therapeutic psychopharmacology

what makes a good drug?

what makes a good drug?

reduces symptoms, few side effects, and a good therapeutic index

therapeutic index

the ratio of the amount of therapeutic agent that causes a therapeutic effect to the amount that causes toxicity

favorable therapeutic index

large gap between the two lines of desire response and toxicity

unfavorable therapeutic index

small gap between the two lines of desire response and toxicity

what determines therapeutic and side effects?

pharmacodynamic factors and pharmacokinetic factors

pharmacodynamic factors

what a drug binds to (unintentional and intentional) and where these targets are expressed

pharmacodynamic factors example

Imodium and heroin bind to the same type of receptor

pharmacokinetic factors

where the drug goes in the body, how long it take for it to get there, and how long it stays

pharmacokinetic factors example

Imodium goes to peripheral receptors and does not pass the BBB, but heroin passes the BBB

causes for unwanted side effects

some drugs are too strong/too high of a dose, some drugs are “dirty drugs” and bind to multiple targets, selective drugs can have “on-target” side effects, and functional selectivity

some drugs are too strong/too high of a dose

can lead to excessive activity or neurons or receptors. they can also block activity too much

some drugs are “dirty drugs” and bind to multiple targets

“off-target” side effects can be due to modulating molecules other than the intended target

selective drugs can have “on-target” side effects

this can be due to modulating the intended molecule in a non-intended area

functional selectivity

an on-target side effect where the targeting of the intended molecule leads to distinct signaling pathways in the same cell, but only one of these pathways is intended (one pathway is ideal and one is the side effects)

why are benzodiazepines safer than barbiturates?

they are less potent

what do benzo’s and barbs both bind to?

GABA-A receptors, but at different sites

positive allosteric regulators

benzo’s and barbs bind to different sites than the normal agonist and potentiate the action of that agonist

why do barbs have a higher chance of overdose?

they can directly activate GABA-a at higher doses and they become the agonist

why do benzos have a lower chance of overdose?

they do not directly activate and less efficacious at promoting GABA neurotransmission

what type of difference is there between benzos and barbs?

pharmodynamic

how are differences in responses to sedatives explained?

on-target side effects; many brain regions that control sleep have GABA receptors, so sedatives can cause GABA to be activated in different locations

why are some sedatives (GABA agonists_ used for sleep and anxiety disorders and others for alcohol detox?

pharmacokinetic factors

pharmacokinetics in sleep disorders

you want a shorter half life than how long you want to sleep (2-6 hours)

pharmacokinetics in alcohol detox

you want a longer half life because it slows down the time from 100% GABA to 0% (100 hours)

what is the major driving force in current antidepressant prescribing?

off-target side effects

tricyclic antidepressants (TCAs)

made as potential antipsychotics and researches saw they induced mania, but shown to be effective against depression

why do TCAs have relatively bad side effects?

they’re mostly non-selective, so when you increase norepinephrine and serotonin you have two time the chance of side effects

imipramine and desipramine (TCAs) targets

block several transporters and receptors (cause of more side effects)

selective serotonin reuptake inhibitors (SSRIs)

selective for the serotonin transporter, so they only elevate serotonin and not dopamine or norepinephrine (unlike TCAs)

SSRIs selection within serotonin

no selective within serotonin, just increases extracellular levels in 15 different receptors; can cause on-target side effects

why are there 7 different classes of serotonin receptors?

they have different functions, signaling pathways, and patterns of expression

location and specificity of expression of serotonin receptors

found in different places, so it is possible they cause different effects

5-ht2a receptors

could be responsible for anti-anxiety effects

5-ht3 receptors

could be responsible for antidepressant effects

therapeutic delay in SSRIs

takes about 4 weeks for them to work, which can be an issue

neuronal structure theory in SSRI therapeutic delay

a change in the number of spines in the neurons

gene expression theory in SSRI therapeutic delay

transcription factor changes and then change in transcription

neurogenesis theory in SSRI therapeutic delay

SSRIs increase neurogenesis

receptor down-regulation theory in SSRI therapeutic delay

changes in the brain to adapt; this can be the reason for withdrawals

what happens to receptors if they are continuously stimulated with neurotransmitters

they become desensitized or down regulated

post synaptic receptors

receive and respond to neurotransmitters released presynaptically

auto receptors

presynaptic receptors that serve to detect and regulate the amount of neurotransmitter than needs to be released

what regulates the release of serotonin?

serotonergic autoreceptors (prevent more serotonin from being released)

down regulation in postsynaptic serotonin receptors

decrease in serotonin neurotransmission

down regulation in presynaptic auto receptors serotonin receptors

increase in serotonin neurotransmission

possible mechanisms for antidepressant action

structural changes, neurogenesis, receptor down regulation, gene expression

testing for structural changes

IHC or histology

testing for neurogenesis

IHC

testing for receptor down regulation

radioligand binding (just gives receptor specificity, not cell type)

testing for gene expression

TRAP for cell type changes

cell-type specific changes of fluoxetine on gene expression

experimenters wanted to compare effects of FLX on P11 and other pyramidal neurons with TRAP

P11 (S100a10)

pyramidal neurons that have a protein involved in serotonin receptor signaling and in the striatum

glt25d2

pyramidal neurons (long-distance projection) in 5b and send axons to pons, thalamus, and spinal cord

mouse lines used in FLX/TRAP experiment

glt25d2-L10aGFP and S100a10-L10aGFP

results of the TRAP experiment

S100a10: in the saline condition the FLX decreased expression, showing down regulation. in the FLX condition, there was FLX increased expression, showing up regulation

glt25d2: straight line with slope of 1, showing no effect on gene expression

why can we not use whole tissue analysis?

it would miss the effect of FLX in the s100a10-expressing cells

wet dog shakes in mice (behavioral assay?)

many 5-ht2a agnoists cause wet dog shakes, but lisuride (ls) does not cause them

egr2 pathway

is upregulated by many drugs

LSD and R-Ls with c-FOS

both showed c-FOS positive cells

LSD and R-Ls with egr-2

showed positive in LSD, but not in R-Ls

results of LSD vs. R-Ls experiment

no egr2 means no hallucinations, but the positive effects of psychedelics

how can you make something that has the benefits of psychedelics without making people trip out?

organic chemistry to make a derivative of IBG

behavioral assay to see if mice trip out

the substance vs the number of head twitches

IBG, TBG, and control vs. head twitches results

the TBG (an IBG derivative) shows less hallucinogenic effects than the parent compound

TBG and structural changes in the brain

change in the number of spines (like ketamine and IBO/IBG) and can occur within a day

structural changes experiment methods

administer IBG, IBO, KET, TBG, and control and count the number of spines with two-photon imagine

structural changes experiment results

between day one and day zero, there was an increase in the number of spines

TBG for antidepressant effects

forced swim test (behavioral assay)

forced swim test methods

day 1 for the pre-test, day 2 administer saline or TBG, day 3 FST for 24 hours, day 9 FST; measure immobility percent vs the injection

TBG for alcohol intake effects

24 hours of alcohol or water, 24 hours of water only, and then 23 hours of alcohol or water in the controls and the TBG mice; measure intake vs. injection

forced swim test results

antidepressant effect; vehicle shows increase in immobility, KET reduces immobility, TBG negative KET reduces immbility, and TBG positive KET shows same as control (TBG is an antagonist of 5-ht2a to show that it is a 5ht2a dependent effect, meaning you activate and block at the same time to make it essentially useless)

alcohol intake results

TBG mice shows less binge drinking than the controls

TBG for heroin intake

use the self-administration and track the level presses vs the sessions

TBG for heroin intake results

when TBG is injected the self-administration is blocked and during the cue test there is no active lever presses