PSY316 - Anxiolytics & Ethanol

DSM-5 Criteria for GAD

excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities, the individual finds it difficult to control the worry

GAD Symptoms

restlessness/keyed up/on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance

Exclusionary category of GAD

not caused by physiological effects of a substance or another medical condition (i.e. hyperthyroidism)

Benzodiazepine

drugs first created in 1957, first big blockbuster drug in this category - diazepam (Valium) in 1963

Benzodiazepines differ in duration

alprazolam (Xanax) - short, clonazepam (Klonopin) - intermediate

Depressants and GABA receptor complex

benzodiazepines and ethanol are positive allosteric modulators for GABAa receptors

Hypofunction of GABA receptors

increases risk or anxiety/anxiety disorders,

Brain areas high in GABAa receptors: anxiolytic effects

limbic system amygdala, orbitofrontal cortex, cingulate cortex

Brain areas high in GABAa receptors: side effects

prefrontal cortex - cognitive, hippocampus - amnesia, brain stem - sedation

Amygdala - anxiety

increased amygdala activity during anxiety, reduced GABAa receptor binding found in PTSD or panic disorder patients

Trazodone (Desyrel)

FDA-approved for depression, off-label for anxiety - inhibiting SERT while also being 5-HT2 antagonist

Trazadone side effects

less sexual side effects and sedation compared to SSRIs as only half of NE and histamine (less sedation) receptors blocked

Buspirone (Buspar)

partial agonist at 5-HT1 receptors, 2-3 weeks for therapeutic effect,

Buspirone side effects

less side effects than other anxiolytics, non-sedating, no amnesia, no significant interactions with other GABAergic drugs or alcohol, low abuse potential

Ethanol oral administration

rapid absorption in stomach, intestines - most through upper intestine, food slows allows enzymes more metabolization, ethanol irritates stomach = inc. hydrochloric acid & pepsin

Dose of ethanol

serving or drink defined as alcohol by volume (ABV%) or in grams

Ethanol distribution

distributes easily throughout body fluids and tissues; both water and lipid soluble, freely penetrates BBB + placenta

Ethanol metabolism

20% occurs in stomach = first-pass, 80% in liver

Ethanol —>

acetaldehyde by alcohol dehydrogenase (ADH)

Acetaldehyde —>

acetic acid aldehyde dehydrogenase (ALDH) —> acetic acid —> CO2 & H2O by adenosine triphosphate (ATP)

Disulfiram (Antabuse)

can treat alcoholism by enzyme inhibition of ALDH

Ethanol metabolism depends on

limited pool of enzymes (short-term), sex, ethnicity, body weight, individual metabolism, ~30-120 min/dose, 25% tolerance due to ADH up-regulation

Sex differences ethanol metabolism

women have higher BAC with same # of drinks (~7% inc. in BAC compared to men) due to average higher body fat %, lower alcohol dehydrogenase enzymes in stomach

Ethnic differences ethanol metabolism

high % of East Asians have mutations in ADH gene - headache, dizziness, skin flush, rapid HR, nausea

Main physiological causes of hangover: headache

dilation of blood vessels surrounding brain (intercranial pressure); increased levels of 5-HT (implicated in migraines) and histamine

Main physiological causes of hangover: dehydration (cotton-mouth)

nausea, dizziness, thirst, weakness; ethanol blocks pituitary vasopressin (antidiuretic hormone)

Main physiological causes of hangover: fatigue

low dose ethanol sedates, but sleep quality suffers; reduced REM sleep and inc. BP/HR, sudden drops in blood sugar

Positive allosteric modulator (PAM)

at GABAa receptors

Negative allosteric modulator (NAM)

at Glu NMDA receptors - sluggish Glu receptors, prevents flow of Na+, Ca2+, during withdrawal, Glu over excitation can induce seizures

Ethanol inhibition causes

mesolimbic DA release esp. 1st doses, chronic alcohol downregulates GABAa and upregulates NDMARs (increases stress responses)

Ethanol heavily effects: frontal lobes

impaired executive function, impulse control, judgement, WM

Ethanol heavily effects: amygdala

relaxation, sociability

Ethanol heavily effects: hippocampus

interferes with attention and memory

Ethanol heavily effects: cerebellum and caudate-putamen

impaired coordination (balance) and movement

Naltrexone (Revia)

opioid antagonist, can reduce alcohol cravings - genetic dysfunction in brain’s endogenous opioid system implicated in risk for alcoholism

Naltrexone and ethanol

ethanol —> opioid release —> DA release in NAc so = reduces opioid and DA release

SSRI antidepressants (i.e. Prozac)

can be effective in reducing drinking in lower-risk alcoholic males, chronic alcohol use increases 5-HT activity = downregulate receptors, serotonin dysfunction (mesolimbic pathway) implicated in alcoholism

Glu NMDA antagonist & GABA agonists

drugs have been evaluated (original use = antiseizure + migraine drugs)

Topiramate (Topamax)

decreases heavy drinking days

Acamprosate (Campral)

1st drug designed both for detox and alcohol abstinence