Summary Chapter 2 Stahl Notes

Chapter 2: Transporters, Receptors and Enzymes as Targets of Psychopharmacological Drug
Action
o Sites of action for therapeutic agents
o Transporters for neurotransmitters (33%)
o Receptors coupled to G proteins (33%)
o Enzymes (10%)

Nomenclature for Medications
o Moving from traditionally naming medications for their therapeutic indications
 Antidepressant, antipsychotic, etc.
 So called antipsychotics being used for depression shows how
ineffective the current nomenclature is
 Changing to nomenclature based on neuroscience
 Serotonin transport inhibitor
 Dopamine D2 and serotonin 5HT2A antagonist
o Genetic Variation
o Moving towards understanding gene variations and how those impacts whether the
patient responds to the drug or not
 Pharmacogenomics

Neurotransmitter Transporters as Targets of Drug Action
o 12-transmembrane-region proteins
o Utilized by presynaptic reuptake and vesicular storage
o Cross the membrane 12 times
 Plasma Membrane Transporters
 Some are presynaptic and others are on glial membranes
o Solute carrier SLC6 gene family
 Includes transporters for the monoamines:
 Serotonin, norepinephrine, dopamine
 Neurotransmitter GABA
 Amino acid glycine
o Solute carrier SLC1 gene family
 High affinity glutamate transporters

 Intracellular synaptic vesicle transporters
 SLC18 gene family
o Vesicular monoamine transporters (VMATs) for:
 Serotonin, norepinephrine, dopamine and histamine
o Vesicular acetylcholine transporter (VAChT)
 SLC32 gene family
o Vesicular inhibitory amino acid transporters (VIAATs)
 SLC17 gene family
o Vesicular glutamate transporters
 vGluT1-3
SLC6 Gene Family as Targets of Psychotropic Drugs
o Monoamines use unique presynaptic transporters (each different)
o Serotonin: SERT
o Norepinephrine: NET

, o Dopamine: DAT
 They still have affinity for the other receptors
 If other transportable neurotransmitters or drugs are in the area they
can also be transported into the presynaptic neuron
o NET also has high affinity for dopamine transport
o DAT has high affinity for transport of amphetamines as well as
dopamine
o SERT has high affinity for MDMA transport
o Same vesicular transporter in the synaptic vesicle membranes of all three monoamines
plus histamine
o Vesicular monoamine transporter 2: VMAT2
o Energy
o Transporters in the SLC6 gene family couple the “downhill” transport of sodium with
the “uphill” transport of the monoamines
 Up a concentration gradient
 Sodium dependent cotransporters (sodium-potassium ATPase)  sodium
pump
 Usually also involves additional cotransport of chloride
 In some cases, also the counter transport of potassium
o Binding sites
o One site for the monoamine to bind
o Binding sites for 2 sodium ions
 Dimer
 The concept that these transporters may exist as 2 copies working
together with each other
 Monamines are believed to exist as dimers
o SSRIs
o Drug binds to the transporter and inhibits the reuptake of monoamines
 They do NOT bind to the substrate site  they bind to allosteric site
 Substrate site: where the monoamine itself binds to the transporter
o Designed for unipolar depression
 Act at SERT, NET and DAT or some combination of these

o “Antidepressant” is misnomer
o Good for treating GAD, social phobia and other anxiety forms
o They help with neuropathic pain and post herpetic neuralgia
o Can improve eating disorders, OCD, trauma and stress related disorders
o We do NOT use agents that block monoamine transporters in bipolar or mixed
states
SLC6 and SLC1 Gene Family as Targets of Psychotropic Drugs
o GABA
o Transported by the GAT1-4
 GAT1-4 is selectively blocked by the anticonvulsant: Tiagabine
 Increases synaptic GABA concentrations
o  therapeutic actions in anxiety, sleep disorders
 No other inhibitors of this transport system are available for clinical use
o Glycine
o Belong to the SLC6 gene family
 No drugs on the market to block glycine transporters