Psychopharmacology 3e Chapter 10 Summary

Alcohol

 

Psychopharmacology of Alcohol

  • The small non-ionized alcohol molecule is absorbed from the GI tract by passive diffusion—a process slowed by food in the stomach. Absorption in women is faster because reduced gastric metabolism and smaller body size increase the concentration.
  • About 95% of ingested alcohol is metabolized by the liver at a constant rate of 1 to 1.5 ounces per hour; about 5% is excreted by the lungs.
  • Alcohol dehydrogenase converts alcohol to the toxic product acetaldehyde. Further metabolism produces carbon dioxide, water, and energy.
  • The cytochrome P450 enzyme CYP2E1 metabolizes alcohol, as well as other drugs. Consuming them together may lead to dangerous blood levels because they compete for the limited amount of enzyme.
  • Acute tolerance occurs within a single drinking episode and may lead to dangerous driving when binge drinkers perceive that they are less intoxicated on the descending limb of the blood alcohol curve.
  • Chronic alcohol use increases cytochrome P450 enzymes (enzyme induction), so metabolism is more rapid, causing metabolic tolerance to the effects of alcohol and cross-tolerance to other drugs metabolized by the same enzyme.
  • Continued presence of alcohol produces compensatory changes in neuron function (pharmacodynamic tolerance).
  • Practicing an operant task under the influence of alcohol leads to improved performance (behavioral tolerance of the operant type). Repeated alcohol administration in the same environment leads to the development of a compensatory response that occurs only in that environment (behavioral tolerance of the classical conditioning type).
  • Alcohol produces physical dependence and cross dependence with other sedative–hypnotic drugs.
  • Withdrawal after chronic heavy use lasts for days and includes tremor, anxiety, high blood pressure and heart rate, sweating, rapid breathing, and nausea and vomiting. Severe withdrawal effects called delirium tremens include hallucinations, convulsions, disorientation, and intense anxiety.
  • Behavioral effects of alcohol are directly related to BAC, but at low doses, the environment and expectations of effects also have significant effects.
  • Dose-dependent effects on the CNS include relaxation, reduced anxiety, intoxication, impaired judgment, impaired memory, and sleep. Higher doses produce coma and death as the result of respiratory depression.
  • Heavy long-term alcohol use causes a vitamin B1 deficiency leading to cell death in the periaqueductal gray, medial thalamus, and mammillary bodies, causing Wernicke’s encephalopathy: tremors, weakness, ataxia, confusion, and disorientation. Multiple brain regions may be damaged by glutamate-induced excitotoxicity. Korsakoff syndrome is caused by permanent damage to thalamic nuclei and brain regions involved in memory subsequent to vitamin B1 deficiency. Symptoms of Korsakoff syndrome include potentially permanent memory loss, personality changes, and hallucinations.
  • Beneficial alcohol-induced cardiovascular effects include vasodilation, elevation of good cholesterol, and lowering of bad cholesterol. Alcohol use disorder increases the risk of high blood pressure, stroke, and heart enlargement.
  • Alcohol has a diuretic effect, increases sexual arousal while decreasing performance, increases appetite, and aids digestion by increasing gastric secretions.
  • Liver damage associated with alcohol use disorder includes fatty liver, alcohol-induced hepatitis, and cirrhosis.
  • Prenatal exposure to alcohol may produce FAS, which is characterized by intellectual disability and other developmental delays, low birth weight, neurological problems, head and facial malformations, and other physical abnormalities. A larger number of infants are affected by a cluster of FAS-related disorders (fetal alcohol spectrum disorders) having highly varied symptom presentation, which makes them harder to diagnose and treat.
  • Effects of prenatal exposure are dependent on blood alcohol level, pattern of alcohol use, fetal developmental stage at time of exposure, maternal nutrition, genetics, and comorbid drug use. Multiple possible mechanisms for alcohol-induced FASD have been identified including maternal alcohol-induced epigenetic effects that alter various stages of neuronal development.

Neurochemical Effects of Alcohol

  • Ethanol has specific actions on multiple neurotransmitter systems but also has nonspecific actions that change the fluid nature of membrane phospholipids.
  • Animal models in alcohol research do the following: (1) control for poor nutrition, liver damage, comorbid drug use, and psychiatric disorders associated with human alcohol abusers; (2) permit the use of techniques inappropriate in humans; (3) allow genetic manipulations; and (4) provide means for investigators to evaluate treatment strategies.
  • Rodent models exist for acquisition and maintenance of drinking, physical dependence, relapse (alcohol seeking), compulsive drinking, and bingetype drinking.
  • Inbred strains of alcohol-preferring and highalcohol-drinking rats provide the means to evaluate behavior, neural mechanisms, and genetics of alcohol use disorders.
  • Alcohol acutely inhibits glutamate neurotransmission by reducing the effects of glutamate at the NMDA receptor and reducing glutamate release.
  • Modulation of glutamate by alcohol has a role in ethanol-induced memory impairment, rebound hyperexcitability during withdrawal, NMDAmediated excitotoxicity causing brain damage, and the intellectual disability associated with FAS.
  • Chronic ethanol up-regulates NMDA receptors in humans and animal models and increases glutamate release, providing an explanation for the hyperexcitability and seizures seen at abrupt withdrawal.
  • Alcohol enhances GABA-induced chloride entry and hyperpolarization by modulating GABAA receptors and stimulating GABA release.
  • The effect of alcohol on synaptic GABAA receptors requires high concentrations that are associated with high levels of intoxication. Extrasynaptic GABAA receptors having δ and α4 or α6 subunits are extremely sensitive to the low concentrations of GABA that remain in the extracellular space, making them more likely to be mediators of low to moderate amounts of drinking.
  • Extrasynaptic GABAA receptors in the shell region of the nucleus accumbens seem to mediate some of the reinforcing effects of alcohol.
  • Chronic ethanol leads to down-regulation of GABAA receptors, making the organism more sensitive to seizure-inducing agents.
  • Alcohol acts on both pre- and postsynaptic metabotropic GABAB receptors and modulates alcohol consumption.
  • Ethanol activates dopaminergic cells in the VTA, causing the release of DA in the NAcc to provide the positive reinforcement that leads to repeated drug taking.
  • In physically dependent rodents, withdrawal of alcohol reduces the firing rate of mesolimbic neurons, decreases DA release in the NAcc, and causes rebound depression of reinforcement mechanisms as shown by an elevation in the threshold for intracranial self-stimulation.
  • Low-frequency tonic stimulation of VTA cells, in contrast to high-frequency phasic stimulation, has produced prolonged low DA efflux and has inhibited compulsive drinking in rats.
  • Acute alcohol increases opioid release and increases gene expression of opioid peptides. Chronic alcohol reduces gene expression and lowers levels of peptides.
  • Blocking opioid receptors with naloxone reduces alcohol self-administration. Mu opioid receptor knockout mice fail to self-administer ethanol. High levels of μ-opioid receptors correlate with scores on craving.
  • Alcohol-preferring rats release more opioids in response to ethanol and show enhanced opioid peptide gene expression.
  • Ethanol modulates the function of many additional neurotransmitters to alter ionotropic and metabotropic signaling.

Alcohol Use Disorder (AUD)

  • AUD involves compulsive alcohol seeking and use despite damaging health and social consequences. Frequency and pattern of drinking are as important as the quantity consumed.
  • Approximately 10% of Americans have an alcohol use problem. There are significant gender differences in alcohol use, binge drinking, and heavy drinking.
  • Defining subtypes of individuals with AUD is important for neurobiological and genetic research, predicting the course of the disorder, and identifying the most effective treatment approach. Babor’s type A and type B have been validated in the general population and are defined by such characteristics as age of onset, childhood risk factors, presence of psychopathology, social impact of alcohol, and so forth.
  • Underage drinking disrupts neurodevelopmental events, causing long-lasting change in neurological function and behavior.
  • Neurobiological, psychological, and sociocultural factors contribute to the vulnerability of a given individual to AUD.
  • Stress reduces or increases alcohol consumption under different conditions. Alcohol increases the activity of the brain stress systems and neuroendocrine stress systems that may lead to further alcohol use. Sensitization to stressors persists long after withdrawal.
  • Early life stress is a risk factor for adult alcohol abuse. Family history is a risk factor and is associated with a greater stress response and greater alcohol-induced suppression of the response.
  • Cortisol sensitizes the DA mesolimbic pathway, which makes drug reinforcement more rewarding.
  • Early (before age 13) drinking, impulse control problems, high novelty seeking, low harm avoidance, and aversion to delayed gratification predict future substance abuse.
  • Genetics explains 50% to 60% of the variance of risk for alcohol dependence. Twin and adoption studies, linkage analysis, association studies, and GWAS provide evidence for a genetic risk for AUD.
  • Genes for the inactive form of aldehyde dehydrogenase, the enzyme that converts the toxic metabolite acetaldehyde, predict low risk for AUD because alcohol has unpleasant effects.
  • Gene polymorphisms for the 5-HT reuptake transporter, associated with anxiety and low sensitivity to alcohol, increase vulnerability to alcohol abuse.
  • Social and cultural factors determine attitudes about drinking and how much alcohol is available. Cultures that restrict use of alcohol have lower rates of AUD.
  • Detoxification under medical supervision is the first step in treatment and is followed by benzodiazepine substitution to prevent withdrawal, and gradual dose reduction.
  • Psychosocial rehabilitation includes individual and group therapies, residential treatment settings, and self-help groups.
  • FDA-approved pharmacotherapies for AUD include disulfiram, naltrexone, and acamprosate. Disufiram inhibits the enzyme that converts acetaldehyde to acetic acid so that alcohol consumption causes very unpleasant effects such as nausea and vomiting, which discourages drinking.
  • Naltrexone is an opioid receptor antagonist that reduces consumption and craving in some individuals with AUD, perhaps by reducing the positive feeling caused by alcohol. Those with a family history of AUD and those with a μ-receptor polymorphism associated with reduced receptor expression respond better to this treatment.
  • Targeting the opioid κ-receptor with an antagonist reduced self-administration only in dependent animals, suggesting that the κ-receptor may have a role in the anhedonic states associated with physical dependence. Blocking μ- and κ-receptors with a dual antagonist like nalmefene may improve abstinence rates in humans.
  • Acamprosate reduces the relapse rate. It reduces the glutamate increase that occurs at withdrawal and returns basal GABA levels to normal in the nucleus accumbens.
  • Promising rodent studies targeting the stress response with CRF1 antagonists suggest that they may be effective in reducing withdrawal-induced increase in consumption, as well as stress-induced relapse behavior.
  • A glucocorticoid receptor antagonist reduced self-administration of alcohol in rodents without altering water or saccharin consumption. The same antagonist reduced craving in response to alcohol cues in humans and reduced drinking.
  • Animal studies suggest that blocking the NK1R for substance P reduces anxiety, alcohol consumption, and relapse behavior after withdrawal. In alcohol-abusing patients, the antagonist reduced craving when patients were exposed to stressand alcohol-related cues. The drug also normalized the brain response to emotional stimuli.
  • The COMBINE study showed the most effect treatment for alcohol dependence is medical management along with either naltrexone or combined behavioral intervention. Since medical management with naltrexone can be provided by family doctors without special training, it provides accessible health care.