Drug Abuse

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Chapter 18

• Drug Abuse

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Background

• Humans discovered long ago that many substances
  in nature (e.g. plants materials) had medicinal
  qualities
• Some of these also served as recreational
  drugs, or substances that produced pleasing
  effects (most notable example is alcohol)

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Addictive drugs
 
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Physical vs Psychological Addiction

• Many people believe that true addiction is
  caused by the unpleasant side effects that occur
  when an addict tries to stop taking the drug
• Physical dependence vs. psychic dependence
• Heroin addiction considered prototype for all
  drug addictions
• Heroin addicts become physically dependent on the
  drug
• Tolerance decreased sensitivity to a drug that
  comes from its continued use
• Withdrawal the appearance of symptoms opposite
  to those produced by a drug when the drug is no
  longer taken
• Tolerance may be produced by the bodys attempt
  to compensate for the unusual condition of heroin
  intoxication, thus when the addict stops taking
  the drug, the compensatory mechanisms will become
  apparent
• However, tolerance and withdrawal do not occur
  immediately, something else must be happening in
  order to get the addict to start taking the drug
  in the first place (i.e. reinforcing effects)

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Positive reinforcement

• Drugs that lad to dependency must first reinforce
  peoples behavior
• Positive reinforcement refers to the effect that
  certain stimuli have on the behaviors that
  preceded them
• Addictive drugs have reinforcing effects
• i.e. their effects include activation of the
  reinforcement mechanism
• Role in drug abuse
• The effectiveness of a reinforcing stimulus is
  greatest if it occurs immediately after a
  response occurs
• This phenomenon explains why the most addictive
  drugs are those that have immediate effects
• e.g. heroin is preferred over morphine because it
  has a more rapid effect
• The immediate reinforcing effects of a addictive
  drug can overpower the recognition of the
  long-term aversive effects

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Positive reinforcement

• Neural mechanisms
• All natural reinforcers cause the release of DA
  in the nucleus accumbens
• Addictive drugs (including amphetamine, cocaine,
  opiates, nicotine, alcohol, PCP, and cannabis)
  trigger the release of DA in the NA
• Some do this by increasing te activity of DA
  neurons in mesolimbic system
• Some inhibit reuptake of DA by terminal buttons

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Negative reinforcement

• A behavior that stops or reduces and aversive
  stimulus will be reinforced. This phenomenon is
  called negative reinforcment
• Do not confuse negative reinforcement with
  punishment
• For neg. reinforcement the response must make
  an aversive stimulus stop
• For punishment the response must make the
  aversive stimulus occur
• Reduction of withdrawal effects (by taking the
  drug again) serve as negative reinforcement
• Could also explain why a person starts taking a
  drug in the first place
• Drug effects may help relieve bad feelings that
  person may be having (e.g. drink when feeling
  upset)

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Cravings and relapse

• When an addictive drug activates the mesolimbic
  DA system, it gives incentive salience to
  stimuli present at that time
• i.e. stimuli associated with taking that drug
  become exciting and motivating
• When a person with a history of drug abuse sees
  or thinks about these stimuli they experience a
  craving, or an impulsion to take the drug
• Small doses of the drug can also elicit cravings
• Reinstatement model of drug seeking in lab
  animals
• First trained to make a response that is
  reinforced by IV injection of drug (e.g. cocaine)
• Next, response is extinguished by only injecting
  saline after response
• Once animal has stopped responding, a free
  injection will be administered, and the animal
  will begin to respond again
• This relapse involves activation of the
  mesolimbic DA system

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Cravings and relapse

• Long-term drug abuse in both humans and lab
  animals produces long-term changes in the brain
• Imaging studies show increase in activity in
  orbitofrontal cortex and anterior cingulate
  cortex when taking or craving an addictive drug
• Decrease in activity during withdrawal
• NMDA-receptor-dependent LTP and LTD can take
  place in NA and VTA of mesolimbic system
• Other stimuli can also trigger relapse
• e.g. stressful situations can cause former drug
  users to relapse
• However, social satisfaction produces less need
  of artifical reward via drugs
• Drug craving elicited by stress depends on the
  secretion of CRH (i.e. if CRH is not secreted,
  then relapse will not occur)

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Opiates

• Opium is derived from resin produced by the opium
  poppy, and has been eaten and smoked for
  centuries
• Opiate use (usually heroin) is illegal in most
  countries, produces tolerance, addicts may often
  use unsanitary needles, and pregnant women taking
  the drug will pass on addiction to fetus
• Opiates (endogenous opioids) are secreted when an
  animal is performing behaviors that are important
  to its survival
• Neural basis of reinforcing effects
• Lab animals will self-administer opiates
• When an opiate is administered it stimulates
  opiate receptors located on neurons in various
  parts of the brain and produces analgesia,
  hypothermia, sedation, and reinforcement
• µ and d receptors responsible for analgesic
  effects ? produces aversive effects (e.g.
  dynorphin endogenous ligand for ? opiate
  receptor)

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Opiates

• Neural basis of reinforcing effects
• Opiate injection caused increased release of DA
  in NA
• The reinforcing effects of opiates are produced
  by activation of neurons of the mesolimbic system
  and release of DA in the NA
• However, opiates can reinforce behavior
  independent of their effects on the mesolimbic DA
  system
• Animals with lesions of NA still have behavior
  reinforced with opiates
• Tested with conditioned place preference, which
  is the learned preference for one location over
  another in which an organism encountered a
  reinforcing stimulus
• CPP still occurs with opiates even after
  destruction of NA
• Neural basis of withdrawal effects
• Periaqueductal gray (PAG), locus coeruleus, and
  amygdala
• Antagonist-precipitated withdrawal sudden
  withdrawal from long-term admin of a drug caused
  by cessation of the drug and admin of an
  antagonistic drug (e.g. naloxone for opiates)
  most sensitive site was locus coeruleus

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Opiates

• Neural basis of withdrawal effects
• Intracellular process involved in development of
  withdrawal symptos to opiates involves a protein
  called CREB (cyclic AMP-responsive
  element-binding protein)
• Long-term exposure to opiates causes tolerance,
  or a decreased sensitivity of neurons to opiates
• This decreased sensitivity (i.e. downregulation)
  occurs even though the number of opiate receptors
  does not change, suggesting some type of
  intracellular alteration
• CREB plays a critical role in the intracellular
  events responsible for the withdrawal effects of
  opioids
• CRH is involved in craving caused by stress for
  opiates

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Cocaine and Amphetamine

• Have similar behavioral effects, because both act
  as potent DA agonists
• Cocaine binds with and deactivates the DA
  transpoter proteins, thus blocking reuptake
• Amphetamine directly stimulates the release of DA
  from terminal buttons
• Excitatory behavioral effects (e.g. euphoria,
  feelings of power, talkative)
• Animals will self-admin
• Also see psychotic behavioral effects (e.g.
  hallucinations, delusions of persecution, mood
  disturbances, and repetitive behaviors) that very
  closely resemble schizophrenia
• May have adverse long-term effects on brain
• Decrease in number of DA transporters

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Cocaine and Amphetamine

• Activate mesolimbic DA system and reinforce
  drug-taking behavior
• IV injection of both increase concentration of DA
  in NA
• NA is critical site for the reinforcing effects
  of cocaine and amphetamine
• Neurons in the NA participate in the reinforcing
  effects of cocaine, with groups of neurons
  participating in triggering behavioral response,
  reinforcing effects, and cravings
• Long-term use does not produce tolerance, and may
  even produce sensitization withdrawal symptoms
  are not physical, but can still be unpleasant,
  such as dysphoria or decreased ability to
  experience pleasure

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Nicotine

• The combination of nicotine and other sustances
  in tobacco smoke is carcinogenic and leads to
  cancer of the lungs, mouth, throat and esophagus
• 1/3 of adult population of the world smokes, even
  when aware of averse health effects
• Lab animals will also self-admin
• Stimulates ACh receptors, and increases activity
  of DA neurons of mesolimbic system and causes DA
  to be released in NA
• Injection of nicotinic agonist directly into VTA
  will produce a CPP
• Injection of nicotinic antagonist into the VTA
  will reduce the reinforcing effects of IV
  injections of nicotine
• Reinforcing effect of nicotine occurs in VTA, but
  not NA
• Some of the reinforcing effects of tobacco smoke
  may be mediated by nicotinic ACh receptors
  located outside CNS

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Nicotine

• The nicotinic ACh receptor exists in 3 states
• When a burst of ACh is released by terminal
  button, the receptors open briefly, permitting
  Ca to enter
• Within milliseconds, AChE has destroyed ACh and
  receptors either close again or enter a
  desensitized state, during which they do not
  react to ACh
• However, when a person smokes, the level of
  nicotine in the brain raises slowly and stays
  steady for a prolonged period of time because it
  is not destroyed by AChE
• Thus nicotine has dual effects on nicotinic
  receptors activation and then desensitization
• The first dose of nicotine in the morning brings
  the most pleasure, because the period of
  abstinence during the night has allowed many of
  their receptors to enter the closed state and
  become sensitized again
• Cravings in long-term caused by LTP in the VTA
• Cessation causes withdrawal symptoms (e.g.
  anxiety, restlessness, insomnia, and inability to
  concentrate)

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Alcohol and Barbiturates

• Alcohol has greater costs to society than any
  other drug
• Has the most serious effects on fetal development
  during the brain growth spurt period, which
  occurs during the last trimester of pregnancy and
  for several years after birth
• Alcohol has 2 primary sites of action
• Serves as an indirect agonist at GABAA receptors
• Indirect antagonist at NMDA receptors
• Both of these actions trigger apoptosis
• Exposure to alcohol later in life may also
  produce long-lasting changes in susceptibility to
  addiction
• At low doses, alcohol produces mild euphoria and
  has an anxiolytic effect at higher doses it
  produces incoordination and sedation also
  removes the inhibitory effect of social controls
  on behavior

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Alcohol and Barbiturates

• Produces both positive (euphoria) and negative
  (anxiolytic) reinforcement
• Unique combination of both positive and negative
  effects that makes alcohol so reinforcing
• Lab animals can be induced to become dependent on
  alcohol
• Most animals find the taste of alcohol to be
  aversive
• However, can add supplements to alcohol to get
  them to consume it
• e.g. sucrose, beer, gelatin (Rowland et al. 2005)
• Increases activity of DA neurons in mesolimbic
  system and increases release of DA in NA
• The perceptual effects of alcohol are mimicked by
  both GABA agonists and NMDA antagonists
• Drug discrimination procedure an experimental
  procedure in which an animal shows, through
  instrumental conditioning, whether the perceived
  effects of two drugs are similar

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Alcohol and Barbiturates

• Like alcohol, NMDA antagonists produce sedative,
  hypnotic, and anxiolytic effects and interfere
  with cognitive performance
• Alcohol also disrupts LTP and interferes with
  spatial receptive fields of place cells in the
  hippocampus
• Withdrawal from alcohol intake decreases activity
  of mesolimbic neurons and their release of DA in
  the NA can also cause seizures that may be
  mediated by activation of NMDA receptors
• These seizures can be blocked by NMDA receptor
  antagonists
• The sedative effect of alcohol appears to be
  mediated by the GABAA receptor
• Barbiturates have similar effects to alcohol
  however, binding sites appear to be different

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Cannabis

• THC, active ingredient in marijuana, activates
  endogenous cannabinoid receptors
• Has a stimulating effect on DA neurons in NA
• Appears to act directly on DA terminal buttons
• Many lab animals will self-admin drugs that
  stimulate CB1 receptors
• A targeted mutation that blocks production of CB1
  receptors abolishes the reinforcing effects of
  cannabinoids, morphine and heroin
• The hippocampus contains a large concentration of
  THC receptors
• Marijuana affects memory it impairs ability to
  keep track of a particular topic, etc.
• Excessive activation of CB1 receptors in field
  CA1 appears to interfere with normal functioning
  of the hippocampus
• Long-term effects of marijuana include
  bronchitis, increased risk for lung cancer, minor
  impairments of memory and attention

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Heredity and drug abuse

• Not everyone is equally likely to become addicted
  to a drug
• 2 possible sources of individual differences
  heredity and environment
• Most research of effects of heredity on addiction
  have been devoted to alcoholism
• Alcohol consumption is not distributed equally
  across the population
• Heredity appears to be more important than
  environment
• 2 types of alcoholics steady drinkers those
  you cannot abstain but drink consistently and
  bingers those who go without for long periods
  of tie, but unable to control themselves when
  they start
• Steady drinking strongly influenced by heredity,
  binge drinking by both heredity and environment
• Personality differences that may lead to
  alcoholism may be due to differences in the
  sensitivity of neural mechanisms involved in
  reinforcement, exploration and punishment
• Also may involve differences in DA mechanisms

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Animal models and drug abuse

• Several different strains of alcohol preferring
  rats have been bred
• P rats (alcohol preferring) vs NP rats
  (non-alcohol preferring)
• When given alcohol for first time, both groups
  show no preference
• However, after a short time of exposure to
  alcohol soltuion in addition to water, P rats
  will show a greatly increased preference for
  alcohol solution during next test
• Found lowered levels of DA in NA of P rats
• A low level of DA in NA correlates with ahedonia
  and dysphoria, and some forms of alcoholism may
  be caused by decreased sensitivity to
  reinforcement

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Therapy for drug abuse

• Most common treatment for opiate addiction is
  methadone maintenance
• Methadone is a potent opiate, which is
  administered by clinics in liquid form, and does
  not produce a high, since the rate of admin is
  slow
• Opiate antagonist, such as naloxone, are used by
  hospitals for treatment of heroin overdose
• Several treatments for nicotine addiction
• Gum, patch, etc. all methods maintain
  sufficiently high level of nicotine in brain to
  decreases cravings once smoking habit is gone,
  the dose can be lowered to wean them off
• 5-HT agonists can help with alcoholism, also NMDA
  receptor antagonists