• tobacco-related health care accounts for ~10% of all health care costs in first-world nations
• more than 5 million yearly deaths
• relapse is extremely hard to escape
• most prevalent preventable cause of death

• cigarettes contain 70+ compounds w/ confirmed carcinogenic activity
  • acetaldehyde
  • N-nitrosamines
  • N-Nitrosamines
  • 1,3-butadiene
  • benzene
  • acrolein
  • aromatic amines
  • polyaromatics
• nicotine itself can have negative effects w/ long-term use on cardiovascular system
  • high blood pressure 
  • high blood glucose

• nicotine can be found in ionized or deionized forms depending on pH of environment
  • important as charged molecules don't pass BBB as easily
• @ acidic pH
  • nicotine is ionized and not well absorbed
• @ alkaline pH
  • nicotine is not charged and absorbed well through lipid membrane
• @ physiological pH (7.3-7.5), ~31% of nicotine unionized

• 10-20% is excreted through urine unchanged
  • nicotine has half life of 2 hours
• 70-80% converted into cotinine and excreted
  • active metabolite w/ half life of 19 hours
  • likely part of what complicates nicotine tolerance
• ~10% converted into other metabolites and excreted
• Excretion occurs through kidney filtration and urine excretion as w/ most compounds but it can also be excreted in breast milk
  • excretion rate is ph-dependent occurring more efficiently in acidic environments
  • important to consider when breastfeeding; don't just stop smoking during pregnancy

• as psychostimulant, nicotine promotes action of sympathetic nervous system 
• binds to receptors in both brain and periphery
  • receptors found in 
    • GI system
    • CV system
    • exocrine glands
    • adrenal medulla
    • PNS
    • CNS
    • NMJ
    • Sensory Receptors
• it interacts directly w/ nicotinic cholinergic receptors (for acetylcholine) as an agonist
• nAchR make-up
  • 5 subunits
  • @ least 2 α-subunits as 2 molecules of Ach/nicotine required for activation
  • receptor types are extremely variable being made up of a variety of different subtypes of different subunits (α7, α4, β2,etc.)
  • different receptors will naturally elicit different effects
  • why the pharmacology of nicotine so complex w/ widely varied effects
    • one example is how quickly specific receptor becomes desensitized
  • localization - different types are distributed differently throughout the brain

• pharmacology of nicotine is extremely complex and symptoms can vary
  
  • effects are also context-specific, w/ tolerance being significantly less when administered in new environments
• effects of nicotine are interesting and variable based on context and how it is administered (volitional or not)
  • plasma epinephrine levels raised substantially in mice receiving nicotine independent of lever pressing
    • effect not seen in nicotine administration dependent on lever pressing or saline administration
    • one would expect a matching increase in BP and HR
  • when self-administered vs. yolked, change in BP is equal but no significant change in HR observed
• pain relief
  • tested using tail flick experiment - how long does it take rats to flick tail in response to applied heat in nicotine v. saline
  • effect does experience tolerance
• reinforcing/rewarding effect - enhances perceived reward from doing other actions that are reinforcing
• behavioral
  • stimulant and relaxant
  • Nesbitt's Paradox
• Cognitive
  • enhancing attention
• physiological effects associated w/ SNS

• nicotine acts as weak primary reinforcer
• nicotine enhances reinforcing properties of reinforcing stimuli
  • the more reinforcing the stimuli, the larger the enhancement effect
  • basically, nicotine makes everything better

• allows researchers to separate responses for visual stimulus from responses for nicotine using separate levers for nicotine and visual stimulus
• results conclude that rats press lever for nicotine less than the lever for visual stimulus

• nicotine receptor blocker
• used to show that reinforcement enhancing effect of nicotine blocked in presence of blockers
  • shows mechanism and causal relationship between nicotine and reinforcement enhancing effect

• nicotinic receptor blocker
• used to show that reinforcement enhancing effect of nicotine blocked in presence of blockers
  • shows mechanism and causal relationship between nicotine and reinforcement enhancing effect

• Zyban
• smoking cessation drug
• has reinforcement enhancing effect like nicotine, but its effect is not blocked by nicotine receptor blockers
  • shows different mechanism

• partial agonist of α4β2 nAchR
• also has reinforcement enhancing effects but also blocks maximal reinforcing effects of nicotine
  • as varenicline dose increases, difference in effect between varenicline and varenicline and nicotine decreases

• short-term tolerance
  • likely occurs because nicotine dissociates from receptor resulting in desensitization; some of this may subside overnight
• long-term tolerance
  • due to homeostatic reactions
  • chronic smokers have increased expression of nAchR in the brain
• withdrawal
  • symptoms begin 1-6 hrs after last cigarette and peak at 48-72 hrs
  • symptoms include
    • headache
    • stomach ache
    • intense cravings (start w/in hours)
    • depressed mood
    • irritability/anger
    • anxiety
    • restlessness
    • poor concentration
    • insomnia 
    • reduced heart rate
    • increased appetite or weight gain

• smokers tend to titrate their nicotine levels
  • if subjects are preloaded w/ nicotine, then smoking is reduced
  • if subject is administered nicotine receptor antagonist, then smoking is increased to overcome effect of antagonist

• Nicotine causes an arousal of brain wave activity
• Nicotine causes release of epinephrine that arouses the sympathetic NS
• However, smokers report that smoking “relaxes” them, and that they ‘need’ a smoke during times of stress
• What are some possible explanations?
  • Acute nicotine deprivation (i.e. between cigarettes) leads to increased stress.
  • Smokers then use cigarettes to reverse these withdrawal effects and normalize their mood.
  • Dependent smokers need regular hits of nicotine just to remain feeling normal
  • Quitting smoking reduces stress levels!
    • The former smoker no longer suffers from adverse mood effects of nicotine withdrawal!
    • Other “post-acute withdrawal symptoms” can last weeks to months after smoking cessation – leading to cravings.

• most widely used behaviorally-active drug in world
  • acts as psychostimulant
  • belongs to methylxanthine class
• originally described in 1000AD by sheep herder in reference to hyperactivity of his sheep in response to eating fruit of coffee tree
  • written in Arabian medical book

• Typical adult consumes 400 mg of caffeine per day (4 cups coffee).  90% in form of coffee and tea
• Absorbed easily via digestive system 
  • Difference between caffeine and other psychostimulants
• Easily passes through blood-brain barrier, found in all body fluids and organs
• Caffeine reaches organs in 5 minutes, peaks in blood in 30 min.  Maximal CNS effects in 2 hours

• primarily metabolized in liver
  • metabolized more quickly by smokers
• 90% is excreted as active or inactive metabolites
• these psycho-active metabolites are known as xanthines
  • theophylline
    • used for asthma
  • theobromine
    • found in chocolate at levels of 50x more than caffeine

• Moderate Doses
  • Most people report slight mood elevation (some report dysphoria)
  • Can enhance thought processes
  • Reduced fatigue/drowsiness
  • As little as 32 mg (< 1 cup) improves auditory vigilance and visual reaction time
  • Produces increased capacity for muscular work, and sustained intellectual task performance.
    • Can disrupt arithmetic skills and task performance when delicate muscular coordination and accurate timing are required
• High Doses
  • Caffeineism (usually in non-users)
    • 7-10 cups of coffee cause insomnia, restlessness, mild sensory disturbances and muscle tenseness
  • Precipitate anxiety or panic attacks in susceptible individuals

• Moderate Doses
  • acts indirectly on SNS to boost heart rate, blood pressure, and vasoconstriction
  • direct actions on heart are as vasodilator leading to decreased heart rate and blood pressure
  • dilates bronchial tubes 
    • theophylline is used as asthma medication
  • as vasoconstrictor, caffeine useful in treatment of headaches
• High Doses
  • insomnia
  • restlessness
  • anxiety or panic attacks in susceptible individuals
• Caffeine Toxicity
  • very rare as lethal dose is 10 g or 100 cups of coffee (@ one time)
  • convulsions and respiratory arrest result from lethal doses
  • convulsions may result from sub-lethal doses in susceptible individuals

• cerebral cortex
• medulla
  • particularly locus coeruleus which is mediator of arousal and vigilance
  • respiratory centers of medulla
    • treatment for newborns

• At lower-higher doses
  • Acts adenosine receptor antagonist
  • Adenosine is a neuromodulator that normally slows down neural activity in the CNS and PNS 
    • reduces excitability, lowers neurotransmission, induces sleep
  • Relief of inhibition increases neuronal activity
  • Therefore, blocking Adenosine receptors increases neural activity
    • increased concentrations of extracellular dopamine and glutamate in shell of NAc after administration of moderate doses
      • high and low doses resulted in no difference from saline
  • Thus caffeine is an AGONIST of transmitter release
• At high concentrations, caffeine can have additional effects in the nervous system
  • GABA receptor antagonist (methylxanthine)
    • GABA is inhibitory, so caffeine is blocking inhibition
  • Blocking GABA receptors reduces inhibition in the brain and leads to overall arousal (may relate to seizures in caffeine toxicity)
  • High doses are required for this effect:  probably responsible for increased anxiety seen with high doses
• one notable mechanism of action for caffeine is that it causes release of intracellular calcium stores making it harder to induce neurotransmitter release

[image]

• adenosine activates potassium channels allowing potassium to leave postsynaptic neuron inhibiting AP fire
• adenosine acts on presynaptic neuron to lower intracellular Ca⁺⁺ concentrations
• increased levels of IP3 cause release of calcium stores making it more difficult for neuron to release neurotransmitter

• can take 2 months of abstinence to lose tolerance
• tolerance is low grade and can be overcome by increasing dose
• caffeine addiction extremely common and does not have serious physical or social consequences in relation to more serious drugs of abuse
• Pharmacodynamic Tolerance
  • some tolerance does develop through up-regulation of adenosine receptors as body's attempt to maintain homeostasis
• withdrawal symptoms are minor 
  • Headaches and increased fatigue
  • Strongest over the first 2 days, decline over 5-6 days

• caffeine does have reinforcing effect like other drugs we have discussed but to a much smaller extent
• rats will sometimes self-administer (shows weak levels of reinforcement)
• Most desirable effects are reported by heavy users, particularly after several hours of abstinence
  • evidence for dependence, could be due to alleviation of withdrawal symptoms
• Non-users are more likely to report unpleasant effects, suggesting that any reward is due to termination of unpleasant withdrawal effects
• other evidence can be seen in spikes in extracellular glutamate and dopamine concentrations after administration
  • this effect is negated at very low and high levels of caffeine
  • similar trend to caffeine's effect can be seen in administration of CTP (A1 receptor antagonist) and SCH (A2A receptor antagonist) 
    • CTP causes spikes in glutamate and dopamine concentrations
    • SCH has no effect
    • suggests that A1 receptor is key to caffeine's mechanism of action
• dependence is mostly physical w/ some psychological dependence

• sedative hypnotic also classified as CNS depressant 
• first alcohol use in humanity is older than significant written records
• used worldwide for both medical and recreational purposes
• 75% of Americans drink casually/socially
• 10% of users are considered to be problem drinkers w/in social groups
• 5% drink excessively and chronically by DSM standards

• alcohol is bulky drug requiring grams (not mg) to give effect
  • this effect can be seen legally @ 0.08% BAC
  • achieved w/ one drink/hr for every 40lbs of drinker
  • drink = 1.5oz 80-proof liquor; 5oz wine; 12oz beer
• the risk of alcohol behind the wheel is proven statistically
  • as BAL increases, so does risk of car crash
  • this significance of this trend decreases w/age
    • age 16-17 have relative risk of 10 for BAL of less than 25mg/100mL of blood
    • age 35-54 have similar relative risk for BAL of ~150mg/100mL of blood

• very different from other drugs due to small size, polarity, and high water solubility of ethanol molecule
• absorbed easily through GI
• oil/water partition coefficient just high enough to pass BBB, but too low to be sequestered in fatty tissue
• these factors allow alcohol to have fast onset and short duration of action 
• low fat solubility means that females will tend to gain higher BAC from less due higher fat percentage (less water volume in which to dissolve alcohol)

• 90% of ethanol consumed reaches bloodstream w/in 1hr
• absorbed rapidly by entire GI meaning effects can be felt w/in minutes
  • most psychoactive drugs absorbed through GI only absorbed by intestines
• carbonation also speeds up absorption
• process slowed by full stomach

• unlike w/ most drugs, metabolism of alcohol progresses @ constant rate and is independent of concentration
  • zero-order kinetics
  • 15mg/100mL of blood/ hr
• 90% metabolized in liver
• 5% evaporates via lungs
  • idea behind breathalyzer test
• alcohol's metabolic degradation 
  1. alcohol -> acetaldehyde
     • rate-limiting step
     • alcohol dehydrogenase
  2. acetaldehyde -> acetic acid
     • aldehyde dehydrogenase
       • genetic variability of gene for enzyme results in build-ups of higher levels of acetaldehyde
       • asian flush - 50% of asians have altered gene
     • rapid conversion
     • failure of this step/buildup of acetaldehyde is toxic
       • leads to symptoms of facial flushing, sweating, and nausea
       • likely part of physiological effects of alcohol

• Alcohol interferes with the normal metabolic activities of the liver
• Reduces the rate at which the liver forms glucose, oxidizes fats, and releases complex fats
• With extensive exposure to alcohol, fat accumulates causing cell death and fibrosis
• Cirrhosis - severe hardening and contraction of the liver.
• Leads to dehydration through excessive urination as alcohol is inhibitor of ADH/vasopressin

BAL Time-course Following Single Drink

(Four Phases of BAL)

• A - Absorption; takes place much more rapidly than excretion
• B+C - plateau phase
  • B - absorption tapers off
  • C - excretion starts to lower BAL
• D - excretion; absorption complete and alcohol is eliminated @ constant rate (zero-order kinetics)

[image]

• BAC
  • 0.05% - social drink
  • 0.08-0.1% - legally intoxicated
  • 0.5% - lethal
• therapeutic index = 6 (super low; not good)
• why is it safe/difficult to consume lethal dose?
  • vomiting occurs @ 0.12%
    • local irritation to GI tract
    • disturbances in vestibular functioning
    • build-up of acetaldehyde
  • most pass out by 0.35%
  • most alcohol poisoning occurs due to instant consumption of high amounts of high-proof alcoholic beverages

• Many effects of alcohol are nonspecific 
• While other drugs affect specific synapses, alcohol affects almost every aspect of conduction and neuronal transmission
• Membrane fluidity.  Alcohol acts directly on membranes, making them more fluid.  This may interrupt channel activity
  • May inhibit the movement of Na and K ions, therefore interferes with neuron’s ability to generate APs

• enhances activity of GABA receptors
  
  • hyperpolarizes neurons by allowing Cl- entry
  • agonist activity
• decreases activity of some glutamate receptors
  • inhibits excitatory effects at NMDA receptor by blocking ion channel pore decreasing amount of Na and Ca entry
  • antagonist activity
• Net result of all alcohol effects is to decrease excitability of neurons, and reduce spontaneous firing

• alcohol effects wide variety of brain areas and systems
• opioid peptides
  • μ, δ, and κ receptors
  • alcohol releases opioid peptides that facilitate dopamine release (VTA -> NAc)
  • significant correlation between μ receptor availability and alcohol craving in detoxified abusers
• GABA
  • GABA_A receptor
  • increase in GABA functioning during intoxication
  • # of GABA_A receptors decreased w/ chronic use
• Glutamate
  • NMDA and AMPA kainate receptors
  • decrease in glutamate functioning during
  • upregulation of NMDA receptors and increase of glutamate levels w/ chronic use
• Dopamine
  
  • D1, D2, D3, D4 receptors
  • alcohol associated w/ release of dopamine in mesolimbic dopaminergic pathway
• Serotonin (5HT)
  • several receptors, particularly 5HT₃
  • 5HT₃ associated w/ reinforcing the rewarding effects of alcohol
  • 5HT_1A associated w/ alcohol consumption, intoxication, and development of tolerance
  • important in stimulating dopamine release in NAc
    • dorsal raphe nucleus projects to cerebral cortex, Striatum, NAc, SNr, GP, and VP

• Dilates peripheral blood vessels, increasing heat loss from body.  But, drinker may feel warm. 
• Fluid balance – decreases levels of vasopressin which increases urine flow
  • results in decreased fluid retention:  dehydration 
• Hormonal systems:  increases pepsin/stomach acid – causes some people to feel hungry

• Alcohol is a CNS depressant
• Used as an anesthetic until the late 19th century.
• Why not still used for this purpose?
  • Slow metabolism compared to others-long duration of action
  • Low therapeutic index (around 6) – dose for surgical anesthesia close to dose that causes respiratory depression
  • Slows blood clotting
• reduces inhibitions 
  • more assertive, less tense, less anxious, enhanced social interaction
  • can cause hyperexcitation and aggression in some individuals
  • why such seemingly stimulant effects?
    • inhibition of inhibitory neurotransmission from frontal cortex and RAS
    • mechanisms of overall depression of CNS activity
      1. reduction in transmission of inhibitory neurotransmitters
      2. reduction in firing of inhibitory pathways
      3. decreased excitatory neurotransmission
• learning and memory deficits

• Reduces release of inhibitory neurotransmitters
• Reduces firing of inhibitory pathways
• Decreases excitatory neurotransmission

• Alcohol tends to disrupt ongoing psychological processes in a dose dependent manner
  1. At threshold dose, alcohol disrupts complex and abstract learned behaviors (problem-solving and planning)
  2. fine learned motor skills 
  3. gross learned motor skills (walking)
  4. visual accommodation and unconditioned reflexes
• Alcohol produces a loss in memory functions
• Decrease in attention to relevant stimuli
• Decrease in ability to encode new information
• Alterations in short term memory
  • Blackouts, amnesia regarding events during intoxication
• Long term memory also effected in alcohol abusers 
  • Korsakoff syndrome
• Reduced REM in sleep (lower sleep quality)

• Peak blood levels and peak effects do not correspond very well
• Effects are more serious when blood levels are rising than when falling.
  • Suggest development of rapid tolerance called tachyphalaxis
• Rate of BAC increase is important
• Faster it rises, more serious the effects
• Peak behavioral effects of alcohol occur prior to attaining peak BAL, and the behavioral effects dissipate considerably before all the alcohol has left the body

• Exposure to no more than 2 oz per day has no negative health consequences and may be helpful (helpful part is controversial)
• Brain damage – seen in enlargement of ventricles and changes in cortex surface 
• Liver damage
  • Fatty liver
  • Alcoholic hepatitis
  • Cirrhosis
• Wernicke-Korsakoff syndrome
  • Caused by lack of thiamine (vitamin B1)
  • Psychosis characterized by inability to remember recent events and learn new information
• Heart Disease
  • Heavy alcohol use may damage the heart muscle
  • Compounds risk of heart attack from coronary artery disease
  • Moderate use may be protective
• Cancer
  • Statistically increases the risks of some cancers.
  • Notably in liver and also likely in stomach

• tolerance
  • Mechanism -
    • induction of liver enzymes
    • decreased neurotransmission may lead to upregulation and sensitization of postsynaptic receptors
      • Upregulation of NMDA receptors – important in central withdrawal symptoms
  • Behavioral compensation – a big component
  • Little tolerance to lethal effects:  therapeutic index gets even smaller
  • Cross tolerance to other sedative-hypnotics
  • Can take significant effect w/in 7 days
    • tachyphylaxis - immediate tolerance build also associated w/ alcohol
  • serious physical dependence can take months-years to develop

• Dependence
  • A double-whammy.  Both physical and psychological dependence
  • Reinforcing properties due to stimulation of serotonin 5HT₃ receptor
    • important step in release of DA in the nucleus accumbens
  • Serious physical dependence may require months to years to develop
  • Short term withdrawal symptoms are felt after taking a large amount of alcohol = Hangover
•  Hangover
  • Related to
    • High levels of acetaldehyde in brain
    • Lack of sleep
    • Dehydration
    • Low blood sugar
    • Congeners (other alcohols besides ethanol)
  • cured by "hair of dog"/more alcohol
    • actually untrue; only holds off hangover until later
• Withdrawal
  • unlike w/ other psychoactive drugs we have discussed, withdrawal from alcohol and other sedative hypnotics can be lethal
  • comes in four stages
    1. tremors, anxiety, rapid heart rate, hypertension, sweating, loss of appetite, insomnia 
    2. (mostly visual) hallucinations
    3. Delusions, disorientation, delirium. Intermittent in nature and often followed by amnesia 
       • quickly follows stage 2 and may make getting to hospital difficult
       • stage 2 is make or break moment
    4. seizures
       • can occur before stage 3, they can occur together

[image]

• cessation/reduction in alcohol use that has been heavy and prolonged
• two or more of following criteria must develop w/in several hours to a few days of beginning of cessation
  • autonomic hyperactivity
  • increased hand tremor
  • insomnia
  • nausea or vomiting
  • transient visual, tactile, or auditory hallucinations or illusions
  • psychomotor agitation
  • anxiety
  • generalized tonic-clonic seizures 
• criteria oddly loose

• hyperexcitability is one the potentially lethal part of alcohol withdrawal
• compounding effects of NMDA and GABA receptor compensatory mechanisms create perfect storm for excitotoxicity
• NMDA
  • up-regulated during chronic use
  • upon withdrawal, ethanol's effect of blocking ion pores of NMDA receptors is gone
  • Ca⁺⁺ can then enter the cell leading to cytotoxicity
  • also increased ability for excitability of neurons (even w/out cell death or damage)
• GABA
  • GABA receptors become desensitized to combat chronic alcohol use
    • α₁ subunit replaced w/ α₄ subunit
  • during withdrawal, removal of alcohol leads to an inhibited ability for GABA neurotransmission
• both create conditions for the hyperexcitability of neurons

• CRF - corticotropin-releasing factor
  • CRF levels increase in rat amygdala during withdrawal
  • CRF antagonists block anxiety-like behavior
  • Conc: high CRF, high anxiety, high drinking
• NPY - Neuropeptide-Y
  • decreases ethanol self-administration in P rats
  • NPY receptor knock-outs self-administer higher amounts of alcohol
  • Conc: low NPY, high anxiety, increased alcohol consumption

• Medical treatment is usually sought during stage 1 or 2 of withdrawal
• Rapid intervention by administration of a sedative drug will prevent stage 3 or 4
• Withdrawal symptoms do not develop at once. - worst in first 2 to 4 days
• Some symptoms continue for several weeks (unstable blood pressure, panic attacks, anxiety, depression etc.)
• Protracted withdrawal syndrome can trigger intense cravings - justifies for 4-6 week inpatient treatment program.

• heritability rate for alcoholism is 50-65%
• polymorphisms exist for particular genes important in mechanisms of alcohol as well as its metabolism;  
  • GABRG3
  • NPY gene 
  • 5HTT serotonin transporter
  • opioid receptor
  • dopamine D2 and D4 receptor
  • muscarinic acetylcholine receptors
  • acetaldehyde dehydrogenase
    • like acetaldehyde dehydrogenase variability (asian flush)
    • greater sensitivity can make alcohol more unpleasing
• Any given alcoholic has a 50% chance of having at least one family member with alcoholism
• Alcoholic parents have alcoholic children 4-5X more often than non-alcoholic parents.
• If one parent is alcoholic, child has 25% chance; if both parents, 50%!
• Greater familial dominance than any psychiatric illness (including schizophrenia and bipolar disorder)
• twin studies
  • Concordance rate for alcoholism in identical twins is double that obtained for fraternal twins
  • People whose biological parents are alcoholic but were raised by nonalcoholic parents have significantly higher incidence of alcoholism than adoptees whose biological parents were not alcoholics
• Some genetic predispositions may specifically enhance tendency for alcohol abuse
  • Altered levels / isoforms of ADH and/or ALDH
  • Genes associated with lower level of response
    • 5-HT transporter – one isoform results in more rapid reuptake, therefore decreasing synaptic levels of serotonin and minimizing effect of alcohol on the nucleus accumbens
    • GABA_A receptor – mutation in receptors expressed in the cerebellum decrease the effects of alcohol on balance, speech and coordination.  Perhaps an example of innate tolerance. (lower level of response)

• Not all alcoholism has a genetic component
• Probably not related to per capita consumption
• Lowest incidence of alcoholism tied to:
  • Exposure to alcohol in a positive setting
  • Alcohol served in low quantities
  • Abstinence is socially acceptable, but excessive drinking is not
  • Drinking not view as proof of adulthood
  • Well established rules for drinking behavior

• People with a low level of response (LR) have an increased tendency to become alcohol-dependent
• People with a high LR have a decreased incidence of alcoholism
  • Asians with genetic variations in alcohol and aldehyde dehydrogenase have increased responses to alcohol and an almost 0% rate of alcoholism.
• Increased tolerance to alcohol in children of alcoholics
  • Cannot be explained by metabolic tolerance
  • Suggests there may be difference in the brain that result in different susceptibility to the effects of alcohol
  • The less the effect of alcohol, the more likely a person is to drink more!
• Thus, heredity is thought to be the physical predisposition to alcohol.
  • Some genetic predispositions may enhance the risk for problems & dependence for a wide range of substances.
    • Exaggerated feelings of reward when taking a substance
    • Higher levels of impulsivity with associated impaired control of behaviors (including substance use)
    • Vulnerability towards psychiatric disorder
      • E.g. schizophrenia and bipolar disorder both have higher tendency for alcohol &/or drug abuse

• Alcoholics Anonymous (AA)
  • Organization made up of alcoholics
  • Use “12 Step Program” to fight alcoholism on a daily basis
  • Fellowship and spiritual support encouraged
• Behavioral Therapy
  • Attempts to stop alcohol consumption by reinforcing behaviors that are not compatible with it
• Drug Therapies
  • naltrexone
  • disulfiram
  • acamprosate
  • topiramate

• Disulfiram
  • inhibits aldehyde dehydrogenase
  • aim is to increase unfavorable effects of acetaldehyde build-up associated w/ decreased functioning of enzyme in presence of alcohol
  • tests do not show extremely significant differences between placebo and disulfiram users
    • likely not especially effective possibly due to patients being non-adherent to treatment
• acamprosate
  • enhancement of GABA signaling via positive allosteric modulation of GABA_A receptors
  • reduces glutamate surge that accompanies withdrawal making it more bearable
  • showed statistically significant improvements in number of abstinent patients over time in comparison to saline
    • still did not show extremely notable differences
• topiramate
  • enhances action of GABA and decreases action of glutamate
  • showed reduction in percentage of heavy drinking days vs. placebo
• naltrexone
  • competitive antagonist @ all three main opioid receptors 
    • also used to treat opiate addiction
  • intended to decrease rewarding effects of alcohol
  • again, statistically significant functioning, but not notable differences

• active ingredient of the opium poppy isolated in 1805 by Frederic Serturner
• all-natural opiate not chemically altered from opium plant
• invention of syringe made drug far more popular 
  • miracle cure of the Civil War
• substitution of hydroxyl for methoxy produces codeine
  • less analgesic effect but fewer side effects
  • potent cough suppressant 

• semisynthetic opioid
• painkilling derivative of morphine introduced by Bayer in 1898
  • substitution of two hydroxyl groups for acetyl groups
  • increases oil/water partition coefficient
• 3x the potency of morphine
• once it has passed BBB, the acetyl groups are removed turning it back into morphine

• Brand Name:  Sublimaze
• Synthetically made in Belgium in 1950’s
• 80x more potent than morphine
• Today mostly used for anesthesia and neuropathic pain
• Started to be used illicitly in 1970’s in medical community
• Has similar effects of heroin but more potent
• What does that mean for Fentanyl’s dose response curve compared to one for heroin??
  • shifted left
• ROA: IV, transdermal, mucosal membranes (like lollipops in mouth)

• High Efficacy
  • morphine
  • hydromorphone
  • fentanyl
• medium efficacy
  • hydrocodone 
  • oxycodone
• lower efficacy
  • codeine
  • propoxyphene
• Relief of severe pain (analgesic) - medium-strong opiates
  • Serious injury
  • Following surgery
  • Severe burns
  • Cancer
• Treatment of acute diarrhea
• Cough suppression - weak opiates
• Routes of Administration
  •  Oral
    • Pills, liquids, Fentanyl “lollipop”
    • First-pass effect
  • Transdermal 
    • Skin patches
  • Mucous Membranes
    • Suppository
  • Intravenous

• Oral
• Inhalation
  • Smoked
• Mucous membranes
  • Snorted (mostly heroin and fentanyl)
• Subcutaneous
  • Skin popping 
• Intravenous
  • Fentanyl – seconds
  • Heroin – minutes
  • Morphine - ~5min

• oral use and injections are the usual routes of administration (raw opium is sometimes smoked).
  • Chronic pain take orally and maintain constant dose / avoid overdose
  • IV injections produce greatest euphoric properties
• Distribution - high levels usually not found in the brain  (except heroin due to high oil/water partition)
• Excretion - 90% of morphine is metabolized by liver and excreted in urine.  10% excreted as pure morphine. (users may actually try to use the excreted drug)

• Constricts pupils
• Decreases movement of contests in the GI tract, resulting in constipation
• First use:  nausea and vomiting
• Dilation of peripheral blood vessels
• Warm, flushed skin due to dilation of subcutaneous blood vessels
• Itchy skin – due to release of histamines
  • can force doctors to find alternatives for certain patients due to extreme discomfort

• Analgesia - reduces pain
  • Actions in medulla suppress cough reflex
  • Actions in the medulla also decrease rate and depth of breathing
  • Depresses release of neurotransmitters associated with pain
• Reduces “psychological pain” 
  • Acts on limbic system to relieve anxiety and aggression
  • Produces a pleasant mood or euphoria in most users
  • patient may feel physical sense of the irritation, but don't really care about it
• Sedative effects
  • In general, opiates depress neuronal firing rate.  Some neurons may increase firing rate though relief of inhibition
  • Therefore, some people feel only stimulant effects

• sedative/hypnotic effects of opium
  • cerebral cortex
• euphoria
  • limbic system and particularly the NAc
• analgesia
  • brainstem
  • spinal cord
  • thalamus
    • periaqueductal grey
    • Raphe nucleus
    • some others
• respiratory depression, suppression of cough reflex, nausea and vomiting
  • medulla

• Opiates/opioids affect both pre- and postsynaptic receptors throughout many areas of brain and spinal cord
• μ, δ, and κ receptors
  • all are metabotropic (neuromodulatory)
  • activation of opiate receptors leads to decreases in neuronal activity
• opiates bind to these receptors and cause inhibition both pre- and post-synaptically
  • pre-synaptically
    • μ, δ, and κ receptors
    • inhibit calcium entry
    • decrease transmitter release
  • post-synaptically
    • μ receptors
    • stimulate potassium exit from cell
    • hyperpolarizes

• Decrease the duration of action potentials of sensory neurons making contact with the spinal cord
• Decrease release of neurotransmitters
• Hyperpolarizes spinal cord neurons
  • Increase # of open K+ channels
  • Inside of cell less positive

• Increased DOPAMINE within NUCLEUS ACCUMBENS
• Heroin is converted to morphine in the brain, which acts at the mu (μ) and delta (δ) receptors expressed on inhibitory GABA neurons.
• This binding causes a reduction in the amount of GABA released. 
  • Normally, GABA reduces the amount of dopamine released in the Nucleus Accumbens but, by inhibiting this inhibition, dopamine level increase
• This leads to the rewarding/euphoric effects of morphine, heroin, etc.

• enkephalins
• endorphins
• dynorphins
• all are neuropeptides that act as neuromodulators

• Continued use results in tolerance to many of the effects of opiates
• Cross-tolerance occurs with all opiates
• Euphoric properties of opiates probably show the fastest tolerance (decreasing therapeutic index)
• Some effects show little or no tolerance
  • constipation
  • pupil dilation
• Mechanism
  • Metabolic tolerance - slight increase in liver enzymes
  • Receptor desensitization and down-regulation (opiate receptors, or receptors in indirectly affected systems) 
  • Psychological conditioning (context-dependent tolerance) – major when we talk about opiates

• Opiates deliver a double whammy dependence  - physical and psychological
• Psychological dependence
  • Rats will self administer opiates (reinforcing)
  • Acts associated with drug can produce euphoria (Pavlovian conditioning)
• Physical dependence
  • Serious and unpleasant withdrawal symptoms
  • Withdrawal symptoms are the exact opposite of the effect of opiates
  • Intensity and duration of of withdrawal directly related to intensity and duration of drug effects.
  • Opiate withdrawal is never fatal on its own.
  • Withdrawal symptoms usually appear after 6-12 hours, peak in 26-72 hours, and are completely over within a week.

• Intensity and duration of withdrawal is directly related to intensity and duration of drug effects.
  • heroin has high intensity and short duration; this carries over into its withdrawal where symptoms are intense but also last less time
  • methadone has low intensity and long duration; this also carries over into its withdrawal
• Symptoms
  • 6 hours:  drug craving, anxiety, restlessness, agitation
  • 12-14 hours:  Yawning, increased agitation, perspiration
  • 14-16 hours:  hot and cold flashes, goosebumps, tremors, muscle aches
  • 24-36 hours:  Stomach, back, and leg cramps, uncontrolled movement of the extremities (kicking the habit), nausea and vomiting, elevated temperature and profuse sweating
  • 36-48 hours:  fetal position, vomiting, diarrhea
• Won't kill you but unpleasant as hell

• “Detox” – not very effective
• Antagonist treatment
  • Giving an opiate antagonist naloxone to block the effects of opiates
  • also naltrexone
    • therapeutic effects can last up to 3 days
    • no addictive properties
• Maintenance therapy
  • provide agonists that suppress opiate withdrawal, block effects of other opioids, and decrease cravings
  •  methadone
    • long-acting μ-receptor agonist
    • analgesic activity
    • efficacy by oral route
    • extended duration of action in suppressing withdrawal
    • shows persistent effects w/ continuous administration
    • patient must come into clinic daily for administration - constraint
  • buprenorphine
    • similar properties to methadone
    • added bonus of having ceiling effect preventing overdose
    • does not work for highly dependent individuals
• “maturing out”
  • Some addicts spontaneously stop using opiates

• caused by opiate depressing breathing to point of suffocation
• However, many deaths due to opiate “overdose” are not actually due to the opiate.
  • Many addicts that die don’t have a high amount of drug in their bodies
  • Addicts often share bags, but only one may die
• Why?   Most likely due to interactions with other drugs.
  • Fentanyl – ‘get high or die trying’
• Another reason?
  • contextual / behavioral tolerance