Neuropharmacology Chapter 9-Alcohol

Cell loss in brain due to alcohol

Enlarged ventricles due to excessive shrinkage of brain tissue. Smaller brain mass. Frontal lobes are most effected, and this may be responsible for the personality changes, including apathy, disinhibition, and diminished executive functioning (ability to strategice and make decisions), seen in alcoholics. Tissue shrinkage in the medial temporal lobe (hippocampus and cholinergic cells in the basal forebrain) contribute to memory disturbances. Cerebellar cell loss is correlated with ataxia and incoordination, particularly of the lower limbs.

Gender Effects on Alcohol Absorption

Enzymes that are present in gastric fluid (alcohol dehydrogenase) are 60% more active in men. This leaves a higher concentration of alcohol that will be absorbed more rapidly in women. Women have a smaller fluid volume and a higher fat-to-water ratio--this causes higher alch concentration than men.

Gender differences on Alcohol problems

91.2% of men consume alcohol sometime during life, only 83.7% of women do ages 18 and up, heavy drinking reported in 10.2% of men, 3.4% of women binge drinking 32.5% in men, 16.7% in women mens drinking declines in 30s womens are higher between 30s and 40s by 6o, drinking fell for both genders

Relationhip between BAC and Risk for Accident

A clear statistical relationship between BAC and the relative risk for an accidetnt has been reported. BAC interacts with age AND driving experience. BAC < 0.05%= chance of an accident is the same for nondrinking drivers BAC between 0.05% and 0.10%= chance of accident is 7x more likely than nondrinking. BAC > 0.10%= risk increases 20x to 50x more likely

Alcoholism

A form of substance abuse that has been historically difficult to define because the drug is legal and is used by most individuals in a way that does not harm themselves or others *frequency and pattern of use is just as important as the amount of alcohol consumed -diagnoses of alcoholism depends on identifying a cluster of behavioral, cognitive, and physical characteristics *approx, 10% of Americans have an alcohol problem, at least 10.5 million adults are dependent on alcohol

Alcohol Effects

A person's belief that alcohol will produce relaxation, sexual desire, or aggression may have a far greater effect on the individual's behavior than the pharmacological effects of the drug, at least in low/moderate doses. Environment plays less of a role in the effects of alcohol as the dose increases.

Cytochrome P450

A second class of liver enzymes that convert alcohol into acetaldehyde.

Delirium Tremens (DTs)

A small percentage of alcoholics undergoing withdrawal demonstrate more sever effects that are characterized by irritability, headaches, agitation, and confusion. In addition, convulsions, vivid and fightening hallucinations that include snakes/bugs/rats crawling on them, total disorientation, and delirium may occur. Withdrawal signs involved with DTs include unstable blood pressure, depression/anxiety, panic atacks, and sleep disturbences that could last weeks.

Alcohol Absorption

10% Stomach, 90% Small Intestine. Presence of food or milk in stomach slows absorption because it delays movement from into the small intestine. Carbonated beverages are absorbed more rapidly.

"Proof"

Based on British army custom. Testing an alcoholic product by pouring it on gunpowder and lighting it on fire. If alcohol content >50%, the gunpowder burns. If alcohol content <50%, water prevents burning. Therefore, 100% proof that its at least 50% alcohol. Proof number now represents twice the percent alcohol concentration.

Asians lacking ALDH

10% of Asians have an inactive form of the enzyme, causing even small consumption of alcohol to produce high levels of Acetaldehyde. (0% chance of alcoholism) This leads to flushing, nausea/vomiting, headache, tachycardia, dizzyness. 40% are heterozygous, both active and inactive enzymes. Exhibit a more intense response to alcohol, but not necessarily an unpleasant one.

"one drink"

12 oz beer 5 oz wine 1.5 oz liquor 12 oz wine cooler

Prohibition

1917-law passed by congress 1920-law became 18th ammendment prohibited the "manufacture, sale, transportation, and importation" of liquor. Increased organized crime, illegal manufacturing, created speakeasies.

College aged alcohol problems

44.7% of 18-24 year old college kids binge drank in the last month 15% of full time 4 year students suffer alcohol related injury 10% were assaulted by another drinking student more than 5000 deaths per year due to alcohol use in this group only 1% believe they have a drinking problem

Alcohol Tolerance

Decreased response to a drug as a direct effect of repeated drug exposure. The effects of alcohol are significantly reduced when the drug is administered repeatedly.

Sedative-Hypnotic Drugs at Low Dose

Depends on setting. Quiet setting: relaxed, less anxious, sleepy Social setting: reduced social inhibition, gregarious, talkative, friendly, outgoing, overconfident Self-perception and judgement are impaired, which may increase risk-taking behaviors, increases risk of unsafe sex. Significant relationship between alcohol and unsafe sex.

Physical Alcohol Dependence

Developed need for a drug, such as alcohol, by the body as a result of prolonged drug use. Termination of drug use will lead to withdrawal symptoms (abstinence).

Blood Alcohol Concentration (BAC)

The amount of alcohol in a given unit of blood, usually given as a percent representing milligrams of alcohol per 100 milliliters of blood. Behavioral effects are described on the basis of BAC. It takes a BAC of .04% to see measurable effects of alch.

Average Rate of Alcohol Metabolism

The rate of metabolism varies from person to person, but the average rate is 1 to 1.5 ounces or 12 to 18 mL of 80 proof alcohol per hour.

Behavioral Tolerance

The reduced effectiveness of a drug administered chronically that involves learning; either instrumental or classical conditioning. In a novel environment tolerance is significantly less because no conditioning is present.

"Rebound" Withdrawal Symptoms

The signs of withdrawal are characteristically a "rebound" phenomenon and represent a hyperexcitable state of the nervous system after the prolonged depressant effects of alcohol.

Alcohol Diffusion

The small alcohol molecules move across membrane barriers by passive diffusion from the higher concentration on one side (GI tract) to the lower concentration on the other side (blood).

Modern definitions of Alcoholism --Jellinek

"Chronic Alcoholism": includes physical and behavioral consequences of long-term alcohol use "Alcohol Addiction": characterized by craving and lack of control Jellinek is responsible for developing the disease model of addiction, which emphasized the lack of willpower and personal weakness -suggests that once th addiction is formed, individual no longer has control over drug taking behavior

Methyl Alcohol

"Wood Alcohol" Highly toxic if consumed because the liver metabolites include formic acid and formaldehyde. Causes blindess, coma, death. Used as fuel, antifreeze, and industrial solvent.

Why are animal models important for alcohol research?

-Because animals are maintained in a controlled and healthful environment, some of the common human correlates of heavy alcohol are eliminated (poor nutrition, liver damage, use of drugs, psychiatric disorders) -Animal models allow us to use methods that are not appropriate for human subjeccts: controlled chronic alcohol consumption can reveal the long-term damaging effects independent of other issues, such as nutrition or drugs. Invasive procedures can be used to measure neurobiological correlates of intoxication, reinforcement, and behavioral effects of alcohol. -Genetic manipulations are possible. Large numbers of animals are screened, and populations can be selectively bred to create offspring from the heaviest drinkers and for the abstainers. Can also be done with knockout mice to evaluate the role of a specific protein or receptor. -Animal models serve as screening tools for evaluating treatment strategies in humans.

Effects of Alcohol on Dopamine

-DA mesolimbic system plays a role in the reinforcement and motivational mechanisms underlying vital behavior -pathway begins in the VTA-->innervates numerous limbic structures, including the NAcc and the central nucleus of the amygdala -NAcc shell: belongs to extended amygdala, involved in integrating emotion with hormonal responses and sympathetic nervous system activity -Core of NAcc: associated with striatum, modulates movement -afferents to & efferents from the NAcc provide means for combining motivational status, emotional content, and other motor responses *Role of NAcc in substance abuse: supplying the primary reinforcing qualities that lead to repeated drug use and the incentive or motivation for the drug (explains why alcohol is addictive) *increased DA transmission in the mesolimbic pathway occurs in response to administration of most drugs of abuse, including alcohol *alcohol consumption at intoxicating levels increases the rate of firing of DA neurons in the VTA and subsequently elevates the amount of dopamine released in the NAcc (rats in operant chambers self-administer ethanol directly into the VTA, which activates those neurons by inhibiting inhibitory cells) *injection of DA receptor antagonists into the NAcc reduces the self-administration of ethanol in rates, because alcohol=induced DA release is ineffective when postsynaptic receptors are blocked. Chronic Effects: -withdrawal of the drug drastically reduces the firing rate of mesolimbic neurons and decreases DA release in the NAcc. -dysphoria is associated with the alcohol withdrawal syndrome -the reduction in mesolimbic DA is also reflected in a rebound depression of reinforcement mechanisms, as shown by elevation of the threshold for interactional stimulation --*(elevated thresholds mean that more electrical current is needed to activate ther reinforcing pathway) **reinforcement is less rewarding than it was during the initial alcohol use -the down-regulation of the neuronal system that modulates reward may be the neuroadaptive mechanism that is responsible for the negative emotional signs (dysphoria/depression) characteristic of withdrawal -release of DA within the NAcc may be instrumental in ethanol-induced reinforcement *destruction of mesolimbic termicals with 6-OHDA does not abolish self-administration of alcohol, suggesting that other dopamine independent mechanisms contribute to ethanol reinforcement

Training methods to get animals to self-administer alcohol

-In one method, all dry food is presented once a day during the drinking session. Initially, water is available, but gradually increasing amounts of alcohol are added over a number of sessions. Finally, food presentation occurs at a different time, but the animal continue to consume the alcohol. -In another method, after operant training to lever press for a sucros solution, the sucrose is gradually reduced in concentration and alcohol is gradually substituted until the animals are self-administering high levels of alcohol.

Effects of alcohol on Glutamate

-Major excitatory NT in nervous system -Of the subtypes, alcohol has its greatest effect on the NMDA receptor, which is a ligand-gated channel that allows positively charged ions (Ca2+ and Na+) to enter and cause localized depolarizations. -glutamate @ NMDA-->associative learning, damaging excessive glutamate activity (excitotoxicity) *Role of NMDA receptors in effects of alcohol: 1. Memory loss associated with intoxication. 2. Rebound hyperexcitability associated with the abstinence syndrome after long-term use. 3. NMDA-mediated excitotoxicity associated with alcoholic brain damage. *Acute effects of alcohol on Glutamate: -inhibits glutamate neurotransmission by reducing the effectiveness of glutamate at the NMDA receptor. -like other glutamate antagonists, alcohol impairs learning and memory. -alcohol significantly reduces glutamate release in many brain areas, including the hippocampus, associated with spatial memory deficits. -combination of temporary inhibition of NMDA receptors by alcohol and reduced glutamate release may produce the amnesia for the events taking place while drunk. *Chronic effects of alcohol on Glutamate: -a neuroadaptive increase in the number of NMDA receptors (up-regulation) in response to reduced glutamate activity. -number of NMDA receptors is elevated in alcoholics -in alcoholics, glutamate release, normally inhibited by alcohol, is dramatically increased at about 10 hours after withdrawal from alcohol. -Strong positive correlation betwen the magnitude of glutamate output during withdrawal and the intensity of the abstinence signs. -Increased glutamate acting on up-regulated NMDA receptors mau be one neurochemical correlate of alcohol withdrawal. -elevated glutamate activity during withdrawal causes excessive calcium influx, which contributes to cell death. -maternal BAC as low aw 0.04% during the final trimester of pregnancy can impair NMDA receptors and decrease glutamate activity in the newborn. *Reduced NMDA receptors-->impairments in learning and memory in children born to alcoholic mothers.

Effects of Alcohol on Opioid Systems

-a family of neuropeptides (called endorphins) that have opiate-like effects modulate pain, mood, reinforcement and response to stress, among other things Opioids also contribute to the reinforcing effects of alcohol -Alcohol enhances endogenous opioid activity in both rodents and humans. --acute administration of alcohol increases endogenous opioid release from brain slices and the pituitary gland and increases blood levels of opioids in humans in vivo. --opioids released into the blood from pituitary gland --acute administration also increases gene expression of both endorphin and enkephalin in selected brain areas, which increases the amount of peptides available --chronic alcohol use reduces gene expression, making less peptides available for release --chronic use leads to reduced brain levels of endorphin *alcohol-induced opioid release may produce reinforcement by modulating dopamine *reduced opiod levels may contribute to the dysphoria that accompanies chronic alcohol use -If alcohol induced enhancement of opioid systems is at least partially responsible for reinforcement, then blocking opioid recetor should reduce alch consumption --opioid receptor antagonists like naloxone and naltrexone significantly reduce alcohol self-administration -If opioids have a role in reinforcement, we should expect to see a difference in opioid systems of genetic strains of animals that show greater/lesser preference for alcohol --in rat strains that have been genetically bred for alcohol preference, endogenous opioid systems are generally more responsive to the effects of alcohol --alcohol preferring rats have higher baseline levels of mu-opioid receptors in selected limbic areas Opioids play a role in alcohol craving -as the number of mu-receptors increases, the craving scores increase -in the frontal cortex, activation of opioid receptors may impair executive control, leading to an increased probability of relapse

Effects of alcohol on GABA

-major inhibitory amino acid neurotransmitter -binds to GABAa receptor, opens Cl- channel, hyperpolarizes the membrane -sedative-hypnotic drugs enhance the effects of GABA on the GABAa receptor by binding to their modulating sites on the receptor complex -drugs in this class produce many of the same actions and show both cross-tolerance and cross-dependence. -alcohol increases Cl- influx and hyperpolarization -Cl- conducatance and GABA binding to the receptor are necessary for the effects of alcohol to occur -increasing GABA increases alcohol-induced behavioral effects -decreasing GABA function with antagonists reduces signs of ethanol intoxiation and its antianxiety effects -relationship between the ability of ethanol to increase GABA-induced Cl- influc and the intensity of the response to alcohol -alcohol acts on some GABA receptors and not others; some respond only to low doses, others only to high -GABA receptors that are highly sensitive to alcohol contain a delta subunit (instead of gamma), along with a4 and a6 subunits, and are located extrasynaptically -extrasynaptic receptors respond in a more persistant fashion to GABA -->more sensitive to alcohol-->more likely to have a role inthe behavioral and subjective effects prduced by low/moderate levels of drinking -may contribute to alcohol abuse *fewer delta and a4 subunits-->lower preference/consumption of alcohol Chronic Effects of alcohol on GABA: -repeated exposure to ethanol reduces GABAa mediated influx of Cl- -makes animals more sensitive to seizure-inducing doses of GABA antagonist bicuculline -GABA receptors down-regulated dueto chronic alcohol -the neuroadaptive mechanism apparently compensates for the initial GABA-enhancing effect of alcohol and may contribute to tolerance and some of the signs of withdrawal such as hyperexcitability, seizures, and tremors because of reduced GABA-mediated inhibitions. *neuronal excitability is caused by a balance between excitation and inhibition

Diagnostic Signs & Symptoms of FAS

1. Mental retardation and other developmental delays: -average IQ is 68 -average reading level is 4th grade, math level is 2nd grade -delayed motor milestone development -poor coordination, slow response time, language disabilities 2. Low birthweight (below 10th percentile) -infants fail to thrive, exhibit poor catch-up growth 3. Neurological problems -infants born with high alcohol levels and experience withdrawal, including tremor and seizures starting within 6-12 hours of birth, lasting as long as a week -abnormal EEG readings -infant shows high degree of irritibility & hypersensitivity to sound -infant shows poor sucking reflexes, hyperactivity, attention deficits, poor sleep patterns 4. Distinctive craniofacial malformations -small head, small wide-set eyes with drooping eyelids, short up-turned nose, thin upper lip, flattening of the ventrical groove between the nose and upper lip -infants may show low-set and nonparallel ears, malformations of the ear that cause hearing deficits, cleft pallette, reduced lower jaw growth 5. Other physical abnormalties -cardiac defects such as a hole betwen the chambers, or deformed blood vessels in the heart, failure of kidney development, undescended testes, and skeletal abnormalties in fingers and toes.

Effect of alcohol on the Reproductive function

Alcohol is believed to enhance sexual arousal and lower inhibitions, however, expectation plays a large role. There is a serious need to distinguish between psychological arousal and physiological response. Research shows that even though objectively alcohol had minimal effect on arousal, subjectively participants reported increased arousal. *Research supports the inverse nature of physiological and subjective arousal with low/moderate alcohol use* *BAC rises -->physiolocial arousal lowers & subjective arousal increases. Therefore, physiological and subjective are inverse

Alcohol Metabolism Rate

Alcohol metabolism is different from most other drugs. The rate of oxidation is constant over time, and does not occur more quickly when the drug is more concentrated in the blood.

Effects of alcohol on the unborn

Alcohol readily passes through the placental barrier, so the alcohol that a pregnant female consumes is delivered almost immediately to her fetus, who reaches the same BAC.

Lethal BAC

BAC level of 0.45% is lethal in 50% of the population. Most people do not reach lethal levels because at about 0.15% vomiting occurs, and at 0.35% unconsciousness occurs, both preventing further drinking.

18th Ammendment Repealed

Ammendment repealed in 1933 by FDR because it was unsuccessful and had many negative consequences.

Blackout

Amnesia that occurs from high doses of alcohol consumed at a rapid pace. Common for binge drinkers/alcoholics. Occurs in 25% of social drinkers.

Death from acute alcohol ingestion

Caused by depression of the respitory control center in the brainstem. Once respitory mechanism is depressed, drinker can survive about 5 minutes, although brain damage may result from oxygen deprivation.

Conflicting animal research results on FAS

Animal research supports that heavy maternal drinking (binge) is associated with significant behavioral/emotional problems, as well as cognitive deficits in offspring. *Effects of low/moderate maternal drinking are unclear* Some studies show mild effects, some studies show no effects, and other inerestingly show a J-shaped relationship between amount of maternal alcohol and scores on offspring problems. This means that mother who were light drinkers showed FEWER problems than those who were totally absitnent. *They do not know why* This is dangerous because it could lead pregnant women to consume alcohol that may actually lead to negative FAS effects.

Pros VS. Cons of animal models for alcohol

Animals to not naturally develop alcoholsim or even alcohol abuse. So, no direct animal model of the complex human condition with respect to alcohol is possible. The best efforts can model only specific components of alcoholism (biomarkers that contribute to the disorder) These models represent efforts to improve the translational research and move discoveries from animal research more quickly into clinical applications.

Hek

Around 3700 BC the Egyptians prepared the first hearty beer, which was thick enough to stand up a spoon.

What was the first alcoholic beverage?

As early as 8000 BC Mead was brewed from fermented honey, producing the first alcoholic beverage.

Effects of Aspirin on Alcohol Absorption

Aspirin generall inhibits gastric alcohol dehydrogenase, but more so in women than in men. Because women have lower levels of Alcohol Dehydrogenase to begin with, aspirin use before drinking may essentially eliminate any gastric metabolism of alcohol in women.

Specific effects of alcohol

At low/moderate doses, alcohol seems to interact with specific sites on particular proteins, and these specific sites are probably responsible for most of the acute effects of alcohol at intoxicating doses. Alcohol influences several ligand-gated channels and directly alters second-messenger systems. *The ability to identify specific sites of ethanol action ultimately will lead to discovery of new drugs that will compete with ethanol to prevent particular undesirable effects.

Fermented Grains

Beer

Temperance Movement

Campaign to educate society of the dangers of long term alcohol consumption. Lead to groups preaching that alcohol was the cause of all evil in the world.

Alcoholic Cirrhosis

Condition seen in chronic alcohol abusers caused by accumulation of acetaldehyfe in the liver that kills cells, stimulates scar tissue formation, and promotes cell death as scar tissue cuts off blood supplies. Cirrhotic livers are usually firm or hard to the touch and develop nodules of tissue that give them a pebbly apperance. As cirrhosis continues, liver function decreases. Consumption of large quantities of alcohol overa prolonged period of time is necessary for development of cirrhosis, and even amoung heavy drinkers, only 10%-20% are likely to develop the disese. Most common in men 40-60 in age. Damage is irreversible, but cessation of drinking slows the rate of damage. Treatment= liver transplant

Binge Drinkers

Consumption of 5 or more alcoholic drinks in 2 hours. Acute tolerance has a significant impact on binge drinkers. Percieve that they are less drunk on the descending limb, and are more willing to drive, even though their driving performance is significantly worse than on the ascending limb. Binge drinkers responsible for 80% of alcohol-impaired driving accidents.

Yeast

Converts each sugar molecule into two molecules of alcohol and two molecules of carbon dioxide.

Fatty Liver

Damaging effect of alcohol characterized by the accumulation of triglycerides inside liver cells. The liver normally takes up and metabolizes fatty acids as part of te digestive process; however, when alcohol is present, it is metabolized first, leaving the fat for storage. This condition produces no warning symptoms, but is reversible, so if drinking stops, the liver begins to use stored fat and returns to normal.

Ethanol

Ethyl Alcohol. Produced by fermentation. Material that provides sugar in fermentation determines the type of alcoholic beverage created.

Wine

First came from Babylonia in 1700 BC.

Aqua Vitae

First distilled conversion of wine into Brandy.

Alcohol related brain damage

Heavy alcohol use produces a serious deficiency in Vitamin B1 (thiamine) as the result of both poor diet and failure to absorb that vitamin, as well as other nutrients, during digestion. Thiamine is critical for brain glucose metabolism, so its deficit causes cell death.

Prostaglandins

Hormone-like substances that are suspected of mediating teratogenic effects because inhibitors of prostaglandins, such as aspirin, reduce alcohol induced birth defects in animals.

Wernicke-Kursakoff Syndrome

In its first state, it's characterized by confusion, disorientation, tremers, poor coordination, and ataxia (loss of muscle coordination). In later stages, the patient remembers the remote past, yet he remembers almost nothing of what goes on around him. Reads the same page over & over, asks the same question, tells the same story. Syndrome is progressive, but treatment with massive doses of Vitamin B1 can stop the degenerative process (if alcohol use stops), although it cannot reverse it. Characterized by bilateral cell-loss in the medial thalamus and the mammillary bodies of the hypothalamus.

Induction of Liver Enzymes

Increase in liver enzymes specific for drug metabolism in response to repeated drug use. Serves as the basis for metabolic tolerance.

Effects of alcohol alters gastrointestinal tract

Increases salivation and secretion of gastric juices which may explain its ability to increase appetite and digestion, although higher concentrations irritate the stomach lining, and chronic use produces inflammation of the stomach and esophagus. Heavy alcohol use causes diarrhea, inhibits utilization of proteins, and reduces absorption and metabolism of vitamins and minerals.

Alcohol Dehydrogenase

Liver enzyme capable of oxidizing alcohol, found in the stomach, and reduces the amount of alcohol available for absorption. Converts alcohol into Acetaldehyde, a potentially harmful intermediate. More active in men.

Acute effects of alcohol on memory vary with dose

Low Dose: memory defecits are based more on expecation than on quantity of alcohol consumed. High Stress: alcohol may enhance performance by minimizing the damaging effects of anxiety. High Doses: may produce total amnesia for events that occurred during intoxication.

Gender Differences in Alcohol Effects

Males are more likely to be heavy/binge drinkers, however, the number of females who drink excessively is increasing. Alcoholism is 20% in men, and 5%-6% in women Alcohol-induced organ damage and related medical issues are more severe in women and develop more quickly. Female alcoholics have a higher death rate. Since BAC predicts effects of alcohol, women experience more acute effects. Pharmacokinetic differences determine the time course of alcohol levels and the degree of organ exposure, which increase a women's risk and speed up the occurance of potential liver damage, circulatory disorders, breast cancer, fertility impairment, and a range of reproductive problems. Estrogen can speed up liver damage because of its role in inflammatory processes and the use or Birth Control may also contribute. Females are more sensitive to acetaldehyde-induced depression of cardiac contraction, may be reason for higher rates of cardiomyopathy in alcoholic women. Alcohol-induced brain damage and reduced brain colume in women rake fewer years of heavy drinking to cause than men. More vulnerable than men to alcohol-induced brain shrinkage. Thiamine deficiency is greater in alcoholic women, may explain the increased risk for dementia and Wernicke-Korsakoff syndrome. Thiamine reduction (by alcohol) permits an accumulation of lead of female bones, hair and liver. (bc thiamine regulates) Large negative (synergistic) effect on unborn fetus. PET imaging followed alch ingestion showing high release of DA in the NAcc to a greater extent in males. Relationship indicates that heavy drinkers who have a greater potential for addiction, release less DA (only men). *Indicates transition from social drinking-->alcoholic *reason for gender differences unknown; but might be gonadal steroid hormone modulation

Effects of alcohol on gender specific reproductive systems

Males: may become impotent and show atrophy of testicles, reduced sperm production and shrinkage of the production and shrinkage of the prostate and seminal vesicles. Females: disrupted ovarion function and a higher than normal incidence of menstrual disorders.

Benefits of low/moderate dose of alcohol

May reduce the rise of heart disease because it increases the mount of "good" cholesterol and decreases the amount of "bad", and seems to reduce the incidence of blood clots and stroke. *Counteracted when consumption is greater.

Fall of Roman Empire

Members of noble class exhibited confusion and dementia, caused by lead poisening from alcohol prepared with flavor enhancer that had high lead content.

Cause of Alcoholism

No specific cause There are multiple factors that stem from three areas: -neurobiological -psychological -sociocultural

Nonspecific effects of alcohol

Nonspecific actions depend on its ability to move into membranes, changing the fluid character of the lipids that make up the membrane. Protein molecules embedded in that membrane are likely to function differently when their environment changes so dramatically and becomes less rigid.

Acute Alcohol Tolerance

Occurs within a single exposure to alcohol. Several subjective and behavioral drug effects vary in intensity depending on whether the blood alcohol level is increasing or decreasing, regardless if the BAC is the same. Interoceptive cues that determine the subjective evaluation of intoxication undergo acute tolerance. Causes people to "feel" sober even when they are drunk. Failure to accurately predict BAC/amount of impairment leads people to risk driving legally intoxicated. *COULD be caused by some rapid adaptation of neuronal membranes.

Alcohol Metabolism

Of the alcohol that reaches circulation, 95% is metabolized by the liver before it is excreted as CO2 and water in urine. Remaining 5% excreted by the lungs, measured in breath.

Effect of alcohol on the liver

One of the most damagin effects of heavy chronic alcohol consumption is liver dysfunction. Three distinct disorders can develop: Fatty Liver, Alcoholic Hepatitis, Alcoholic Cirrhosis

When are the effects of alcohol the most dangerous?

Organ systems are most vulnerable to damage during the period of most rapid development. Drinking at the time of conception significantly increases risk of teratogenic effects. Drinking during the 4th to 9th week (a time when many are unaware they are pregnant) produces the most severe formative damage and severe mental retardation.

Distillation

Performed after fermentation to raise the alcohol concentration above 15%. Involves heating fermented mixture, passing it through a series of tubes, and condensing it. Creates "hard liquor". 40%-50% alcohol.

Cause of Brain Changes

Probably caused by multiple mechanisms, but glutamate-induced hyperexcitability of neurons during abstinence may play a central role.

Gin

Produced by the dutch. Credited with the start of serious alcohol abuse in Europe. More potent than wine. Very inexpensive. Associated with lower class.

Effect of alcohol on the Renal-Urinary system

Produces larger volumes of urine that is far more dilute than normal. Loss of fluids is caused by reduced secretion of antidiruetic hormone.

Alcohol Placebo Effects

Pronounced behavioral effects occur under placebo condition when the individual believes that he has ingested alcohol.

Acetaldehyde Dehydrogenase (ALDH)

Rapidly converts Acetaldehyde into acetic acid. (This can be followed by further oxidation into CO2, H20 and energy). Prevents the harmful effects of Acetaldehyde. ALDH gene is a marker for low risk of alcoholism.

FAS research done on lab rats to draw conclusions about human FAS

Research has been done to control for other variables that may contribute to birth defects other than alcohol. Early conclusions agree that prenatal alcohol consumption does induce physical/behavior defects. *The pattern of alcohol use that leads to the peak maternal BAC is equally as important as the BAC itself* 12 equally spaced, small doses of alcohol producing a low BAC did not effect fetal brain growth. In contrast, the same total amount of alcohol given in a short period of time raise maternal blood levels to a range between 0.2%-0.35%, and caused a significant decrease in brain weight.

Fermented Rice

Sake

Alcoholic Hepatitis

Serious lethal condtion seen in chronic alcohol abusers caused by accumulation of acetaldehyde (a metabolite of alcohol formed in the liver) in the liver and characterized by inflammation of the liver, fever, jaundice and pain.

Hangover

Some investigators think that "hangovers", even just after a single night of heavy drinking, may be evidence of withdrawal. (others think acute toxicity) Possible explanations for hangover symptoms: residual acetaldehyde in the body; alcohol-induced gastric irritation; rebound drop in blood sugar; excess fluid loss the previous night; toxic effects from congeners, which are small quantities of by-product from fermentation/distillation that may accumulate after heavy drinking. Usual signs: nausea, vomiting, headache, dehydration, fatigue, malaise.

Effects of alcohol on neurotransmitters

Suggets possible connections between neurotransmitter action and specific drug effects of alcohol. No neurotransmitter system works in isolation; changes in each one certainly modify other neurotransmitters in an independent fashion.

What causes the damaging effects of fetal alcohol exposure?

The cause for the damaging effects is unclear. Potentially caused by: Acetaldehyde as a toxic agent Decreased blood flow in the uterine artery Reduced oxygen availability Placental dysfunction (reduces transport of vital amino acids, glucose, folate, and zinc)

Fetal Alcohol Syndrome (FAS)

The damaging developmental effects of prenatal alcohol exposure. Most common cause of mental retardation in the US, even though it can be prevented. There are several diagnostic signs/symptoms of FAS

Cardiovascular Effect of Alcohol

The dilation of peripheral blood vessels which brings them closer to the surface of the skin and makes an individual look flushed and feel warm (Vasodilation). Heat is actually being lost from the body. Drinking alch when you are cold produces and even more serious drop in body temperature. May improve cognitive function in older adults.

CYP 2E1 (Microsomal Ethanol Oxidizing System (MEOS)

The enzyme of importance within the Cytochrome P450 family. Metabolize many drugs in addition to alcohol. Alcohol & drugs must compete for the same enzyme; therefore, alch consumption may lead to high/dangerous levels of the other drugs. Chronic alch consumption leads to an increase in the number of these liver enzymes, which increases the rate of metabolism.

Alcohol Withdrawal

The intensity and duration of withdrawal signs are dependent on the amount and duration of drug taking. Withdrawal signs can be terminated by taking the drug again, or by taking any drug in the same class that shows cross-dependence. Withdrawal from repeated heavy drinking over months/years produces an intense abstinence syndrome that develops within a few hours after drinking stops, and that might last 2-4 days, depending on the previous dose.

Alcohol Content Equation

To calculate the amount of alcohol in a given beverage: multiply the number of ounces in the container X by the percent alcohol content by volume = ethyl alcohol per serving. 5 oz X 21 oz = 0.60 oz

Alcohol Cross-Tolerance

Tolerance to a specific drug can reduce the effectiveness of another drug in the same class. Alcohol has cross-tolerance with a variety of other drugs in the sedative-hypnotic class, including the barbituates and the benzodiazepines.

Alcohol Poisening

Toxis effects associated with the ingestion of excess alcohol, characterized by unconsciousness, vomiting, irregular breathing, and cold, clammy, pale blue skin.

Pharmacodynamic Tolerance

Type of tolerance formed by changes in nerve cell functions in response to the continued presence of a drug. Neurons can adapt to the continued presence of alcohol by making compensatory changes in cell function.

Metabolic Alcohol Tolerance

Type of tolerance to a drug that is characterized by a reduced amount of drug available at the target tissue, often as a result of more-rapid drug metabolism. Chronic alcohol use significantly increases the P450 liver microsomal enzymes that metabolize the drug. More rapid metabolism means that blood levels of the drug will be reduced, producing diminishing effects.

Ulcer Medications Effect on Alcohol Absorption

Ulcer Meds also impair gastric metabolism, increasing alcohol concentrations and hence increasing absorption. Ex.: Tagamet and Zantac

Ethyl Alcohol

Used as a beverage. 2 Carbons, 2 Hydrogens, Hydroxyl group. Cannot be ionized. Mixes with water. Low lipid solubility. Easily absorbed from GI tract and diffuses into most tissues, including the brain.

Isopropyl Alcohol

Used as rubbing alcohol and disinfectant. Dangerous to consume.

Problem with operant self-administration

Used to evaluate the reinforcing effects of various drugs. Self-administration procedures are more difficult with alcohol than other drugs of abuse because most animals will not spontaneously consume enough alcohol to produce intoxication. *However, other "training" methods can be used to get animals to self-administrater alcohol.

Fermented Grapes

Wine

Effects of Alcohol on Sleep

With increasing doses, mild sedation deepens and produces sleep. Alcohol suppresses REM episode (where most dreams occur), and withdrawal after repeated use produces a rebound in REM sleep that may interfere with normal sleep pattersm and produce nightmares.

Alcohol Cross-Dependence

Withdrawal signs occurring in a dependent individual can be terminated by administering drugs in the same class. Barbituates and Benzodiazepines

Psychological factors

one vulnerability factor for alcoholism is response to stress some have used the term "symptomatic" drinking to describe the reinforcing effects of alcohol when stress and tension are relieved. acute stress typically reduces alcohol consumption chronic stress increases it A circular association is seen because alcohol can be shown to reduce stress under some conditions, but alcohol also increases the function of brain and endocrine systems, making alcohol itself an additional stressor that may lead to further alcohol use. acute alcohol administration elevates levels of stress hormones: CRF, ACTH, and gluccocorticoids withdrawal of alcohol after several weeks of chronic use increases anxious behavior anxious behavior can be reduced by blocking CRF receptors, so CRF mediates anxiety *during withdrawal, CRF expression was greater in brain areas regulating anxiety * the fact that stressors frequently lead to further alcohol consumption suggests the potental usefulness of CRF receptor antagonists in preventing relapse