Alcohol Action & Effects on Body

Alcohol

• Alcohol oxidization is completed by alcohol dehydrogenase and aldehyde dehydrogenase (ALDH).
• Three genetic variations in ALDH are responsible for diverse individual reactions to alcohol.
• BAC is impacted by differing oral dosages and stomach fullness.
• Ethanol is a "dirty drug", creating varied mechanisms of action.
• It works as a CNS depressant by being a GABA agonist and a glutamate antagonist.
• It also has rewarding effects through dopamine and increased synthesis/release of endogenous opioids.

Alcohol - Receptor Level

• Glutamate: Acute alcohol diminishes glutamate effects at NMDA receptors and reduces glutamate release, while chronic use upregulates NMDA receptors.
• During withdrawal, glutamate release increases, correlated with CNS hyperexcitability, seizures, and excessive Ca2+ influx.
• GABA: Alcohol stimulates GABA release, with some receptors responding to low doses and reinforcing effects.
• Repeated ethanol exposure reduces GABA functions, contributing to tolerance and withdrawal.

Alcohol - Circuit Level

• Ethanol boosts dopamine release in the Nucleus Accumbens (NAc) by inhibiting GABA neurons in the Ventral Tegmental Area (VTA), creating reinforcing effects.
• Alcohol boosts endogenous opioid release from the pituitary gland, where endorphins contribute to reinforcing effects.
• Blocking opioid receptors reduces alcohol self-administration. µ-opioid receptor knockout mice fail to self-administer ethanol.
• Chronic alcohol use reduces accessible endogenous opioids for release.

Alcohol - Tolerance and Withdrawal

• A single exposure to alcohol results in greater effects as blood level rises and smaller effects as it falls.
• After repeated exposure to ethanol, ethanol in the blood is metabolized more quickly.
• Rodent experiments show withdrawal after chronic alcohol use reduces mesolimbic neuron firing and dopamine release in the NAc.

Chronic Alcohol Use and Fetal Alcohol Syndrome

• Chronic alcohol use causes brain damage from the alcohol, acetaldehyde, and inadequate liver function and nutrition.
• Korsakoff's syndrome can occur, leading to progressive permanent memory loss.
  • Results in anterograde amnesia and/or retrograde amnesia.
• Korsakoff's syndrome is related to thalamus damage from chronic vitamin B1 deficiency.
• Chronic alcohol use can cause liver disease.
  • Alcohol is metabolized first and causes triglycerides to accumulate in liver cells.
  • Acetaldehyde accumulation causes liver cell damage, known as alcoholic hepatitis.
  • Alcoholic cirrhosis occurs when death of liver cells stimulates scar formation.
• Alcohol readily passes through the placental barrier, and can cause fetal alcohol syndrome.
  • Fetal alcohol syndrome: intellectual disability, cognitive/behavioral developmental delays, low birth weight, craniofacial malformations, cardiac defects, and kidney development failure

Alcohol - Treatment

• Thiamine (Vitamin B1) treatment can stop degeneration from Korsakoff's syndrome, but will not reverse damage.
• Coffee can fight liver disease.
  • Mixing caffeine and alcohol can result in dangerous effects.
  • Caffeine will mask depressant effects and promote more risky behaviors
• Alcohol use disorder (AUD) treatments
  • Detoxification: Uses Benzodiazepines (BDZs) like Librium and Valium to prevent dangerous withdrawal symptoms.
  • Psychosocial rehabilitation programs: Uses self-help groups or therapy for AUD.
  • Pharmacotherapeutic treatments: Reduces withdrawal symptoms using alternative GABAĀ agonists or Disulfiram/Naltrexone (reduces alcohol consumption and craving).
  • Possible new treatments: CRF1 antagonists, glucocorticoid receptor antagonists, and ketamine.

THC (Tetrahydrocannabinol)

• THC is easily absorbed by the lungs, and blood plasma levels rise quickly.
• Oral administration has a slower time course of onset but lasts much longer
• Metabolites are excreted via feces and urine
  • Complete elimination is slow because THC accumulates in fat tissue.
• Cannabinoid receptors are in many brain areas, including the basal ganglia, cerebellum, and hippocampus.

Cannabinoid Receptor Functions

• CB1 - Principal cannabinoid receptor is present in the brain but can also appear in other organ systems.
• CB2 - Is mainly in the immune system, but can also affect behavior.
• Presynaptic CB1 receptors on nerve terminals have an inhibitory effect on transmitter release.
• CB receptors modulate gene expression which promotes synaptic plasticity, learning, and memory.
• Activating cannabinoid receptors in the hypothalamus increases appetite.

Endocannabinoids

• Endocannabinoids are cannabinoid receptor agonists synthesized by the body like Anandamide and 2-AG.
• 2-AG is a full agonist at CB1 and CB2, and anandamide is a partial agonist.
• Endocannabinoids regulate mood, anxiety, fear, stress, eating, hunger, energy storage, and pain.
• Mechanisms of endocannabinoid signaling include retrograde, non-retrograde, and signals through astrocytes

Cannabidiol

• Cannabidiol is not a cannabinoid receptor agonist.
• Has a similar structure to THC but is not intoxicating or dependence producing.
• Brain imaging shows THC promotes regional brain activation and enhanced blood flow. CBD tends to decrease these processes.
• Not psychoactive, but medically relevant with anti-anxiety, anti-inflammatory, and anti-nausea effects.

Dose-dependent Intoxication

• Cannabinoid effects are based on dose, frequency, user characteristics, the setting, and expectations.
• Marijuana affects cognitive functions like learning, memory, attention, impulse control, and decision making.
• Cannabinoid use impairs hippocampal-dependent learning and memory.
• CB1 receptor agonists impair memory, and THC reduces willingness to expend cognitive effort.

Rewarding and Reinforcing Effects

• THC has some reward and reinforcing properties, but much less than opioids.
• Cannabinoid reinforcement is dependent on CB1 receptor-mediated activation of VTA dopaminergic cell firing and DA release in the Nacc.
• Cannabinoids decrease GABA release, which inhibits the activity of dopamine neurons in the VTA.
  • Increases dopamine release in the nucleus accumbens (NAC).
• Chronic cannabis usage can lead to cannabis use disorder and tolerance.
  • Tolerance involves desensitization and down-regulation of CB1 receptors.
  • May underlie cognitive deficits and motivational differences in CUD.
• Chronic marijuana use may lead to amotivational syndrome, characterized by apathy, aimlessness, reduced motivation, lack of planning, and decreased productivity.
  • Evidence is mixed, as to a causal relationship

Cannabis Impact

• Large-scale studies show a relationship between early heavy marijuana use and a later development of psychotic disorders like schizophrenia.
• Brain imaging studies of chronic cannabis users show lower gray matter volume in some areas, which may reflect changes in dendritic arborization and/or synaptic connectivity.
  • fMRI studies show brain areas are differentially activated in cannabis users vs. controls.

Opioids

• Opioids: all substances that act on opioid receptors to produce morphine-like effects.
• Opiates: drugs derived from opium like morphine.
• Opioid drugs are narcotic analgesics (narcotic = sleep-inducing and analgesic = pain-relieving)
• Morphine is the standard measurement and treats pain, especially in hospital settings.
• Codeine, isolated soon after morphine, is a less powerful pain reliever.
• Heroin is has increased lipid solubility, allowing it to cross the blood-brain barrier more quickly.
• Naloxone is a mu opioid antagonist
• Fentanyl is 80x more potent than morphine
• All have similar structures, producing varied effects.

Opioid Effects and Regions

• Analgesia: Periaqueductal Gray, Spinal Cord, Thalamus
• Sedative (Sleepiness & Daydreams): Cortex
• Euphoria: Mesolimbic (VTA/NAC)
• Dulling of negative emotions: Amygdala/Limbic System
• Respiratory Depression: Brain Stem, Cortex, Periphery
• Suppression of Cough Reflex: Brain Stem
• Nausea/Vomiting: Brain Stem (blood contaminants)
• Opioid receptor-mediated cellular changes are inhibitory. Opioid receptors produce inhibitory effects, primarily in neurons related to pain processing.

Cellular Changes

• Opioid drugs mimic endogenous opioid's inhibitory action.
• Opioid drugs inhibit inhibitory GABA cells, increasing mesolimbic cell firing and dopamine release in the nucleus accumbens (NAC).
• µOpioids inhibit neurotransmission by blocking Ca²+ presynaptically, which reduces neurotransmitter release, and by opening K+ channels postsynaptically, which leads to hyperpolarization.

Opioid Pathways

• The PAG is a nucleus in the midbrain to inhibit pain signals from the spinothalamic tract.
• The mu opioid receptor is a metabotropic receptor.
• Animal testing shows that opioids have significant reinforcing properties
• Reinforcement value and the pattern of opioid use in animals are quite similar to those seen in humans, resulting In:
  • Physical dependence
• Withdrawal or abstinence syndrome
• Cross dependence
• Tolerance to opioid effects in the locus ceruleus (norepinephrine neurons)

Opioid Treatment

• Methadone
• Suboxone
• Opioid antagonist therapy
• Naltrexone

Psychedelic and Hallucinogenic Drugs, PCP, and Ketamine

• Psychedelic drugs: cause changes, visual hallucinations, altered awareness, and cognitive distortions without toxic delirium.
• Types: Lysergic acid diethylamide (LSD), mescaline, psilocybin, bufotenine, dimethyltryptamine (DMT), 5-methoxy-dimethyltryptamine (5-MeO-DMT), salvinorin (Salvia), and ibogaine

Pharmocokinetics of Hallucinogens

• Potency varies widely
  • LSD is most potent, whereas mescaline and ibogaine are the least potent
• Drugs taken orally are effective in 30 - 90 minutes.

Psychedelic Drugs

• Phases of a trip include: onset, plateau, peak, and comedown
• Synesthesia occurs, for example, colors are "heard".
• Physiological responses activate the sympathetic nervous system (pupil dilation, heart rate, blood pressure, and body temperatures and can induce dizziness, nausea, and vomiting.

Psychedelic Drug Actions

• Hallucinogens are 5-HT2A receptor agonists (except ibogaine).
• 5-HT2A receptor knockout mice and humans given 5-HT2A antagonists show no response to these drugs
• Mechanism of LSD is a 5-HT presynaptic receptor partial agonist
• Mechanism of salvinorin A and ketocyclazocine
• Opioid receptor agonists
• Little effect on 5-HT receptors
• Mechanism of ibogaine
• Opioid receptor partial agonists
• NMDA receptor antagonist
• Little effect on 5-HT receptors
• Inhibits 5-HT and dopamine reuptake

Neural Circuitry

• Drug-induced activation of the 5-HT2A receptor increases glutamate release and excitation in the cortex, disrupting a cortico-striatal-thalamo-cortical loop.
• Decreased gating of sensory and cognitive input from subcortical to cortical areas.
• Psychedelic drug therapy: peak experience is the desired state, followed by an afterglow.
• May treat depression, OCD, PTSD, etc.
• A good therapeutic response is related to the intensity of the psychedelic experience.
• Antidepressant actions from rapid glutamate dependent neural plasticity
• Psychedelics are not dependence forming or as addictive for most users
  • Few meet the DSM-5 diagnostic criteria for other hallucinogen use disorder
• Most 5-HT drugs cause tolerance with repeated use, related to 5-HT2A receptor down-regulation
• May induce adverse effects, such as bad trips, flashbacks, and hallucinogen persisting perception disorder (HPPD).
• High doses of a psychedelic can cause toxic psychiatric and/or somatic symptoms.

Phencyclidine (PCP) and Ketamine

• PCP and ketamine are dissociative anesthetics.
• PCP and ketamine are noncompetitive antagonists at the ionotropic NMDA receptor.
• NMDA receptor blockade on cortical GABAergic interneurons increases cortical glutamate release. Glutamate hypothesis of schizophrenia hypoactivity of the glutamatergic system, specifically with NMDA receptor signaling.
• Rodents, humans, and primates test drug and demonstrating the drug's reinforcing properties
• Activate midbrain dopamine cell firing, and stimulates dopamine release in the striatum, nucleus accumbens, and prefrontal cortex
• Chronic use can lead to urological symptoms, GI disturbances, memory deficits, other cognitive dysfunction, gray and white matter abnormalities
• Ketamine is given for immediate relief of depression, before SSRIs. It can be given as a non-opioid analgesic for acute and chronic pain conditions

Schizophrenia and Antipsychotic Drugs

Brain imaging shows cerebral atrophy and ventricle enlargement • Reduced in brain volume is a reduced # of nerve cell somas & dendritic trees and spine density • Hippocampal cells disorganized Abnormal myelination and organization of white matter tracts reduces connectivity between brain regions • Reduced function of PFC Some brain show more activation, and other less Genetic, environmental, and developmental factors interact • Genetic vulnerability may increase probability that events during perinatal brain development will contribute to risk Two hit model of schizophrenia development Perinatal events in a genetically vulnerable individual cause altered brain development • In adolescence, neurodevelopmental errors + environmental produce diagnosable symptoms Four Dopamine pathways of the brain Dopamine hypothesis of schizophrenia Positive symptoms are caused by excessive mesolimbic DA activity • Amphetamine produces positive symptoms that are reversed by dopamine antagonists

• Amphetamines make symptoms worse in schizophrenics Strong correlation between blocking D2 receptors and reducing symptoms Schizophrenics show exaggerated dopamine release after challenge and in basal conditions DA imbalance hypothesis

Symptoms of Schizophrenia

• Reduced DA function in mesocortical neurons, plus, excess DA function in mesolimbic neurons
• Negative symptoms and impaired thinking explained by impaired (low activity) PFC function
• Positive symptoms are improved by reducing dopamine in mesolimbic neurons
• The neurodevelopmental model
• Integrates anatomical and neurochemical evidence
• Negative/cognitive symptoms result from reduced frontal lobe function
• Excessive mesolimbic DA results from early mesocortical cell loss
• Hypoglutamate hypothesis of schizophrenia
• Inadequate glutamate may explain the apparent increase in mesolimbic DA and decrease in PFC function. Evidences for importance of using NMDA , challenge studies, genetics say hypofunction is central
• Neuroleptics and Atypical Antipsychotics
• Classic (typical) Modeled on blocking D2 receptor Modeled on the extrapyramidal motor system
• 2nd generation (atypical)
• Modeled on blocking 5-HT2 and D2 receptor
• Fewer side effects

Side Effects of Neuroleptics

• Maintenance maintenance therapy to prevent relapse.
• Unpleasant side effects that cause many to patients treatment, so psychotherapy is an importany addition
• Effects block dopamine receptors, which is responsible for therapeutic action
• Blocking dopamine receptors triggers a developing change to cause critical effect takes weeks
• Side effects relate to neurochemical action
• Four brain pathways help understand drug action:
• Mesolimbic pathway: effects positive
• Mesocortical pathway: cognitive and negative
• Nigrostriatal pathway: motor
• Tuberohypophyseal pathway: affects production
• Parkinsonian symptoms extrapyramidal Incidence dyskinesia increases with amount of treatment Blockade of receptors (dopamine) that regulate stimulation in the pituitary, produce endocrine, decreased inhibition and weight Is life-threatening (Neuroleptic) malignant and includes fever, altered, and autonomic nervous

Antipsychotics

• Reduces positive ones without side effects that selective reduce antagonists.
• Block other receptor types, for reduces and multiple receptors

Mood Disorders and Antidepressants

• Conditions affect 8% of population and have a lifetime risk of nearly 20% Types of Affective Disorders characterized by extreme exaggeration of mood Major depression disorder episodes of dysphoria, is in behavior Bipolar cyclic swingsmania Damage quality of life Reactive response for loss of a loved one Clinical includes

Depression Symptoms

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Dysfunctional Brain Regions

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Serotonin Issues

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