4. psychopharmacology (for exam 2)

agonist

facilitates NT effects

antagonist

inhibits NT effects

precursor

building blocks of NT

which class of drugs usually increase precursors?

agonists

which class of drugs stimulate autoreceptors and how?

antagonists

autoreceptors located on the pre-synaptic terminal buttons — if NT docks, it creates a negative feedback loop that closes the calcium ion channels which create NT release

which class of drugs blocks autoreceptors?

agonists

4 criteria for NT

1. must be found in the neuron

2. with an AP, must be released from terminal buttons

3. must make EPSP or IPSP on target tissue

4. must have a mechanism to “turn it off”

2 ways which NTs can be “turned off”

• enzyme degrades it in the synapse

• reuptake into presynaptic neuron

who discovered the first NT? what is this NT? how did he do it?

Otto Loewi, ACh

• stimulated vagus nerve of frog and saw that it lowered heart rate (parasympathetic, craniosacral vagus nerve)

• then absorbed the NT fluid and put it on another frog’s heart without a vagus nerve, whose HR also declined

acetylcholine (primary NT secreted by what cells, % of CNS neurons it takes up, 2 places where it’s found in the periphery, 2 places where it’s found in the brain)

• primary NT secreted by efferent PNS cells

• 10-15% of all CNS neurons

• in the periphery, neurons found in

  • autonomic ganglia (e.g. the heart)

  • the neuromuscular junction (activation of muscle mvmt)

• in brain, neurons are found in

  • nucleus basalis (mvmt)

  • hippocampus (memory)

ACh synthesis pathway

note: choline is derived from lipid breakdown

2 natural drugs that release ACh

black widow spider venom, botulinum toxin

black widow spider venom (what does it do, where does it work)

• stimulates release of ACh (agonist) to make muscles contract (looks like paralysis)

• usually not lethal; just works at neuromuscular junction

botulinum toxin (what it causes and what it’s caused by, class of drug, what it does)

• botulinism, caused by improperly canned food

• ACh antagonist

• extremely toxic → paralysis, death

hemicholinium

prevents reabsorption of ACh, ACh antagonist

acetylcholinesterase + process it’s involved in

destroys ACh into choline and acetate in the synapse, and ~50% of choline is recycled into new NTs

termination of ACh

neostigmine + what disease it helps

interferes w AChE activity → increases ACh and therefore restores muscle strength for those affected by myasthenia gravis

myasthenia gravis

autoimmune disorder that attacks peripheral ACh receptors

what else inhibits AChE?

insecticides

2 types of receptors (excitatory or inhibitory, where it acts, metabotropic or ionotropic) + give examples of agonists and antagonists

• nicotinic - excitatory (either Na+ or Ca2+), in skeletal muscle, ionotropic (ligand-gated channels)

  • agonist: nicotine

  • antagonist: curare

• muscarinic - inhibitory (mostly K+ channels), acts on heart and other smooth muscle, metabotropic (GPCRs, slower than nicotinic)

  • agonist: muscarine (found in poison mushrooms)

  • antagonist: atropine (blocks receptors; “belladonna”) (prevents parasympathetic arousal)

2 things ppl w alzheimer’s have less of + why?

• ACh

• ACh synthesizing enzyme, choline acetyltransferase

• prolly due to the degeneration of ACh neurons in the hippocampus and inferior frontal lobes

aricept

AChE inhibitor to keep ACh in synapse of still-living receptors

2 types of monoamine transmitters + examples

• catecholamines - dopamine (DA), norepinephrine (NE), epinephrine (EPI)

• indolamines - serotonin (5-HT)

process of making catecholamines

tyrosine → L-DOPA (hydroxyl group was gained) → dopamine (carboxyl group was lost) → norepinephrine (hydroxyl group was gained) → epinephrine

nigrostriatal system (location + function)

projects from the substantia nigra to the mid and hindbrain regions (basal ganglia, substantia nigra)

for motor processing

mesolimbic system (location + function)

projects from ventral tegmental area to the limbic system (tegmentum, nucleus accumbens, amygdala, hippocampus)

involved w emotion

mesocortical system (location + function)

projects from the ventral tegmental area to the prefrontal cortex

involved in thinking, planning

nucleus accumbens

associated w reward/pleasure

what 2 things block DA reuptake?

• amphetamines

• cocaine

so these physiologically addictive drugs INCREASE DA release, and so they feel more rewarding

3 disorders due to catecholamines

• Parkinson’s

• depression

• schizophrenia

Parkinson’s

DA neuron degeneration within the basal ganglia, or btwn substantia nigra and caudate nucleus

depression

decreased catecholamines within, perhaps, all systems

schizophrenia

increased DA within the mesolimbic and mesocortical systems

2 treatments to Parkinson’s

• L-DOPA

• deep-brain stimulation to basal ganglia — often done in later stage Parkinson’s, has IMMEDIATE effects on motor symptoms

reserpine

an antagonist that prevents the storage of dopamine within vesicles by blocking monoamine transporters within the neuron

Monoamine oxidase (MAO-B)

destroys excess DA in terminal button

Deprenyl

blocks MAO-B to increase catecholamines, agonist

ways motor, emotion, and cognition are affected by depression

• motor - increased isolation, decreased activity

• emotion - self-critical thoughts, relative inability to experience pleasure

• cognition - reduced ability to concentrate

foot-shock avoidance in rats experiment

dopamine antagonists decrease “escape” tendency while dopamine agonists increase it

• antagonist rats: 10% escape

• placebo: 50%

• agonist: 90%

related to learned helplessness model of depression

describe CA (catecholamine) levels in depression and mania

aka catecholamine hypothesis of depression

• depression associated w decreased CA lvls within the brain

• mania results from increased CA lvls

abt 15% of humans who take __ for hypertension (to decrease NOR and adrenaline) develop clinical depression

reserpine

tricylic antidepressants (function + 3 examples)

treatments for depression that serve as reuptake blockers; affect primarily both NOR and SER

• amitriptyline (Elavil)

• desipramine (Norpramin)

• imipramine (Tofranil)

side effects of tricylics

• rapid heartbeat and dizziness upon standing

  • prone to overdose (cardiac complications)

• occasionally “anticholinergic effects”

  • dry mouth/eyes

  • bright light sensitivity (dilation of pupils)

  • blurry vision

types of symptoms of schizophrenia + examples

positive symptoms (most recognizable)

• hallucinations/delusions

• disorganized thoughts, speech, and behavior

• stereotyped behavior - repetitive behavior without significant meaning

negative symptoms

• decreased affect

• alogia - decreased verbal output

• avolition - difficulty initiating goal-directed behavior

how did we find the cause of schizophrenia to be increased DA lvls?

found out bc amphetamine blocks DA reuptake → amphetamine psychosis (similar to paranoid schizophrenia)

typical/classic antipsychotics/neuroleptics, what they affect

have more effect on reducing “positive” relative to “negative” symptoms

• chlorpromazine (Thorazine)

• haloperidol (Haldol)

• mesoridazine (Serentil)

• thioridazine (Mellaril)

side effects of antipsychotics

• decreased DA → Parkinson’s disease

• acute dystonia

• oculomotor crisis

• akathisia

• tardive dyskinesia

acute dystonia

uncontrolled mvmt of face, neck, and tongue

oculomotor crisis

uncontrollable eye mvmts

akathisia

restlessness and agitation

tardive dyskinesia

“late appearing mvmt disorder” (starts w neck/tongue and, eventually, can involve the whole body)

atypical antipsychotics + examples + what it’s better at treating

attempt to have more specific effects on psychosis w fewer extrapyramidal side effects (basal ganglia) by targeting receptors as opposed to DA

Zyprexa (D2), Clozapine (D4), Risperdal (D2)

negative symptoms

the __ within __ gives rise to NE (norepinephrine) fiber systems to areas responsible for __ (frontal systems). what system is it a part of?

locus coeruleus, pons, vigilance/attentiveness

sympathetic nervous system

are noradrenergic receptors metabotropic or ionotropic?

metabotropic - slow-acting, diffuse effects

what is NE synthesized from and where?

dopamine within synaptic vesicles

what leads to NE breakdown? what 2 drugs inhibit NE breakdown and how? what are the effects?

excess NE destroyed by MAO-A

• moclobemide inhibits MAO-A (increases NE, agonist)

  • increases attentiveness, alertness, vigilance

• Ritalin - an NE agonist used for ADHD, stimulant, DA/NE reuptake blocker

3 antagonists/agonists for NE based off its relation to DA

• L-DOPA - agonist

• AMPT - antagonist

• reserpine - antagonist

epinephrine (aka…, synthesized from what, synthesizing enzyme, where it’s released from, what it does to the body)

• adrenaline

• synthesized from norepinephrine/noradrenaline

• PNMT (phenylethanolamine-N-methyltransferase)

• released from adrenal medulla

• preps body for action under stress… usually as a sympathetic hormone

serotonin location + involved in + synthesized from

serotonin cell bodies are located in brainstem raphe (RAS) and project to cortex

involved in emotion, arousal [sleep-wake cycles], visual system

tryptophan

substances responsible for 5-HT/serotonin release and termination

serotonin release

• 8-OHDPAT is an autoreceptor stimulator that reduces 5-HT release → antagonist

serotonin termination

• reuptake is blocked by fluoxetine, which elevates 5-HT → agonist

• degradation: MAO-A converts serotonin to 5-HIAA

relationship btwn serotonin and aggression in animals

serotonin suppresses aggression

• Higley studied wild rhesus monkeys. 5-HIAA (metabolite) in CSF was inversely associated w aggression

• low 5-HIAA → increased attacks on dominant monkeys + longer leaps from tree to tree (so more risk-taking behavior) → often leading to death

• 5-HT higher in dominant rather than submissive male vervet monkeys

• removing dominant monkey increases 5-HT in 2nd dominant male

• restoring dominant male lowers 5-HT once again

relationship btwn 5-HT and aggression in humans

in humans, aggression is rare

• reduced 5-HT and 5-HIAA in brains of suicide completers relative to those severely depressed

  • reduced 5-HIAA and 5=HT in those completing suicide via VIOLENT relative to non-violent means

• reduced 5-HIAA is associated w the “urge to act out hostility” subscale of the Hostility and Direction of Hostility Questionnaire

neuromodulators (what are they, how far do they travel, how much is secreted, 2 important types, function)

• chains of amino acids

• travel farther than NTs (not “private” communication)

• secreted in larger amounts than NTs

• glutamate (produces EPSPs), GABA (produces IPSPs)

• well-suited for setting lvls of central neural activity underlying behavioral states

  • alertness, arousal, anxiety by modulating the excitability of the postsynaptic cell

  • relaxation

how does glutamate and GABA produce EPSPs and IPSPs?

• glutamate increases likelihood of neuronal firing → Na+ or Ca2+ channels open → EPSPs

• GABA decreases likelihood of firing → K+ or Cl- channels open → IPSPs

4 receptor types glutamate interacts w

• NMDA receptor - controls a Ca2+ channel, closely associated w learning

• AMPA receptor - controls sodium channels

• kainate receptor - controls sodium channels

• metabotropic glutamate receptor

2 receptors GABA acts on + examples of drugs that affect them

• GABAsubA - ionotropic receptor (controls a chloride channel) - benzodiazepines (e.g., valium) bind here → reduce anxiety and seizures; promote sleep and muscle relaxation

• GABAsubB - metabotropic receptor (controls a K+ channel)

  • Baclofen (major muscle-relaxant) acts as a direct agonist

what receptors does alcohol affect, and how?

• direct effect on GABAsubA receptors

• GABA agonist by increasing the amt of time that Cl- channels are open

relationship btwn seizures and GABA + drug that may help

• seizures (uncontrollable neuronal firing) appear associated w decreased GABA

• tiagabine reduces GABA reuptake

tetrahydrocannibol (THC) (what is it, what does it stimulate, associate w 4 things)

• a lipid

• stimulates cannibinoid receptors

• associated w

  • analgesic effects

  • increased appetite

  • reduced nausea

  • distorted perception of time

soluble gases + example

can diffuse somewhat and affect more distant cells

• nitric oxide (NO) exerts effects within intestinal muscles, dilates brain blood vessels