protein which stimulated rats’ immune system to develop antibodies to cocaine Prevented cocaine from passing BBB, less sensitive to activating effects of cocaine Clinical studies underway (and with other drugs) GABA agonist (gamma-vinyl GABA – GVG) Decreased DA released in NAC after injecting a rat with cocaine Baboons given GVG no longer learned a CPP for cocaine GVG is not addictive, used to treat epilepsy Clinical studies underway THERAPY FOR DRUG ABUSE Copyright © Allyn & Bacon

 Nicotine Nicotine maintenance therapy Rimonabant - CB1 antagonist Bupropion – antidepressant drug, catecholine reuptake inhibitor Varenicline – partial agonist for the nicotinic receptor  Alcohol Naltrexone – opiate antagonist Acamprosate – NMDA-receptor antagonist THERAPY FOR DRUG ABUSE Copyright © Allyn & Bacon