How does the Blood-brain barrier work?
tight junctions help to restrict passage of molecules
CNS drug effects at synapse
� many "drugs"
� increase neurotransmitter concentrations in synapse
or
� agonize the GPCR receptor
for the neurotransmitter
� drugs can increase synaptic concentrations by:
� inhibiting re-uptake (e.g. at NET)
� inhibiting cytosolic MAO, COMT
(degradation enzymes)
� upregulation of enzymes (e.g. tyrosine hydroxylase, Tyr -> L-dopa)
� promoting reverse transport by interfering with vesicular transport (high cytosolic concentr
� Amphetamines may increase dopamine by
1 inhibiting re-uptake (at DAT)
2 inhibiting MAO (breaks down dopamine)
3 causing reverse transport
4 interfering with vesicular transport (as a weak base, depleting protons) causing high cytosolic concentrations of dopamine causing it to diffuse out of c
� Vesicular transporters
� VMAT
� relies on proton gradient
DAT
Dopamine Transporter
NET
Nor-epinephrine Transporter
SERT, 5-HT
Serotonin Transporter
� Reuptake transporters
� DAT � NET � SERT
� all use Na/Cl
gradient
lower IC50
0
Stimulants
� activity at NET may partly explain heightened activity = feeling adrenaline
� activity at DAT may partly explain rewarding feeling = feeling rewarded
� activity at SERT may partly explain positive feelings = feeling good and happy.
Degradation of cystolic neurotransmitters
� monoamine oxidase (MAO)
� catechol-O-methyl transferase (COMT)
MAO (monoamine oxidase)
� mainly removes amines (deamination)
Found in neurons and on mitochondrial membrane
Trace amine-associated receptor 1
� TAAR1
� autoinhibition
� TAAR1 agonists activate pre-synaptic D2 autoreceptor (D2Sh)
� DA binds to pre-synaptic D2 to inhibit further DA release
� TAAR1-KO mice
� exhibit more addictive behavior
� have higher levels of post-synaptic D2
lower values of Ki =
stronger binding affinity
Ki =
dissociation constant
higher pKi =
stronger binding
Addiction
� addictive substances typically enhance synaptic dopamine
� favors prioritizing the drug over other typical social values
* genetic predisposition for addiction is a thing, by replacing a/the T with a C in the A1 Alle increases addictive behavior.
Phenethylamines
phenyl + ethyls + amines
examples: Dopamine, epinephrne, phenylallanine, ephedrine, mescaline, amphetamine, cathinone, cathine etc.
Tryptamines
indole + ethyl + amine
examples: Serotonin, melatonin, tryptophan, tryptamine, psilocybin, LSD, DMT, Bufotenin.
caffeine
purine
nicotine
pyrdine
opiates
morphinans
calein and salvinorin
terpenes
THC and CBD
Cannabanoids
Cocaine and Scopolamine
Tropane (alkaloids)
Ephedra spp.
ephedra
not actually active at norepinephrine receptors tey just cause increased release.
� ephedrine (a phenethylamine)
� 1 extra methyl group vs. epinephrine
� increases norepinephrine concentration in synapse
� high affinity for norepinephrine transpor
Amphetamines History
� 1880s synthesized by Edeleano (interested in dyes)
� 1930s explored as a substitute for ephedrine
� ephedrine as a decongestant, bronchodilator, incr.
blood pressure
� amphetamine marketed as decongestant
� in low-moderate doses soon thereafter noted fo
Adderall
Racemic mixture of ampehtamines
Methylphenidate
ritalin
� 1944 synthesized to elevate wife's blood pressure
� her name was Rita
� 1950s
� noted for stimulating properties
� has similar mechanism/structure to cocaine
� DAT inhibition
Erythroxylum coca, E. novagratense
coca
� neurotransmitter release
�About 5% for both DA Release and HT release
� passive diffusion is usually invoked to explain transport of many drugs into CNS
� unknown proton antiporter may be involved in transport of cocaine and other drugs cross blood
Erythroxylum coca, E. novagratense
low Ki value = high/strong binding at DAT
low IC50 = strong inhibition of DAT and NET and a little moren
This drug does not cause a lot of release of Dopamine and NET but it DOES STOP REUPTAKE OF THESE RECEPTORS!
Cocaine overdose
� increased adrenergic stimulation (norepinephrine)
� hyperthermia
� hypertension
� tachy-arrhythmia
� treated with cooling & benzodiazepines (e.g. valium)
� benzoes enhance GABA-bound GABA receptors
� incr. hyperpolarization
Catha edulis
khat
*has some affinity for binding to DAT and a lot more afinity for NET.
* Stronger inhibition of NET than DAT.
� dopamine releaser
�About 50% DA release
�About 5% HT release
MDMA
ecstasy
� originally synthesized as a precursor during exploration of hydrastine & hydrastinine from Hydrastis canadensis to treat/stop bleeding (styptic)
�30% DA Release and 5-HT release
MDMA Effects
� increased social activities
� decreased recognition of negative emotion in others
� possibly partly due to increased oxytocin?
*Very strong inhibition of NET and less so at SERT but not very high at DAT which is why it is not as addictive.
� adverse eff
Nicotiana tabacum
� nicotine
� nicotinic receptor endogenous agonist
� increased release of
dopamine
Purines: caffeine
� caffeine (found in: Coffea, Camellia, Theobroma, Ilex, Paullinia, Cola)
� antagonizes adenosine receptors
� inhibits phosphodiesterase
Adenosine
� adenosine binds to adenosine receptor
� slow-acting inhibition of neuron (e.g. hyperpolarization)
� typically promotes
� bradycardia, vasodilation (incr. blood flow & oxygenation), sleep, inhibition of lipolysis, anti-inflammatory
Caffeine
� antagonist of adenosine receptors (GPCR)
� preventing neuron inhibition
� promoting excitation
� opposing effects of adenosine
� increased wakefulness,lipolysis
� increased NE release
Caffeine & Blood brain barrier
� diffuses across BBB
� also transported by
nucleoside transporter (e.g. CNT2?)
� very minor
competition/ inhibition with adenine
activity at NET may partly explain
heightened activity
activity at DAT may partly explain
rewarding feeling
activity at SERT may partly explain
positive feelings
DA=
dopamine
DAT=
dopamine transporter
VMAT=
vesicular monoamine transporter