Combo with Psychopharmacology Exam 3: Cannabis and 2 others

Experiment by Goldstein, Kaizer and Warren

effect on human performance and behavior. - participants asked to rate effects of caffeine on their alertness, physical activity and wakefulness -then given caffeine and tested on ability to detect number in array of numbers flashed on screen for 1/32 second. - also tested on coordination in line-drawing tasks - assessment of their alertness didn't correlate with real abilities = PLACEBO EFFECT

Romberg sway test

- detect impairment - close eyes and feet together - increase in sway could be due to effect of alcohol on sensitive organs of balance in inner ear and its effect on the cerebellum

Aminophylline

- (bronchodialator used to treat asthma) is most widely used methylxanthine preparation. - mixture of theophylline and ethyllenediamine. - ethylenediamine is considered therapeutically inert but it increases the amount of dissolved theophylline 20 times, and therefore speads absorption.

Effects of alcohol on performance

- BAC between 50 and 100 mg/100ml: people are more talkative, use higher pitch of voice, show mild excitement - BAC between 100 to 150 mg/100ml: appear more talkative, loud and boisterous and later sleepy - BAC above 150 mg/100ml: feel nauseous and may vomit followed by lethargy and sometimes stupor - BAC between 200 and 290 mg/100ml: stupor, blackout, loss of understanding and unconsciousness

Unconditioned behavior

- THC has a biphasic effect on spontaneous motor activity (SMA). many species have increase in activity followed by depression in behavior. depressant effect is more powerful, appears in more species, lasts longer, and is more resistance to tolerance - high doses cause staring into space and stuff - taming effect or reduction in aggression. reduces attack behavior and preditory attack behavior is also reduced - THC causes increased preference for sweet things - half as potent at amphetamine at reducing appetite, rats lose weight - analgesic effects. CBN also has analgesic effects but they are only as potent as aspirin. none were found for CBD. metabolites of THC are probably more potent than their parent compound

Oral administration

- THC is a weak acid of pKa of 10.6 and is not ionized at the pH of body fluids - extremely lipid soluble and hardly dissolve in water - taken orally it's absorbed rather slowly from digestive system - when THC is taken in form of pill absorption is also incomplete and erratic and there is considerable first pass metabolism so dose must be doubled or tripled to have same effect as when inhaled - peak effects are usually 1 to 3 hours after ingestion and can last 5 hours or longer after oral administration - more likely to cause nausea and vomiting

Neuropharmaclogy

- a much higher concentration of alcohol is required than most other drugs. alcohol concentration is measured in mM not micromolar or nanomolar - alcohol works by altering neural transmission at receptor sites and ion channels in manner similar to other drugs - effects of alcohol aren't confined to one receptor; it affects many systems at same time and can have different effects on different systems at different concentrations - principal neurotransmitter systems that mediate behavioral effects of alcohol are GABA and glutamate, but it affects other systems as well like glycine, serotonin, acetylcholine, dopamine, and endogenous opioid system

Absorption

- absorbed from the stomach - absorption is more rapid through walls of the intestine

Adenosine

- acts as a neurotransmitter at postsynaptic synapses and as a neuromodulator at presynaptic sites where works mostly by inhibiting the release of a number of neurotransmitters - in general its effect is to inhibit neurotransmission in many synapses of the brain

Reproduction

- acute alcohol consumption may increase interest by diminishing inhibitions but in higher doses it reduces sexual arousal in males and females - low doses may increase duration of erections in males - males experience decreased sensitivity to female social cues and are less able to differentiate between friendliness and sexual interest - high doses decrease sexual arousal in females but moderate doses didn't

Intravenous self-administration in nonhumans

- administered through a cannula implanted in bloodstream. avoids issue of bad taste, CTA, and slow CNS effects and most mice and monkeys learn to self administer but rats are difficult to train this way but do learn to press lever to receive water containing alcohol in various concentrations which they can drink - when infusion readily available self administration is somewhat erratic. periods of high level intake followed by self imposed abstinence lasting 2 to 4 days during which withdrawal may occur. don't follow regular pattern and is similar to human alcohol intake

Perception

- detrimental effect on vision: increases both absolute and difference thresholds but usually only at high doses. - decreases in sensitivity to tase and smell occur at low doses - decrease in pain sensitivity common at BAC over 80 to 100 mg/100 mml changes in visual perception after acute alcohol consumption may be due to decrease in lateral inhibition wherein an excited neuron reduces that activity of neighboring neurons - lateral inhibition is essential process used by many sensory organs to process incoming info

Effects of alcohol on driving

- alcohol begins to affect performance at about 50 t0 80 mg/100ml - significantly disrupts most of brain networks involved in driving dose-dependent manner depending on the task - acute alcohol impairs cognitive control through decrease in cortical activation and in regions implicated in error monitoring like anterior cingulate and inferior frontal gyrus - performance deficits corresponded with decreased activation of orbitofrontal cortex and certain motor regions of the brain - neural basis of alcohol influence on hippocampus, anterior cingulate, and dorsiolateral prefrontal cortex are associated with attentional processing and decision making so intoxicated drivers are less able to orient and detect novel or sudden stimuli like road obsticals - hippocampus processes visuospatial memory

Distribution of alcohol

- alcohol dissolves much more readily in water than in fat so it is distributed almost entirely in body water - individuals with different proportions of fat may reach different BAC after drinking same amount - males have lower body percentage of fat and so women who drink same amount will have higher BAC if similar first-pass metabolism because alcohol is more highly concentrated in blood because less body water to dilute it - age difference in males because male body fat increases with age - distributed rather evenly though out body water - crosses blood-brain barrier and placental barrier without difficulty - alcohol levels in most tissues of body including brain accurately reflect blood alcohol content of drinker which is why breathalyzers can be used because passes through lungs

Alcohol and GABA-alpha

- alcohol is known to only act on GABA receptor complexes that contain a delta subunit in combo with alpha4 or alpha6 subunits - alcohol functions at these receptor complexes as a positive allosteric modulator, enhancing the ability of GABA to open the ion channel - GABA-A receptor complexes with delta subunits are unusual and are sensitive to low levels of GABA and alcohol and appear to have specialized functions. believed to be located in two places in relation to neuron. extrasynaptic receptors. 1. post synaptic membranes, but not at GABA synapse. these are normally activate by spillover GABA that diffuses from a GABA synapse. function is to enhance a tonic or long term inhibition of the cell 2. presynaptic membrane where they enhance transmitter release into the cleft, and intensify the inhibitory effect of GABA - alcohol sensitive GABA-A receptors containing delta subunit are located in the cerebellum which is responsible for balance, coordination, and motor control. - purkinje neurons which are responsible for cerebellar output are stimulated by low concentrations of alcohol but at higher doses the alcohol releases GABA from connecting cells and this inhibits the purkinje neurons. the alterations in purkinje cell output cause many of impairments in motor control caused by alcohol

Absorption

- alcohol is normally administered orally and absorption takes place in the digestive tract - molecules of alcohol can't be ionized so neither the pH of the digestive system or the pH of the blood has an effect on absorption - alcohol readily dissolves in water and may pass into the blood from the stomach, intestines, or colon - absorbed most rapidly from the small intestine - as long as alcohol is in the stomach it is exposed to high levels of alcohol dehydrogenase, the main enzyme for breaking down alcohol - the stomach is where first-pass metabolism of alcohol happens and it's catalyzed by alcohol dehydrogenase - after solid food is consumed the digestion process usually keeps food in the stomach for a period of time before released in small quantities so the longer the alcohol stays in the stomach, the more slowly it will be absorbed into the blood and more is broken down through first-mass metabolism causing the overall level of alcohol to be lower - in general alcohol absorption is faster on an empty stomach and more will get into the body - peak blood levels are higher when no food in stomach but peak will occur at about same time and will take about same time for blood levels to return to zero

Heart disease and alcohol

- alcoholic cardiontyopathy: degeneration of heart muscle. likely arrises from effect alcohol has on metabolism of membrane of cells of heart muscle - moderate consumption can reduce risk, high consumption increases it

Discriminative stimulus properties

- animals can be trained to very easily discriminate alcohol from saline - using electrified T-maze found rats trained to discriminate alcohol from saline generalized the alcohol response when given barbiturate and vice versa but after additional tests can discriminate between alcohol and barbiturates - stimulus property of alcohol can be blocked by serotonin 5-HT receptor blockers but not by haloperidol, a dopamine D2 blocker - indication that serotonin rather than dopamine may mediate the subjective effects of alcohol - discriminative effects can be blocked by mu-selective doses of the opioid receptor blocker naltrexone, showing opioid system also involved in subjective effects - alcohol is known to increase release of endogenous opioids - effects of ethanol on both GABA and NMDA glutamate receptors have separate stimulus effects that can be differentiated experimentally

Loss of control associated with alcohol

- assumed that exposure to one or two drinks will cause relapse of alcoholic - theory that alcoholics can never be social drinkers and need to abstain forever - no significant support - studies in lab show that alcoholics can in fact moderate alcohol intake - could be due to poor impulse behavior control but no evidence that loss of control is inevitable from one drink - reinstatement: learned self administration response stopped to point no longer respond and administration of small dose causes self administration response to resume. social drinkers are more likely to choose an alcoholic drink and report increased craving for alcohol after given a dose of alcohol. also demonstrated in lab animals. not loss of control - loss of control theory only applies for alcoholics and alcohol

Discriminative stimulus properties

- at dose of 32 mg/kg rats can be trained to discriminate between caffeine and saline in a two-lever skinner box. rats generalize the state produced by caffeine to lower doses of caffeine and higher doses of theophylline but no generalization to nicotine. - share some subjective effects of cocaine and amphetamine at least at low doses - discriminative effects of caffeine can be blocked by antagonizing dopamine receptors - adenosine A1 receptors can prevent caffeine discrimination, but presence of an A2A receptor blocker does not alter caffeines discriminative effects, in fact it counteracts the ability of A2 receptor blockers to interfere with the stimulus effects of caffeine

Chronic tolerance to alcohol

- develops fairly rapidly in humans and nonhumans - maximal tolerance develops in a few weeks and reaches point where dose increases 30 to 50% a to reach same effects - disappears in rats after 2 to 3 weeks of abstinence but develops more quickly with repeated exposure

Harmful effects of caffeine on reproduction

- at high enough levels caffeine will damage chromosomes. doesn't usually occur at concentrations normally found in human body. - might enhance chromosome damaging activity of other agents like x-rays - can affect fetus by mechanisms like raising level of circulating catecholamines, which could reduce blood flow to the fetus - studies in animals show low levels of caffeine slow embryonic and neonatal growth - effects on human reproduction and growth show maternal caffeine intake was related to retardation in fetal growth - impossible to demonstrate a casual effect using correlational methodology so hard to know what's true - suggested that women of reproductive age should limit caffeine to 300 mg per day - pregnant women should abstain from all caffeine just in case - methylxanthines are found in high concentrations in breast milk. because rate of methylxanthine metabolism in newborns is so low even small amounts could accumulate to possibly toxic levels so should limit caffeine consumption when breast feeding too

Neuropharmacology

- at least two types of receptors which are both coupled to second messenger systems that use cyclic AMP as the second messenger - CB1 receptor: found primarily in the CNS. concentrated primarily in the cortex, hippocampus, cerebellum, and substantia nigria but also occur in the hypothalamus, brainstem, and spinal cord. located mostly in neurons on the terminal buttons: presynaptic and enzyme that destroys endocannabinoids is located in the cell body and dendrites of the postsynaptic cell - CB2 receptor: located mainly outside the nervous system altogether. found primarily in the spleen and immune system and are structurally different from those found in the brain. seem to be associated with effects of cannabinoids on immune functions. can also be affected by CBN. study found that it is found in the brain as well and its activation may have protective effect against destruction of neurons by immune system. this could be used to slow progression of neurodegenerative disorders like huntingtons and alzheimers

Antabuse (disulfiram)

- blocks action of aldehyde dehydrogenase, the enzyme that breaks down acetaldehyde - drinking alcohol without aldehyde dehydrogenase leads to build up of acetaldehyde in body and makes you feel sick - taking it regularly prevents drinking because will be ill but people who want to drink can simply stop taking drug - people motivated enough to take it regularly will be motivated enough to not drink

Three species

- c. sativa 1. hemp 2. psychoactive - c. indica - c. ruderalis

Distribution of caffeine

- caffeine crosses the blood-brain barrier and placental barriers without difficulty and reaches all body organs but the rates of entering and leaving the organs may vary - about 10 to 30% of the caffeine in the blood becomes bound to protein and trapped in the circulatory system - caffeine is present in all body fluids, including breast milk - theophylline and theobromine are less lipid soluble than caffeine and are slower getting through the blood-brain barrier

Effects on human performance and behavior

- caffeine is associated with improvements in cognitive function and performance - caffeine improves mood and makes tasks seem easier. this often leads to belief that performance has improved when it actually hasn't so subjective reports aren't reliable - effect of caffeine on performance may be placebo effect - caffeine is capable of reversing decrements in performance caused by boredom, fatigue, drugs, caffeine withdrawal, and the common cold. - caffeine improves attention and speeds both simple and choice reaction times - improvements have also been seen in reaction times on visual, cognitive, and verbal reasoning tasks in regular coffee users who weren't experiencing withdrawal as well as in non-coffee consumers

Self-administration in nonhumans

- caffeine isn't a robust reinforcer in lab animals - only reinforcer under limited circumstances and not able to support a lot of behavior - study where bar pressing delivered an intravenous caffeine infusion but only 2 out of 6 monkeys self-administerd the caffeine spontaneously. the 4 monkeys that didn't voluntarily self-administer it were given automatic infusions of caffeine for a period of time. this succeeded in establishing caffeine as a reinforcer in 3 of the 4 remaining monkeys. pattern of self-administration was irregular and no tendency to increase dose over time - though not robust reinforcer has been shown to potentiate reinforcing effects of cocaine and will act as a primer for cocaine (injection of caffeine will reinstate previously extinguished cocaine self-administration in rats. this can be blocked by administration of dopamine receptor blockers

Effects on unconditioned behavior of nonhumans

- caffeine will increase spontaneous motor activity of mice in an open field with maximum effects appearing at 20 to 40 mg/kg doses. - a dose of 80 mg/kg will greatly decrease spontaneous motor activity. - increases in activity are also produced by theophylline at similar doses but some evidence that theophylline may be slightly more potent than caffeine - chronic treatment with caffeine results in depression of spontaneous activity - LD50 of caffeine for rats and mice is about 250 mg/kg by intraperitoneal administration. - death may be due to convulsions but some die at lower doses from bleeding as result of attacking themselves - automutilation observed in rats with dosage of 185 mg/kg for 14 days. bite tails and paws though seem to retain sense of pain.

Effects on sleep

- causes drowsiness and increases sleeping time in humans but high doses can interfere with sleep, causing restlessness and insomnia - high doses disrupts normal sleep stages

Tolerance

- chronic administration of caffeine causes an up regulation in the number of adenosine receptors, presumably as in an attempt to restore the influence of adenosine prior to caffeine - tolerance demonstrated in rats. 100mg/kg injection would depress bar pressing on an FI schedule to about 40% saline control rates. after 8 injections the dose could only depress responding to 75% of baseline. chronic treatment with caffeine shifted the caffeine dose response curve to right by a factor of 6. this means after exposure to caffeine a six-fold increase in dose was required to produce same effect as before exposure - human experiments shown caffeine has less effect on heavy coffee drinkers than nondrinkers - many effects of caffeine seem to disappear within a week at usual levels of consumption. - some acute effects of caffeine like effect on spontaneous motor activity and susceptibility to convulsions reverse with chronic treatment

Cannabinoid system within CNS

- contribute particularly to functions involved in stress recovery - evidence CB1 receptors are important in reinforcing effects and development of physical dependence on opioid drugs such as morphine and heroin - few cannabinoid receptors are found in the medulla in the brain stem which isn't surprising because they have little effect on breathing reflex

Concentration of alcohol and absorption speed

- diffusion rates increase with increase in concentration - alcohol from drinks with high alcohol content diffused into blood faster than same amount of alcohol mixed in weaker concentration - upper limit to this though because high alcohol concentrations slow down rate at which stomach empties contents into the intestine and thus can interfere with absorption - most rapid absorption is at about 40% alcohol

Other effects of alcohol

- diseases of digestive system like ulcers, cancers, and inflammation - disorders of the pancreas - pneumonia and other lung and respiratory diseases - alcoholics are more susceptible to many infectious diseases and are less responsive to treatment

Disinhibition and behavior control

- disinhibition is loss of restraint or an inability to withhold behavior under influence of alcohol - causes disregard for personal risk and social norms and long-term consequences in favor of short-term gratification - low doses of alcohol help with anxiety in tasks - go-stop task: will go when signal says go but have trouble stoping at signal. alcohol weakens connections between frontal areas of the cortex and the striatum, a motor region of the brain - alcohol related images tend to be associated with provocative terms

Caffeinism and anxiety

- doses 5 to 10 cups per day caffeine can cause sensory disturbances like ringing in the ears, seeing flashes of light, as well as mild delirium and excitement. (CAFFEINE INTOXICATION) - can be seen after as little as 100 mg for caffeine intoxication - for caffeinism brought on by consumption of more than 1g of caffeine per day and also include psychomotor agitation, twitching, rambling flow of thoughts and speech, irregular heart rhythm, and periods of inexhaustibility - higher doses of caffeine, more than 300 mg are known to induce anxiety - caffeine can also cause panic attacks and increase anxiety in people with panic and anxiety disorders but doesn't have this effect on individuals without these unless used extensively - ability of caffeine to generate anxiety is associated with particular phenotype of A2A adenosine receptor, suggesting this effect is mediated by actions of caffeine on adenosine receptors

GABA-B and alcohol

- effect of alcohol on NMDA receptors is known to interfere with long-term potentiation, a mechanism necessary for formation of memories in the hippocampus - ethanol is known to prevent formation of new neurons in hippocampus (neurogenesis) which could be why alcohol has effect on memory - prefrontal cortex is higher cognitive abilities like impulse control, planning, problem solving, etc. effects of alcohol are similar toeffects of brain damange on prefrontal cortex including impulsivity and impaired synapse control - prefrontal cortex is mostly glutamatergic pyramidal projection neurons, which send axons throughout rest of the brain, and inhibitory GABAergic interneurons, which suppress activity of pyramidal neurons - alcohol impairs cognitive processes

Acamprosate

- effective in suppressing glutamate activity, which is hyperactive in the postwithdrawal phase of alcoholics - goal is to reduce aversiveness of withdrawal and diminish motivation to drink - results are mixed

Acute tolerance to alcohol

- effects of alcohol are more pronounced while BAC is rising than later when BAC is falling - develops during single administration - speed of cognitive performance recovers during declining BACs but alcohol increased errors do not - effects on cognitive functioning depend on dose and prior exposure

Elimination of alcohol

- eliminated in breath, sweat, tears, urine, and feces - between 90 and 98% of all alcohol consumed is metabolized by liver - remaining is metabolized by kidneys, lungs, and through the skin Steps of elimination: 1. rate limiting step. alcohol is converted to acetaldehyde by alcohol dehydrogenase. slowest step in alcohol metabolism. rate at which conversion takes place limits speed of entire process. rate of conversion is determined by amount of alcohol dehydrogenase available and is independent of concentration of alcohol. metabolism usually takes place at steady rate throughout most BACs 2. acetaldehyde is converted into acetyl coenzyme A by several enzymes, the most common being aldehyde dehydrogenase. acetyl coenzyme A is converted mainly into water and CO2 through series of reactions of the citric acid cycle and usable energy is released into body. acetyl coenzyme A is also involved in things like production of fatty acids and steroids and as a result alcohol consumption and its metabolism can alter lots of body chemistry

Endocannabinoids

- endogenous ligands - anandamide - 2-arachidanyl glycerol (2-AG) - N-arachidonoyl dopamine - 2-arachidonoyl glycerol ether - virodhamine - THC is stronger and longer lasting than endocannabinoids - endogenous ligands seem to function more as neuromodulators of many different neurotransmitters than as neurotransmitters themselves. - endocannabinoids are signaling mechanism between postsynaptic cell and presynaptic cell. membrane of postsynaptic cell is depolarized, this triggers release of endocannabinoid at CB1 receptors on the presynaptic membrane, causing ion channels to open and consequently blocking the action potentials as they arrive. result is that the presynaptic neuron is disabled and thus the post synaptic neuron is able to shut down the presynaptic neuron - if neurotransmitter released by presynaptic neuron is inhibitory the result is depolarization induced suppression of inhibition (DSI) - if neurotransmitter is excitatory, the result is depolarization induced suppression of excitation (DSE) - this lasts for tens of seconds and will affect other synapses in the area - when THC is administered it would have same effect of shutting down both excitatory and inhibitory transmission in neurons that have these CB1 receptors in the entire brain for a much longer period of time than would endocannabinoids

Factors affecting absorption

- factors that decrease stomach emptying time like presence of food will SLOW absorption - methylxanthines are BASES so when dissolved in the ACIDIC environment of the digestive system they might be expected to be highly ionized and not lipid soluble. - methylxanthines have very low pKa = .5. - at pH of digestive system and any other pH encountered in the body the methylxanthines won't be ionized at all and will be free to dissolve in any tissue in accordance with their lipid solubility. - methylxanthines are lipid soluble and dissolve poorly in water

Male vs female plants

- female plants grow taller and have denser leaves - males have thicker stems and fewer leaves - female must be fertilized from pollen of male flower to produce seeds. exudes sticky resin

Alcoholism

- first form of drug addiction accepted as a disease - different theories 1. disease theory: not caused by alcohol but is genetic and people are alcoholics from when they are born. everyone starts drinking in same way but some who progress to drink more and more and enter progress to prodromal phase of alcoholism which is characterized by frequent blackouts. these are problem drinkers. some people progress to gamma alcoholics and this progression is marked by loss of control over drinking and physical dependence indicated by high levels of tolerance and withdrawal symptoms like seizures, hallucinations, and the delirium tremens. distinction between gamma and prodromal isn't amount consumed, but presence or absence of physical dependence and loss of control.

Cannabinoid receptors

- found in the nucleus accumbens, and THC increases dopamine levels and activity in the mesolimbic dopamine reward system. likely through potentiation of effects of endogenous opioid peptides, which in turn function as neuromodulators of dopamine transmission - also found in the cerebellum and basal ganglia, and other parts of the extrapyramidal motor system, and the hippocampus

Cultural factors affecting consumption

- generally a male activity - more acceptable in those who engage in physical labor - spree drinking in finland: stay relatively sober with binges occasionally - consume fixed amount every day steadily over the course of the day and exhibit few symptoms of intoxication: france - don't influence rate of alcoholism or rate of alcohol related diseases but may be significant when acute intoxication is important: like when driving

Medically useful effects

- glaucoma: pressure in eyes too high. THC reduces the pressure - a drug that stops nausea and vomiting. useful for chemo - mood disorders and spasticity: people with damaged spinal cords from diseases like multiple sclerosis often have uncontrollable muscle spasms and loss of motor control and pain. effective treatment for spasticity. also for tourettes syndrome - CNS neurons in pain centers become less responsive to pain inducing stimuli after administration of synthetic cannabinoids - blockade of CB1 receptors in the spinal cord increases sensitivity to pain measured by hot plate test - appetite stimulation - reducing psychotic symptoms of schizophrenia and could be useful in treating other mental disorders like bipolar disorder - potential for use as treatment for anxiety, arthritis, dystonia, insomnia, microbial infections, seizures, and tumors

American consumption of alcohol

- goes through cycles - consumption peaks every 60 to 70 years - periods of decline are accompanied by preoccupation with health and morality and public concern over alcohol harm - decline period followed by sharp increase in consumption - US now in decline

Performance

- hand eye coordination can be off - study found impaired ability in inexperience subjects but enhanced with experienced subjects - complex - delay in visual motor response - amount of THC is directly related to level of impairment in performance based testing

Mood changes and getting high

- happy - experience is almost always pleasant but occasionally feelings are of anxiety and foreboding - if taken in social setting everything seems funny - if taken alone have dreamy state reflecting on subjective experience - feel creativity is enhanced - lots of different factors can change mood! - seems after smoking a person becomes more susceptible to being influenced by mood of others

Titration

- hard to titrate it - often over estimate how much need to smoke to get high - in able to adjust intakes accurately in the face of variations in the potency of the marijuana - reinforcing effect of marijuana increase with higher THC potency

Distribution

- highly lipid soluble so distributed to all areas of body according to blood flow but tend to be more concentrated in lungs, kidneys, and bile of liver - only about 1% of administered dose at peak blood concentration actually enters the brain. this is about 2 to 44 micrograms - effect may be delayed because THC levels in brain continue to increase for several hours after drug has been consumed

Benefits of alcohol consumption

- hormesis: toxic at high doses, beneficial at low. from evolutionary adaptation - U-shaped relationship between alcohol consumption and mortality among adults over age 45. has one for coronary heart disease and one for diabetes and ischemic strokes - most conditions where alcohol is beneficial are associated with aging - under 60 relative risk for dying was related to increased risk of dying from any cause (no J/U curve) but for light to moderate drinkers over 60 relative risk of dying was less than for heavy drinkers and abstainers - this research is correlational, not experimental!

Excretion of caffeine

- in humans less than 2% of caffeine is excreted unchanged in urine - remainder is converted to paraxanthine and other metabolites in the liver - for an individual the half life of caffeine is relatively constant, but it may vary from 2.5 to more than 4.5 hours in different individuals, with a mean of 3.5 hours - half lives of theophylline and theobromine are considerably longer than caffeine at 6.2 and 7.2 hours - half life is dose dependent: higher the dose, the longer the half life - half life of caffeine doesn't accumulate over days in the body - nonhuman half lives vary considerably from 11 to 12 hours in pigs and squirrel monkey to 2 hours in the rat

Reproduction and alcohol

- in males chronic consumption causes impotence, shrinking of the testicles, and decrease in sexual appetite - can cause menstrual dysfunctions -Fetal alcohol syndrome: mental retardation, poor coordination, loss of muscle tone, low birth weight, growth deficiency, malformation of organ systems and characteristic facial features like small eyes, smooth area between nose and upper lip, and thin upper lip. - thought to be caused by disruption of neurogenesis, cell migration, cell adhesion, neuron survival, axon outgrowth, synapse formation, and neurotransmitter function - structural abnormalities seen in cortical development, corpus callosum, basal ganglia, hippocampus, and cerebellum - maternal consumption can also cause low birth weight

Subjective effects

- positive effects more reliably detected under restricted set of conditions 1. caffeine is administered to people who are not caffeine users or caffeine users who have been deprived 2. low doses (20 to 200 mg). higher dose, more likely unpleasant effects reported. 3. in individuals for whom caffeine acts as a positive reinforcer

Perception

- increased sensory sensitivity - decreases in sensitivity or no change in auditory, visual and tactile thresholds - these distortions may be due to the physical distribution of CB1 receptors as they are densely located in the inferior colliculus and posterior thalamus, both of which are involved in sensory processing - has analgesic properties - time distortion may be due to decrease in cerebellar blood flow during use as the cerebellum is associated with the body's internal timing system

Alcohol and blackouts

- individuals with BAC of 310 mg/100 ml blood or greater have .5 greater probability of experiencing alcohol blackout 1. grayout: most common. remember bits 2. blackout: less frequent, more serious. don't remember anything. no evidence anything put in long term storage of memory

Route of administration for medicinal purposes

- inhale smoke - rapid absorption - oral administration is slow absorbing and makes titration difficult

Conditioned behavior

- interfere with tasks that require short term memory like the radial arm maze and matching to sample test where animal has to remember stimulus for brief period of time - correlated with suppression of cell firing in rats hippocampus and can be caused by direct injection - THC interferes with timing - increases avoidance responding doesn't increase behavior suppressed by punishment with electric shock

Source of alcohol

- isopropyl alcohol: rubbing alcohol - methanol (methyl alcohol): wood alcohol - ethanol (ethyl alcohol): alcohol we drink isopropyl and methanol alcohols are toxic to be consumed but have similar effects to ethanol

Tolerance

- lab animals tolerance effects of THC on operant behavior develop rapidly depending on dose and route of administration complete tolerance can develop in 5 to 6 days of repeated injections of THC - lasts for more than a month and is cross tolerance between 9-delta-THC with 11-hydroxy metabolite - no tolerance at all to anorexic effect or discriminative stimulus effect - tolerance isn't due to alteration in absorption, metabolism, or distribution of the drug but is associated with decrease in number of cannabinoid receptors in selected brain regions and downregulation/desensitization of cannabinoid receptors - reverse tolerance is observed only outside of lab

Lethal effects of caffeine

- lethal dose in humans is estimated to be between 3 and 8 g (30 to 80 cups of coffee or stay awake pills) taken orally. death results from convulsion and respiratory collapse.

Variety in elimination rates

- lots of variety between individuals - majority of individuals range is between 10 and 20 mg/ml per hour. - also influenced by drinking experience. nondrinkers metabolize alcohol at slightly slower rate - food has effect. eating speeds up rate of metabolism by 25 to 45%. doesn't depend on type of food eaten and probably is result of increased blood flow to liver caused by food in stomach

Effects of alcohol on the body

- low and moderate doses cause dilation of capillaries in skin. why flushed face and feel warm but actually body cools down much faster because they are open - inhibiting antidiuretic hormone (ADH) secretion so increased urination or loss of water but only when BAC is steady or falling

Effects on body

- low and moderate doses of marijuana usually fully apparent within a few minutes after smoking and last about 2 to 3 hours - bloodshot eyes caused by dilation of small blood vessels in whites of eyes. peaks about an hour after smoking - dry mouth and compulsion to drink - intense feeling of hunger. peaks after 3 hours when other effects have declined. eventually shows tolerance - increase in heart rate - muscle relaxation - unpredictable fluctuations in blood pressure and body temp - alterations in perception, euphoria, feeling of well being, and increased appreciation of humor

Withdrawal

- main symptom in lab animals is decrease in locomotor activity and disruption of ongoing operant responding. - in humans most common symptom is headache. also reported drowsiness, decreased energy, and fatigue or lethargy. also decreased motivation for work and impaired concentration, decreased feelings of well-being and self confidence, increased irritability, and flu like symptoms like muscle aches and stiffness and hot and cold spells, nausea, etc. - SEVERITY OF WITHDRAWAL SYMPTOMS IS DIRECTLY RELATED TO THE DOSE - doses as high as 600 mg per day can cause physical dependence after only 6 to 14 days of exposure. - withdrawal symptoms can also be seen at daily exposure of as little as 100 mg per day over longer period of time - withdrawal symptoms usually start within 12 to 28 hours of last coffee intake, peak at 20 to 51 hours, and last 2 to 9 days

Gender factors affecting consumption

- men report more drinking and more drinks - need to take into account body composition = women typically have about same BAC as men when socially drinking

Excretion

- metabolism starts as soon as cannabinoids enter the body - some metabolism in the lungs if inhaled and some in intestines of taken orally but most is in the liver - delta-9-THC is converted primarily into 11-hydroxyl-delta-9-THC, a substance believed to be more active than delta-9-THC and penetrates blood brain barrier more easily - then these substances are rapidly converted into more than 100 other metabolites, with varying effects. most are less lipid soluble and more easily excreted - CBD only has slight effect on its own but has direct effect on metabolism of THC in liver. it blocks the enzyme that metabolizes 9-delta-THC, slows its metabolism, and prolongs its duration of action - CBN may speed metabolism of THC - blood levels of delta-9-THC fall rather rapidly at first because of redistribution. this has a half life of about 30 minutes in humans but is followed by a phase with much slower rates of decline and a half life of about 20 to 30 hours. during this phase the rate of metabolism is limited by rate at which THC is released from body fat into the body, which is quite slow - traces can be detected in the body as long as 30 days later. duration of time that can be detected depends on body composition: it's shorter for people with least amount of body fat - not sure if regular users metabolize and excrete it faster than non users - THC is excreted primarily through the feces (55%) and the urine (20%)

Route of administration

- methylxanthines are normally taken orally. - when given medically the purified drugs can sometimes cause nausea and gastric irritation, especially in children so drugs may be given in form of a rectal suppository or by intramuscular or intravenous routes.

Effects on sleep

- methylxanthines can produce insomnia - effect is increasing the "stability of wakefulness" by increasing length of time to fall asleep and reducing total sleep time - study showed 300 mg of caffeine increased latency of sleep onset from 18 to 66 minutes and reduced total sleep time from 475 to 350 minutes compared to control - lowers acoustic arousal threshold while sleeping so people wake up to sound more easily in the night. variable among individuals - tolerance can build up - can counteract the sleep inducing effects of pentobarbital (tranquilizing medicine). sleep inducing effect of pentobarbital (100mg) given in combo with 250 mg of caffeine produced same effect on sleep as a placebo

Effects of caffeine and methylxanthines on the body

- methylxanthines cause release of epinephrine from the adrenal gland which results in stimulation of the sympathetic nervous system - much of caffeine's effect outside the central nervous system is due to its direct effect on muscles: smooth muscles tend to relax and striated muscles are strengthened - smooth muscle relaxation results in dilation of the bronchi of the lungs and a decrease in airway resistance - theophylline is the most potent methylxanthine in producing this effect so commonly used to treat asthma. - methylxanthines also reduce susceptibility of striated muscles to fatigue - caffeine has different effects on blood flow in different parts of the body. causes constriction of blood vessels in the brain but dilation in the rest of the body. by constricting blood flow to the brain caffeine can reduce headaches caused by high blood pressure. caffeine is in many over the counter headache medicines - high levels of caffeine stimulate the spinal cord. this manifests first as increase in excitability of spinal reflexes. higher doses result in convulsions which can be lethal. - regulatory centers of medulla are also stimulated by high doses, producing an increase in the rate and depth of breathing. - ability to stimulate respiration makes methylxanthines useful in treatment of babies born with breathing difficulties

Neurophysiology of caffeine

- most of all effects of methylxanthines appear to arise from fact that they are ADENOSINE RECEPTOR BLOCKERS - adenosine has many functions in the body - receptors of adenosine often participate in formation of receptor mosaics where two or more receptors become attached to each other and influence each other operation - these can involve same types of receptors or several different types - known to block benzodiazepine receptors but this effect requires higher doses of caffeine than those that normally cause behavioral effects. at dose about equivalent to 10 cups of coffee as many as 20% of benzodiazepine receptors are blocked. no correlation between ability to block benzodiazepine receptors and drug effects - three substances that occur naturally in chocolate resemble anandamide, the endogenous transmitter that works at cannabinoid receptors. other compounds in chocolate have also been found to block metabolism of anandamide. don't cause high but presence might contribute to enjoyment and popularity of chocolate beyond effects predicted by presence of caffeine

Memory

- no effect on ability to recall material already well learned or on recognition memory but disrupts ability to recall words or narrative material - occur primarily in short term memory - temporal disintegration: lose ability to retain and coordinate info for a purpose. likely to remember initial idea but everything else is disjointed - effects similar to symptoms of korsakoffs psychosis, seen in long term alcoholics. hippocampus could play crucial role in this - smaller right hippocampus volume was found to be associated with high cannabis use during adolescence which could be due to neurotoxic effects of THC

Conditioned behavior in nonhumans

- on both FI and FR schedules, alcohol increases rate of responding at low doses and decreases rate at higher doses - trained rats to run down a runway for food but give shock when start to eat. adjusted food deprivation and shock levels until rats willing to run partway down runway but wouldn't touch food. found alcohol would cause rats to approach and eat food immediately but rats given placebo required frequent trials. ethanol will increase response rates that are suppressed by an administer shock = alcohol reduces control of consequences on behavior

DSI and DSE

- operate on neurons that use many different neurotransmitters including 1. norepinephrine (NE) 2. dopamine (DA) 3. serotonin (5-HT) 4. acetylcholine (ACh) 5. histamine 6. opioid peptides 7. GABA 8. prostaglandins - cannabinoids are known to increase synthesis of Ne, DA, 5-HT, and GABA. - cannabinoids can potentiate the actions of Ne, ACh, GABA, and opioid peptides and can alter the functioning of receptors for NE, DA, and ACh.

Naltrexone

- opioid receptor antagonist - oral and extended release injection approved by FDA - blocks activity of the opioid system and shown to reduce normal high or level of intoxication after alcohol consumption - reported to reduce craving for alcohol in abstinent heavy drinkers - modestly effective in preventing relapse to heavy drinking and enhances possibility of complete abstinence from alcohol - respond best if have positive family history for alcoholism and higher baseline rate of craving - can cause side effects including vomiting, diarrhea, and somnolence - extended release injection reported to cause nausea, decreased appetite, dizziness, and some injection site pain

GABA-alpha receptor

- part of a receptor-ionophore complex; contains a ligand-gated channel permeable to Cl- ions. - pentameric: five subunits around central pore. each subunit is a protein or chain of amino acids folded into complex unit. - lots of variability in composition of subunits, each of which is created by different gene. - 8 major types of GABA-alpha subunits: alpha, beta, gamma, delta, epsilon, theta, pi, and ro. - six varieties of alpha subunit, three varieties of beta, gamma and ro, and remaining four have only one variety. -every GABA-A receptor complex is made up of five of the possible 19 subunits put together in variety of combos. - most common type of GABA-A receptor is made of 2 alpha subunits, two beta subunits, and 1 gamma subunit. - most common receptor subunit varieties are alpha1-beta2-gamma2, alpha2-beta3-gamma2, and alpha3-beta3-gamma2. - different GABA-A receptor subunit configurations are found in different parts of the brain so location and variety of receptor complex may determine function and how affected by alcohol. - two actual receptor binding sites for GABA transmitter molecule, each located between interface of an alpha and beta subunit = orthosteric sites. natural ligand (GABA) binds to its specific receptor site. - when orthosteric site is activated the ion channel that forms the central pore of the GABA-A receptor complex opens and lets Cl- influx in, hyperpolarizing the postsynaptic membrane and inhibiting the cell. - GABA-A also has allosteric biding sites. when drug binds to these it can alter the function of the complex by creating conformational change and in turn affect the functioning of orthosteric sites. - GABA-A receptor complexes contain allosteric sites for benzodiazepines located between alpha and gamma subunits - other allosteric sites for alcohol, barbituates, neuroactive steroids, picrotoxin, and general anesthetics are located on membrane-spanning portion of the receptor complex - in most cases activation of the allosteric site doesn't open the Cl- ion channel to cause hyperpolarization, instead it alters binding affinity (forming of receptor-ligand complex) and efficacy (elicitation of a biological response) of GABA to open ion channel - activation of allosteric sites can either enhance effects of GABA or lessen them - if enhancement of GABA than drug is POSITIVE ALLOSTERIC MODULATOR - if GABA effects diminished than drug is NEGATIVE ALLOSTERIC MODULATOR - ALCOHOL IS A POSITIVE ALLOSTERIC MODULATOR!! - different GABA-A receptors associated with different parts of brain and have different functions. also GABA-A receptors made from different subunit combos are differentially sensitive to different allosteric modulators

Cannabinoids

- primary active ingredient is delta-9-THC - found exclusively in cannabis - belong to chemical class terpenophenolics of which 85 are identified in cannabis and delta-9-THC is most psychoactive - cannabinol (CBN) - cannabidiol (CBD): anxiolytic and psychoactive properties - amount of active ingredients depends on preparation and route of administration - new cannabinoids are created during burning, digestion, and metabolism - content changes over time and with time THC can be converted to CBN - not sure which cannabinoids have which effects - highly soluble in alcohol

GABA

- principle inhibitory transmitter in the brain - stimulation of GABA receptors more pronounced in men than women - two types and alcohol affects both but in different manner 1. GABA-alpha. 2. GABA-beta

Hangover

- produced from alcohol produced effects like low blood sugar levels, dehydration, and irritation of linings of digestive system - miniature withdrawal from alcohol! - can be serious for people with epilepsy, heart disease, or diabetes - consuming more alcohol relieves hangover by depressing rebound excitability in same way other depressant drugs used to treat withdrawal

Drug state discrimination

- rats can easily discriminate THC from placebo when administered intravenously, intrperitoneally, orally. - THC won't generalize to CDB but some generalization occurs to CBN - partial generalization to sedative drugs and no generalization to drugs of any other classes - can be blocked by SR-414716A, cannabinoid receptor antagonist

Behavioral tolerance to alcohol

- rats on treadmill. quickly developed tolerance to disruptive locomotor effects of alcohol presumably due to practice - tolerance depends on expectancy: experiment with equal doses of alcohol in familiar form of beer or unfamiliar drink and those who received unfamiliar drink showed poorer performance and rated themselves more intoxicated - voltage gated calcium and potassium ions may be partially responsible for behavioral tolerance. mice with genes for these ion channels taken out developed more rapid tolerance at cellular and behavioral levels than those with active channels

Dopamine and alcohol

- reinforcing effects of alcohol result from increased ability in mesolimbic dopamine system, specifically heightened dopamine release in the nucleus accumbens - normal conditions mesolimbic dopamine neurons are inhibited by GABAergic interneurons synapting on dopaminergic cell bodies within the ventral tegmental area. these GABA interneurons are themselves innervated by GABAergic neurons projecting from nucleus accumbens and ventral palladium - when alcohol consumed the nucleus accumbens and ventral pallidum neurons release increased quantities of GABA onto inhibitory interneurons within the ventral tegmental area, and this decreases their activity - as a result these interneurons release less GABA, thereby diminishing inhibition of ventral tegmental dopaminergic neurons, enabling an increase in firing and in the level of dopamine output in the nucleus accumbens - glutamate activity likely plays a role - nucleus accumbens has GABAergic medium spiny neurons, special type of inhibitory cells that integrate the myriad of signals coming into nucleus accumbens - these receive glutamerergic input from prefrontal cortex, amygdala, and hippocampus and send output to nucleus accumbens and ventral pallidum - ethanols effects on GABAergic, glutamergic, and dopaminergic cells converging in the nucleus are key to its reinforcing effects! - serotonin input is known to further increase activity in ventral tegmental area dopamine neurons

Cancer and alcohol

- related to cancers of mouth, throat, colon, and liver - acetaldehyde has a genotoxic effect and can cause damage to genetic code - alcohol is a solvent for tobacco carcinogens and the reactive oxygen species, which are chemically reactive by products of alcohol consumption may contribute to alcohol's carcinogenic effects - breast cancer?

Genetics of alcoholism

- risk of becoming alcoholic is increased as much as four fold if close relative is an alcoholic - amount of drinking in identical twins is more similar than in fraternal - closer genetic make up more similar drinking problem is Four characteristics under genetic control that contribute to drinking vulnerability: 1. low level of response to alcohol 2. personality characteristics that include impulsivity, sensation seeking, and neuronal and behavioral disinhibition 3. flushing response to alcohol 4. psychiatric symptoms - no single alcoholism gene but linked to several chromosome regions associated with each of these four factors - genes encoding enzymes associated with metabolism of alcohol are most well-established genes that have polymorphisms associated with alcohol dependence: example flushing response is result of genetically controlled inability to metabolize acetaldehyde - need right combo of genetic and environment!

Extracted and synthetic cannabinoids

- sativex: oral spray for treatment of multiple sclerosis and severe neuropathic related cancer pain - nabilone and dronabinol are used to clinically treat anorexia and weight loss in patients with aids and to treat nausea and distress in patients receiving chemo

Withdrawal

- seen after prolonged administration in high doses to nonhumans. not severe and frequently appear as increase in motor behavior - in humans greatest severity are appetite change, restlessness, and thoughts of and craving for cannabis

Self-administration in humans

- self administration is fairly consistent when alcohol is freely available. consumed at high levels for several days followed by self imposed period of low consumption lasting 2 or 3 days during which withdrawal symptoms may appear

Cardiac disease and caffeine

- showed positive relationship between caffeine consumption and cardiovascular disease, but only in individuals with "slow metabolizing" form of the CYP1A2 enzyme (CYP1A2*1F)

Harmful effects of an acute administration of alcohol

- single dose, if large enough, can be lethal. BAC of 300 to 400 mg/100ml usually causes loss of consciousness - BAC of 500 mg/100ml died within an hour or so - highest BAC ever recorded was 1500 mg/ml - death by alcohol usually results from respiratory failure - alcohol is toxic and lethal dose is uncomfortably close to usual social dose. the therapeutic index for alcohol is about 3.3 - alcohol has built in safety features like vomiting and unconsciousness which will occur before death - people who die have to drink large amount quickly and in high concentrations to get lethal dose in body before lose consciousness

Effect of alcohol on performance

- slows rxn time by about 10% at BAC 80 to 100mg/ml - deficits in hand eye coordination - decreased blood flow to cerebellum which has GABA-A receptors with alcohol-sensitive delta subunit - small deficits occur at doses as low as 10 to 20 mg/100 ml - study showed that at low doses many response deficits will disappear if subjects are paid or provided with an incentive to overcome the effects of the drug

Inhalation adminstration

- smoking is efficient route - normal smoking causes about 10 to 25% of cannabinoids in marijuana to enter lungs and virtually all of that enters the body - blood levels of THC peak within 15 minutes and effects may begin to be felt within a few minutes and reach peak about 30 to 60 minutes later - holding in smoke may not contribute much to absorption of THC, the depth of inhalation is much more important than the duration in determining THC absorption - vaporizers allow pulmonary function to significantly improve without reduction in drug use

Harmful effects on of chronic consumption on the liver

- starts with buildup of fatty acids in liver cells - alcoholics frequently get alcoholic hepatitis, which usually develops into cirrhosis, or scaring. liver cells swell and experience cellular hardening, membrane damage, and eventually cell death. eventually can't function and leads to death if alcohol consumption isn't stopped - generally need more than 5 drinks a day for at least 5 years for development of cirrhosis

Metabolic tolerance to alcohol

- stimulation of alcohol dehydrogenase and MEOS by heavy drinking - light to moderate drinkers metabolize alcohol faster than those who abstain

Receptor mosaic involving A1, A2A, D1, and D2 receptors

- studied in the striatum where they determine dopamine effects by integrating the activity of dopamine and glutamate on GABAergic neurons. - effects of methylxanthines on activity in the striatum are further complicated by presence of cannabinoid CB1 receptors, which sit on striatal GABAergic neurons. the sensitivity of these receptors can be enhanced by chronic caffeine administration - net result of these effects is an increased transmission at D2 receptors and modulation of the release of dopamine, glutamate, and acetylcholine

Withdrawal

- two kinds 1. early minor syndrome: symptoms appear 8 to 12 hours after end of drinking but can be seen during latter part of long term drinking. starts in form of agitation and tremors but also muscle cramps, vomiting, nausea, sweating, vivid dreaming and irregular heartbeat. usually over in 48 hours 2. late major syndrome. delirium tremens. last as long as 7 to 10 days. can have hallucinations of bugs and stuff. discomfort, agitation, disorientation, etc. - effective treatment is combo of supportive care and another depressant drug to suppress withdrawal symptoms and things to treat hallucinations and stuff

Glutamate

- used throughout brain as excitatory transmitter - ALCOHOL BLOCKS GLUTAMATE TRANSMISSION - level of excitability of CNS is maintained by delicate balance between GABA and glutamate. - shown in several parts of the brain that acute doses of alcohol at concentrations achieved by normal drinking depress functioning of the ion channel controlled by glutamate and the NMDA receptor - NMDA receptor biding site for alcohol is within ion channel itself and alcohol molecules have effect of blocking ion channel - NMDA receptors composed of many different subunits and there specific subunit configurations that are particularly sensitive to alcohol - effects of alcohol on glutamate and GABA converge. GABA stimulation depresses neural activity and effect of glutamate diminishes excitability. together they lead to suppression of neural activity in particular parts of CNS. as result of chronic exposure to alcohol brain up regulates NMDA receptor ion channel functioning: the brain becomes more sensitive to glutamate as means of compensating for prolonged depression by alcohol. this increase may be responsible for withdrawal symptoms when alcohol is no longer being consumed

BAC

- usually mg of alcohol per 100 ml of whole blood - BAC 80 mg/100ml = .08

Cannabis preparations

- usually smoked in pipe or cigarette or cigar - sometimes backed into things - Bhang from india is similar to marijuana. it's dried leaves of uncultivated cannabis plants or female plants with resin removed. very potent - ganja: made from tops of female plants with resin not removed and is 3 to 4 times more potent than Bhang - Hashish: dried resin from top of female plant. pale yellow when harvested but black when dried. consumed by smoking alone or in mix with tobacco and can be baked into things. also hashish oil - now THC content is raising in percentage. can be up to 30% in crossbred and hydroponically grown marijuana

Harmful effects of chronic consumption on the CNS

- wernike-korsakoff syndrome: loss of memory for past events, inability to remember new material, disorientation and confusion. results from deficiency in thiamin (vitamin B1) - many conditions can be traced to vitamin deficiencies - things like epilepsy, cerebellar syndrome and alcoholic dementia also occur - MRI of chronic alcoholics shows decrease in cerebral blood flow and widespread reduction in brain tissue, including loss of glial cells and neurons in the prefrontal cortex, hypothalamus, cerebellum, and hippocampus - neurodegeneration occurs mainly due to increased oxidative stress and pro inflammatory proteins which are neurotoxic - can also arise from glutamate excitotoxicity, in which high levels of glutamate lead to cell death. normally protected against this by blockade of NMDA receptors and glutamate activity but increased alcohol consumption causes upregulation of glutamine release during hangover and withdrawal. reversed with prolonged abstinence and greatest increase in brain volume are during first month of withdrawal

Oral self-administration in nonhumans

- when alcohol is freely available to rats and monkeys they will drink it but not in quantities to cause obvious intoxication or dependence. resembles human drinking patterns. hard to test because alcohol has bad taste. increase intake by subjecting animal to period of forced consumption when only source of food or water is laced with alcohol. after forced to consume, its voluntary increase may increase. depriving of food or water will also induce to consume higher levels and will sometimes remain high even after food and water returned. can also add sugar. - animal will learn to press lever on a reinforcement schedule for access to oral alcohol - tried to look at genetic basis but could be that you are selecting rats that are unable to learn the conditioned taste aversion rather than ones with genetic disorder similar to alcoholism in humans

Differences in first-pass metabolism

- women have lower levels of alcohol dehydrogenase - abstainers reach lower peak BAC than moderate drinkers - time to reach max BAC after drinking is highly variable but the time to reach beginning of plateau is usually about an hour with peak about 15 minutes later - after a few drinks absorption rates seem to increase and peak and plateau will be reached 20 to 25 minutes sooner - beer passes out of stomach more slowly than other alcoholic beverages so beer creates lower BAC than same amount of alcohol consumed in some other beverage - passage can also be facilitated by carbonation

How is caffeine metabolized?

-caffeine is metabolized by one of the cytochrome P450 enzymes, and the CYP1A2 gene carries instructions for building this enzyme - there are two forms of the CYP1A2 gene 1. CYP1A2*1A: rapid caffeine metabolizers 2. CYP1A2*1F: slow caffeine metabolizers - same amount will have greater effect on a slow metabolizer and may be more likely to have an adverse effect

GABA-beta

-metabotropic - not directly linked to an ion channel but use a second messenger and indirectly control functioning of K+ channel - varieties responsible for different functions 1. works as an autoreceptor on presynaptic membrane of GABA synapses where it stimulates GABA release 2. located on postsynaptic membranes and blocks release of other neurotransmitters by altering calcium channels - GABA-B receptor activity is implicated in levels of cyclic AMP which can alter synaptic plasticity - alcohol is known to alter the function of some subtypes of GABA-B receptors, particularly at dopamine synapses stimulating the release of dopamine

FHP vs FHN

compare alcoholics and nonalcoholics based on difference in biochemistry, personality, or response to alcohol - problem is any difference might be caused by alcohol consume and not alcohol - compare those less likely to become alcoholics with those likely to be before drinking and note differences - FHP: family history of problems. have greater risk. differ in sensitivity of reward circuit - FHN: low risk

Self-administration in humans

Garrett and Griffiths - within subjects design - examined effects of caffeine dependence by maintaining participants for 9 to 12 days on a daily dose of caffein (300mg/70kg per day = caffeine dependent phase) or on a daily dose of a placebo (caffeine nondependent phase). - when switched from caffeine dependent to caffeine nondependent phase participants demonstrated typical withdrawal symptoms - caffeine dependent participants willing to forfeit money to avoid placebo administration and pay more money for caffeine than those in nondependent phase - when dependent, twice as likely to take dose of caffeine vs placebo as when nondependent - study shows people actively avoid caffeine withdrawal and seek effects of caffeine higher doses aren't as reinforcing as lower doses - increasing doses beyond 100mg usually decreases rate of self administration and doses 400 to 600 mg are usually avoided caffeine preference may also be linked to task requirements after ingestion. prefer caffeine when have to do things

Operant and respondent conditioned behavior

Pavlov: showed drug could disrupt conditioned discriminations by increasing response to the negative stimulus. drug produced an increase in excitability of the CNS. - profile of effects of caffeine on operant behavior is similar but not exactly the same as the profile caused by psychomotor stimulants like amphetamine. probably a result of the increased catecholamine release and dopamine activity caused by caffeine - in general caffeine seems to increase avoidance respondence - CAFFEINE CAN'T BE THOUGHT OF AS A MILD AMPHETAMINE

Tea

contains caffeine, theophylline and theobromine. - made from camellia sinuses leaves. best quality leaves are only the bud and the first two leaves of each twig. lesser quality is made from third and fourth leaves.

Alcohol antagonists

RO-15-45-13 - antagonizes only some effects of alcohol mediated by GABA - allosteric binding site on GABA-A contain delta subunit - little likelihood has medical use because doesn't antagonize alcohol's lethal effects so can't be used to treat overdose and it may cause convulsions so couldn't treat alcoholism because alcohol affects so many sites it's unlikely single antagonist could antagonize all of its effects

Brain centers involved in sleep

Ventrolateral preoptic nucleus (VLPO) - located on the subcortical preoptic region - sleep inducing center - when active it causes sleep by generating synchronous activity in the cortex, which shows up on an EEG as slow waves Several other centers in brainstem and midbrain that are waking centers - arouse and desynchronize cortical activity, which wakes up the brain and keeps it active Waking centers and sleeping center send inhibitory axons to each other so control of cortex tends to flip-flop between these centers - after awake for some period of time the sleep center is triggered to become active and it inhibits the waking centers, same thing happens when sleeping for long time. - numerous environmental, neural, and chemical events that trigger the flip-flop but build up of adenosine is one trigger that can activate the sleep center! - caffeine blocks or suppresses this activation by blocking adenosine receptors with the result that you can stay awake longer

When are peak blood levels of caffeine?

after drinking coffee or tea a person completely absorbs caffeine from the digestive system. - peak blood levels of caffeine are reached in about 30 minutes. - peak blood levels of drinking colas or chocolate are between 1.5 and 2 hours. - THERE IS NO SIGNIFICANT FAST PASS METABOLISM

Subjective effects of alcohol

alcohol is biphasic with regard to time and dose - low doses and while blood levels rising it's stimulant and people feel elation and euphoria - high doses and when blood levels falling feel sedation, anger, and depression - in lab mice trained to self administer alcohol showed heightened levels of aggression are due at least in part to GABA modulation in dorsal raphe nuclei

Caffeine and trade export/import

among agricultural and food exports products with methylxanthines are fifth behind meat, dairy products, vegetables, and fish products. - average consumption of caffeine in worlds population is about 70mg per person per day, 90% of which is consumed in form of coffee and tea.

Beneficial effects

coffee consumption may have protective effects against parkinson's disease - in study in men consumption of caffeine from a variety of sources appeared to reduce incidence of parkinson's - also reduce some symptoms of parkinson's such as tremors and the deterioration of motor skills - connection between parkinson's and caffeine might be expected in light of fact that parkinson's is caused by a deficiency in dopamine-producing cells in the substantia nigra, and caffeine increases dopamine activity by blocking adenosine receptors speculated that caffeine may cause weight loss or prevent weight gain and obesity because of its ability to increase metabolic activity and increase energy expenditure consumption of coffee related to reduced risk of developing type 2 diabetes, but not sure if due to caffeine or ingredient in coffee

Most common source of methylxanthines

coffee, tea, and chocolate.

Dissociation

both delta-9-THC and delta-8-THC cause dissociation in rats. unable to transfer to a nondrug state what they had learned in drug state and vice versa. in humans too - not demonstrated for motor skills and perceptual tasks like card sorting and tasks requiring hand eye coordination even though marijuana impaired performance on those tasks

Effects on athletic performance

caffeine in doses of about 6.5 mg/kg has been shown to improve some types of athletic performance. only improves performance in tasks that require submaximal output for long periods of time like running, cycling, etc. - lowers the threshold for the exercise induced beta-endorphin and cortisol release, which may contribute to reported benefits of caffeine on exercise endurance

Three kinds of methylxanthines

caffeine, theophylline, and theobromine. - most widely self-administered drugs in the world.

Caffeine in medicines and food additives

can be found in common analgesics like anacin, weight control aids, allergy relief compounds, and stimulants. -theophylline and caffeine are used as respiratory stimulants for newborn babies and people suffering from asthma.

Alcohol induced behavior

can be responsible for changes in behavior and can cause things like social, psychological, financial, and physical harm to drinker and others - hard to quantify and may not be direct result of alcohol

Caffeine metabolism in newborns

can't metabolize caffeine well. - excrete about 85% of it unchanged in urine, with a half life of about 4 days - adult pattern of metabolism isn't developed until 7 to 9 months

Medicines that increase BAC

cimetidine and ranitidine, which are commonly used to reduce stomach acidity can increase BAC - these drugs are histamine H2-receptor antagonists and the reduce the stomach levels of alcohol dehydrogenase which reduces amount of first-pass metabolism significantly - effect is greater with cimetidine - effects of both are greatest when alcohol is taken on full stomach - on empty stomach there is little first-pass metabolism in digestive system

Metabolism of caffeine in women

closely related to hormone levels - half life in women is longer during luteal phase (after ovulation) than during the follicular phase (before ovulation) - half life of women taking oral contraceptives is twice that of women ovulating regularly - elimination is slowed during pregnancy due to alterations in enzyme levels

Types of adenosine receptors

four types 1. A1: widely distributed in the brain 2. A2A: primarily in the striatum 3. A2B 4. A3 - methylxanthines appear to be effective blockers of A2 and most potently A2A types - both A1 and A2A receptors appear to modulate levels of dopamine in the brain and because methylxanthines block these receptors, METHYLXANTHINES INCREASE DOPAMINE LEVELS - the increase in dopamine is responsible for most of the behavioral and reinforcing effects of methylxanthines

Route of administration and pharmacokinetics

graph made of several phases A. absorption phase when absorption takes place more rapidly than excretion B. plateau phase when absorption tapers and excretion starts to lower alcohol levels. blood alcohol levels peak here. C. same as B but if rapid absorption might have brief period immediately following peak where decline in blood levels is rapid D. excretion phase. alcohol is eliminated from the body at a constant rate

What form is the caffeine in coffee, tea, and chocolate?

it's in the alkaloid form.

How is the CYP1A2 gene stimulated?

it's stimulated or inhibited by medicines and foods. - caffeine metabolism is slowed by alcohol and grapefruit juice - caffeine metabolism is speeded by broccoli - smokers eliminate caffeine twice as fast as nonsmokers - fluoroquinolones (family of antibiotics) slow caffeine metabolism by inhibiting the CYP1A2 gene

Memory

low and moderate levels alcohol affect attention, encoding, storage, and retrieval of info but storage function is most strongly affected - errors in long and short term visual memory increase during declining of blood alcohol

Cocoa

made from seedpods of theobroma cacao. contains both caffeine and theobromine in varying concentrations.

Nonhuman species and caffeine metabolism

metabolized differently and using different enzymes and created different metabolites - have to be careful testing on nonhumans because of this

MEOS system

microsomal ethanol-oxidizing system - alternative to alcohol dehydrogenase system - normally handles 5 to 10% of metabolism of alcohol but increases at higher levels of blood alcohol - activity of MEOS can be doubled or tripled by continuous alcohol consumption which could by why for 50 to 60% of the increased alcohol metabolism induced by heavy drinking, a change which partially accounts for alcohol tolerance - responsible for metabolism of number of other drugs like barbiturates, so if MEOS is stimulated by continuous alcohol use the metabolism of these other drugs will be speeded up and vice versa so alcoholics have lots of resistance to effects of barbiturates and other drugs

Coffee

most common species are arabica and canephora (robusta). roasting only serves to enhance flavor. robusta has twice the caffeine as arabica.

Guarana

paste made from seeds of Paullinia cupana. - 2 to 6% caffeine. - MOST POTENT NATURAL SOURCE OF CAFFEINE - paste molded into sticks or bars and dried in the sun. for use powdered and mixed with water.

Age factors affecting consumption

people drink just as frequently as they age but they tend to drink less on each occasion. can't be explained by body composition changes

What form is caffeine in the medicinal form given in?

salts, which can be more readily absorbed.

Distillation

starts with ordinary fermentation of sugary substance and then when complete the mixture is heated. alcohol has lower boiling point than water so steam given off will have greater content of alcohol. vapor condensed and can be redistilled if wanted. - brandy is result of distilling wine - whisky is distilled from fermented grains

Bone density and caffeine

study showed daily consumption of two to three cups of coffee accelerated bone loss in the spine and body of postmenopausal women who consumed less than the recommended daily source of calcium

Fermentation

sugar dissolved in water and left exposed to air. yeasts consume sugar and multiply rapidly. metabolic process of yeasts convert sugar into ethanol and CO2. - fermented beverages have alcohol levels of about 10 to 15%