Download - Copyright © Allyn & Bacon 2010 Drug Abuse Chapter 18

Copyright © Allyn & Bacon 2010

Drug Abuse

Chapter 18

http://www.youtube.com/watch?v=oax3cUFsBSwALCOHOL


Among Canadians 15 years and older, the prevalence of past-year cannabis use is 10.7% in 2010.

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


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


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


7

Drug Sites of Action

Ethyl alcohol NMDA receptor (indirect antagonist), GABAa receptor (indirect agonist)

barbiturates GABAa receptor (indirect agonist)

Benzodiazepines (tranquilizers) GABAa receptor (indirect agonist)

Cannabis CB1 cannabinoid receptor (agonist)

Nicotine Nicotinic ACh receptor (agonist)

Opiates (heroin, morphine, etc) μ and δ Opiate receptor agonist

Phencyclidine (PCP) and ketamine NMDA receptor (indirect antagonist)

Cocaine Blocks reuptake of dopamine (and 5-HT and NE)

amphetamine Causes 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


• 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



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



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


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


Neural Mechanisms At 1st, 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



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)



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



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)



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



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



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



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



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



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



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



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)



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?



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



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



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



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



Opiates Stimulant drugs

• Cocaine • Amphetamine

Nicotine Alcohol Cannabis

COMMONLY ABUSED DRUGS


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


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• 150-300% increase in levels of DA in NAC while a rat pressed a

lever that delivered IV heroin

OPIATES


•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


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


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



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



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


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


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


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


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


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


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


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


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


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


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


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


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



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



Download - Copyright © Allyn & Bacon 2010 Drug Abuse Chapter 18

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