psychopharmacology chapter 3

quiz 1

drug targets

psychotropic drugs have many mechanisms of action, but they bind to specific molecular sites

• 1/3: target neurotransmitter transporters

• 1/3: target G-protein-coupled receptors

• 10% target enzymes

• the rest target ion channels

location of transporters

they are found on neuronal membranes and glial cell membranes

membrane is semi-permeable, selective movement

maintains proper neurotransmitter levels and prepares for future neurotransmission

recapture/reuptake

transporter takes neurotransmitter back into the presynaptic neuron

transport into synaptic vesicle

storage and future release

structure of transporters

belongs to a superfamily of 12-transmembrane-region proteins

each transporter crosses the membrane 12 times

major subclasses of transporters

1. sodium/chloride-coupled transporters (SLC6 family)

2. glutamate transporters (SLC1 family)

sodium/chloride-coupled transporters (SLC6)

• handles monoamines: serotonin, norepinephrine, dopamine

• transports GABA and glycine

glutamate transporters (SLC1)

clears out glutamate to prevent excitotoxicity (excess glutamate can damage neurons)

sodium-potassium ATPase (sodium pump)

how energy is provided for transporting neurotransmitters

• transport into neurons is an energy-dependent process

• energy comes from the sodium pump

includes co-transport of chloride ions and the counter-transport of potassium ions

the ion movement sets the gradient up to allow neurotransmitter reuptake to occur

ATPase

• enzyme that breaks down ATP to release energy

• pumps sodium ions out and potassium ions in

• generates the electrical potential needed for action potentials

presynaptic monoamine transports

presynaptic → different for each one

vesicular → same for all

transporters are sodium-dependent cotransporters

• have binding sites for sodium + the monamine

• without sodium present, the transporters cannot bind it

importance of monoamine transporters for drugs (normal process)

• monoamines have little time to act on receptors before they are recaptured by presynaptic transporters

• prevents neurotransmitter overload

importance of monoamine transporters for drugs (drug mechanism)

• to increase neurotransmitter activity, drugs block the transporters, so more neurotransmitters stay in the synapse

• boosts signaling and therapeutic effects

importance of monoamine transporters for drugs (conditions targeted)

• ADHD

• unipolar depression

• anxiety disorders

• pain

• erectile dysfunction

• OCD

• trauma

3 types of intracellular vesicle transporters

1. vesicular monoamine and acetylcholine transporters

2. vesicular inhibitory amino acid transporters (VIAATs)

3. vesicular glutamate transporters (vGluTs 1-3)

vesicular monoamine and acetylcholine transporters

• VMATs (monoamines) and VAChT (acetylcholine)

• gene family: SLC18

• handles serotonin, norepinephrine, dopamine, histamine

vesicular inhibitory amino acid transporters (VIAATs)

• gene family: SLC32

• handles neurotransmitters like GABA and glycine

vesicular glutamate transporters (vGluTs 1-3)

• gene family: SLC17

• handles glutamate

vesicular transport

system keeps the charge balance constant, so vesicles remain ready for future neurotransmission

1. a proton ATPase (proton pump) uses energy to pump H* ions out of the vesicle

2. this creates a charge gradient (more negative inside)

3. neurotransmitters use this gradient to enter the vesicle

4. once inside, neurotransmitters are stored until the next action potential triggers release

why vesicular transporters are drug targets

• no known drugs currently target glutamate, ACH, and GABA transporters

• vesicular monoamine transporters (VMATs) are important drug targets, increases dopamine signaling, explaining stimulant effects