pharmacology of Serotonin and Central Adrenergic Neurotransmission/Antidepressant therapy

What are the two major mood disorders

bipolar disorder and major depressive disorder

what are the modulators of mood, the sleep wake cycle, motivation and reward, cognitive processing, pain perception, and neuroendocrine function, migraine and GI system

serotonin and norepinephrine

what are the serotonergic projections

spinal cord and forebrain

what does the spinal cord modulate due to serotonergic projections

pain perception, visceral regulation, motor control

what does the forebrain modulate due to serotonergic projections

vigilance, stress responses, neuroendocrine function, pain control, and sympathetic nervous system

which enzyme metabolizes tyrosine for dopamine (rate limiting step)

tyrosine hydroxylase

which enzyme metabolizes tryptophan for serotonin (rate limiting step)

tryptophan hydroxylase

which enzymes are tightly regulated by inhibitory feedback via autoreceptor-mediated signaling

tyrosine hydroxylase and tryptophan hydroxylase

what are characterized as 12 transmembrane spanning proteins that couple neurotransmitter transport to the transmembrane sodium gradient

selective monoamine reuptake transporters (SERT)

what transporter recycles 5-HT from the extracellular space back into the presynaptic neuron

SERT

what transporters are capable of transporting the other monoamines, although less efficiently

SERT, NET, DAT

Once 5-HT is returned to the neuronal cytoplasm, the neurotransmitter is transported into vesicles via what

VMAT

If the neurotransmitter is not transported into a vesicle once 5-HT is returned to the neuronal cytoplasm, its degraded by what

MAO

what oxidizes 5-HT, NE, and DA

MAO-A

what preferentially oxidizes DA

MAO-B

what chemical reaction does MAO's use to inactivate monoamines by using a covalently attached flavin adenine dinucleotide (FAD) cofactor as an electron acceptor

oxidative deamination

what is another important degradation enzyme for monoamines

COMT

out of all 5-HT receptors, how many are G-protein coupled

1

which 5-HT receptor is the only ligand gated ion channel receptor

5-HT3

which receptors are presynaptic autoreceptors important for feedback inhibition

5-HT1B and a2-adrenergic

what is characterized by single or recurrent depressive episodes

major depressive disorder

what is characterized by presence of mania or hypomania as well as periods of depression

bipolar disorder

what is referred to as persistent depressive disorder

dysthymia

what are less extreme manifestations of depression

cyclothymia

decreased 5-HT and/or NE levels cause mood disorders, based largely on the molecular mechanism of action of known antidepressants as well as animal models suggested to correspond to depression or mania

monoamine hypothesis

most severe and disabling form of depressive disorder

psychotic depression

this is associated with irritable, elevated or euphoric mood, as well as increased overall activity.

manic episode

what has associated symptoms that often include an inflated sense of self worth (grandiosity) and distractibility

manic episode

what is characterized by (literally, a "little mania") last for at least four days without such a adverse outcome

hypomanic episode

what results from pathologically decreased 5-HT and/or NE neurotransmission

depression

based on the hypothesis what can happen if 5-HT and/or NE neurotransmission is increased

ameliorate or reverse depression

true or false: antidepressants including reserpine show unexplained delation (about six or more weeks continuous treatment) in their onset of full effect

**unexplained effect remains central conundrum and strong challenge to monoamine theory

true

what type of treatment results in increased release of neurotransmitter into the synaptic cleft

acute treatment

what results in desensitization of the presynaptic autoreceptors thus the inhibition of neurotransmitter synthesis and exocytosis is reduced.

The net effect is enhanced postsynaptic receptor activity leading to a therapeutic response

chronic use of antidepressants

pharmacologic agents that alter serotonergic signaling have diver reactions on what areas of the body

brain, GI, temperature, hemodynamics

what are inhibitors of serotonin storage

amphetamine, methamphetamine, methylphenidate, lisdexamfetamine

what is a prodrug that is slowly converted to dextroamphetamine

-has less abuse potential than other amphetamines

-widely used for ADHD

lisdexamfetamine

while increased NE promotes attention and higher cognitive processes in CNS, peripheral increases in NE can cause what adverse effects

increase heart rate, BP, and induce tremors

what blocks the deamination of monoamines by binding to and inhibiting the FAD cofactor of MAO

MAOIs

what does MAOI's increase making them available in the cytoplasm of presynaptic neurons for increased uptake and storage

5-HT and NE

iproniazid, phenelzine, and isocarboxazid are classified as what

irreversibility inhibitors

moclobemide, befloxatone, and brofaromine...

selective for MAO A and bind reversibly

what is a selective MAO-B inhibitor at low doses and inhibits MAO-A at higher doses

selegiline

what decreases the reuptake rate of serotonin resulting in a net increase in the concentration of 5-HT in the extracellular space

inhibitors of the serotonin reuptake transporter

true or false: serotonergic is maintained at steady state by the balance between transmitter release and reuptake

true

what drugs alleviate psychiatric conditions such as depression, anxiety, and OCD

inhibitors of the serotonin reuptake transporter

what are the four classes of reuptake inhibitors in use

TCAs, SSRIs, SNRIs, NRIs

Imipramine, amitriptyline, clomipramine, desipramine, nortriptyline are apart of what reuptake inhibitor class

TCAs

what class inhibits reuptake of 5-HT and NE from synaptic cleft by blocking 5-HT and NE reuptake transporters, thereby enhancing postsynaptic response

TCAs

TCAs with secondary amines preferentially affect what system

NE

TCAs with tertiary amines primarily affect what system

5-Ht

what tends to be more selective for the NE system

tetracyclic (maprotiline)

TCA adverse effect what

cardiovascular system

fluoxetine (prozac)*, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram are apart of what drug class

SSRIs

what inhibitor class selectively inhibits the reuptake of serotonin and thereby increase synaptic serotonin levels

-also cause increased 5-HT receptor activation and enhanced postsynaptic responses

-at high doses binds to NE transporters

SSRIs

MOA:

what inhibitor is involved in these clinical applications: depression, pain syndrome, migraine headaches, chronic fatigue syndrome

TCAs

MOA

what inhibitors take part in these clinical applications: depression, anxiety, OCD, PTSD, pain syndromes

SSRIs

what adverse effect can be caused by the use of SSRIs (characterized by hyperthermia, muscle rigidity, myoclonus, rapid fluctuation in mental status and vital signs)

serotonin syndrome

true or false: all SSRIs can cause some degree of sexual dysfunction, diminishing libido and/or delaying orgasm

true

duloxetine*, venlafaxine, desvenlafaxine, milnacipran are drug apart of what inhibiting class

SNRIs

MOA:

what class blocks 5-HT reuptake transporter and NE reuptake transporter in a concentration dependent manner

SNRI

what class takes part in these clinical applications:

depression, anxiety, panic disorder with or without agoraphobia, pain syndromes, major depressive disorder, fibromyalgia

SSRI

reboxetine, atomoxetine, and maprotiline are apart of what class

NRIs

MOA:

what drug selectively blocks NE uptake transporters leading to increase NE levels

NRIs

what class takes part in the following clinical application:

ADHA

NRIs

all antidepressant drugs, including MAOIs are...

hydrophobic and cross BBB

what drug can induce depression in humans and animal models, blocks the VMAT mediated uptake of monoamines into synaptic vesicles, which ultimately destroys the vesicles

reerpine

*what drug is considered a serotonin receptor agonist (5-HT1A) that treats anxiety

buspirone

rizatriptan, almotriptan, frovatriptan, eletriptan, zolmitriptan, ergotamine are characterized by what

(treat headache)

serotonin receptor agonist

what drugs show varying degrees of receptor subtype selectivity and often cross react with adrenergic histamine and muscarinic receptors

serotonin receptor antagonist

what drug is a 5-HT2 antagonist

ketanserin

what drug is a 5-HT3 antagonist

ondansetron

what are the adverse effects of serotonin receptor antagonist

IBS

what mood stabilizer has this MOA:

inhibits electrical neurotransmission by use of dependent block of neuronal voltage gated sodium channels

carbamazepine

*what mood stabilizer has this MOA:

inhibits the low threshold T-type calcium channels

valproic acid

what mood stabilizer has this MOA:

blocks the phosphatidylinositol signaling cascade in the brain

-low TI, and the frequency and severity of adverse reaction are directly related to the serum level

lithium

which antidepressants are characterized as:

- potent muscarinic cholinergic antagonists

- weak a1 antagonists

- weak H1 antagonist

heterocyclic antidepressants (TCA)

what produces direct effects by inducing a net outward current by promoting either an influx of anions or an efflux of cations

inhibitory neurotransmitters

what produces direct effects by inducing a net inward current either by enhancing inward current or indirect effects by reducing outward current

excitatory neurotransmitters

what does binding of the inhibitory neurotransmitters cause

hyperpolarization of the neuron

what receptors affect arousal, attention, memory formation, anxiety, sleep, muscle, tone

GABA receptors

modulation of what signaling is important for treatment of focal or widespread neuronal hyperactivity in epilepsy

GABA

what mediates GABA synthesis which decarboxylates glutamate to produce GABA in GABAergic nerve terminals

glutamic acid decarboxylase (GAD)

GABA is transported into vesicles via what transporter

vesicular GABA transporter (VGAT)

what converts GABA into succinic semialdehyde (SSA)

GABA transaminas (GABA-T)

succinic semialdehyde (SSA) is oxidized to succinic acid by SSA dehydrogenase to in order to enter the kreb cycle and form what

a-ketoglutarate

what does GABA-T regenerate from a-ketoglutarate

glutamate

GABA-T is irreversibly inhibited by what

vigabatrin

blocking the conversion of GABA to succinic semialdehyde increases or decreases the amount of GABA-T available for release at inhibitory synapses

increases

what enzyme transforms glutamate into glutamine in the glial cell

glutamine synthetase

when glutamine is transferred to the neuron, what converts it back to glutamate

mitochondria associated glutaminase

what are the two types of GABA receptors

ionotropic and metabotropic GABA receptors

GABAa and GABAc bind to GABA and open intrinsic Cl- channels

ionotropic GABA receptors

GABAb heterodimeric G protein coupled receptors activate neuronal potassium channels through second messengers

metabotropic GABA receptors

the distribution of GABAc receptors distribution in the CNS is restricted primarily to where

retina

true or false: no drugs currently in use target GABAc repetors

what requires simultaneous binding of two molecules of GABA (one to each binding site at the interface of the a and b subunits) for activation

GABAa

what response is activated by very brief (high frequency) bursts of GABA release at synapses

inhibitory postsynaptic currents

what does the GABAa contain

four membrane spanning regions and a cysteine loop in the extracellular N terminal domain

what binds to a site near the junction alpha and beta subunits causing conformational changes that open the chloride ion channel and lead to neuronal membrane hyperolarization

GABA