tbl 2.1/2.2

a. What is esketamine used for, and how is it administered (and why?) 

• depression

• Admin intranasal spray = fast brain access + avoid first pass metabolism

b. What receptor is preferentially targeted by ketamine, what type of receptor is it and where is it expressed? 

• NMDA receptor

• Ionotropic 

• Brain GABA neurons/excitatory neurons

c. What signaling pathway is implicated in the rapid effects of esketamine? (And how rapid?) 

• Targets glutamate receptor

• Hours 

• mTOR signal pathway to increase synaptic protein syth/plasticity 

d. What is brexanolone, what is it used for and how is it administered (and why?)

• Neurosteroid replacement therapy

• Post part depression

• Admin IV

f. What is the mechanism of brexanolone – what is its target and what type of receptor is it?

• GABA_A (ionotrop)

• Positive allosteric modulator = enhance inhibitory signalling in brain

Which property best explains why AMPA receptors
are the main mediators of fast excitatory synaptic
transmission in the CNS?

High calcium permeability
B. Voltage-dependent magnesium block
C. Rapid activation and deactivation kinetics
D. Exclusive expression on excitatory neurons

c

Q: During LTP, which signaling process mainly
determines whether synaptic strengthening will persist
beyond minutes to hours?
A. Removal of the Mg²
⁺ block from NMDA receptors
B. Rapid insertion of AMPAR postsynaptically
C. cAMP-mediated activation of PKA and CREB
D. Increased presynaptic glutamate release

c

Apremilast and crisaborole do not meaningfully
affect cognition because they:
A. Increase cGMP rather than cAMP
B. Do not inhibit PDE-4
C. Selectively inhibit PDE-3 instead
D. Are designed to minimize CNS penetration

d

All of these statements are true EXCEPT:
A. Creatine participates in a phosphocreatine
system that buffers ATP levels in cells
B. Creatine is synthesized endogenously and
also obtained from dietary sources
C. Creatine directly increases synaptic
plasticity by activating NMDA receptors
D. Creatine is expressed in brain tissue as
well as in skeletal muscle

c

ACTH became of interest in cognitive
neuroscience because early studies found that:
A. ACTH directly opened glutamate receptor ion
channels
B. ACTH fragments influenced learning and
memory independent of adrenal effects
C. ACTH functioned as a classical
neurotransmitter in cortex
D. ACTH was required for NMDA receptor
activation

b

Esketamine treatment requires post-administration
monitoring primarily because it can cause:
A. Severe hypertension and arrhythmias
B. Dissociation and increases in blood pressure
C. Potentially irreversible neurotoxicity
D. Profound respiratory depressio

b

Q: Inhibition of NMDA receptors on inhibitory interneurons
would most likely produce which circuit-level effect?
A. Reduced glutamate release
B. Increased cortical excitatory signaling
C. Increased monoamine degradation
D. Reduced AMPA receptor activity

b

Q:Which downstream signaling pathway has been
implicated in rapid antidepressant effects of esketamine?
A. mTOR signaling and synaptogenesis
B. Inhibition of acetylcholine synthesis
C. Dopamine receptor downregulation
D. Histamine receptor activation

a

ne hypothesis for esketamine’s rapid
antidepressant effect is that it preferentially
targets the receptor listed above, expressed pre-
synaptically on which cell type?
A. Dopaminergic neurons
B. Astrocytes
C. GABAergic interneurons
D. Serotonergic neuron

c

Q: Monitoring during brexanolone treatment is
required primarily because of the risk of:
A. Seizures
B. Excessive sedation or loss of consciousness
C. Liver failure or elevation of liver enzymes
D. Severe hypertensio

b

Q: GABA-A receptor modulation can produce rapid
changes in neural circuits because these receptors:
A. Mediate fast synaptic inhibition
B. Are coupled to gene transcription factors
C. Only function in the hippocampus
D. Control serotonin synthesis

a

Brexanolone exerts its primary pharmacological
effect in postpartum depression by:
A. Inhibiting serotonin reuptake
B. Antagonizing NMDA receptors
C. Positively modulating GABA-A receptors
D. Activating dopamine D2 receptor

*brex = benzos

c

pregnanolone

Steroid hormone derived from progesterone – role
in hormone signaling, supports cognitive function,
neuroprotection, memory, neurogenesis

How do levels of allopregnanolone change during
pregnancy / postpartum, and why might this change
contribute to symptoms of postpartum depression

increase during pregnancy, sharp drop after birth

tonic vs phasic inhibition

• Phasic inhibition (fast/synaptic) handles rapid, transient communication at the synapse

• tonic inhibition (slow/extrasynaptic) involves a persistent, low-level inhibition of neuronal activity

What indications have ampakines mainly been studied for? Are any approved in the US

Studied for CNS enhancement, enhancing LTP for learning / memory. None approved, due to risk of
excitotoxicity (high-impact) or low efficacy (low-impact)

Researchers in the1980s proposed that subtly
enhancing AMPA receptor signaling without directly
activating the receptor could increase synaptic efficacy,
facilitate LTP and improve cognition. What type of agonist
or antagonist (e.g., inverse, full, etc.) is this describing

Positive allosteric modulator (not a direct agonist or
antagonist) binds to other site on receptor – direct agonist
could over-activate glutamate receptors, risk of seizure

rolipram

PDE4 inhibitor, originally studied for depression.
Decreases rate of toxic protein aggregation,
improved memory in animal models, LTP effects,
effects on CREB, BDNF

What types of evidence led researchers to
propose that creatine could be helpful as a
cognitive enhancer?

Crosses BBB could impact neuronal energetics
(mechanistic rationale)

increases ATP –

supplementation helps w cognitive disorders like
Alzheimer’s – creatine deficiency causes cognitive
impairment

Semax, treats what

peptide

differs from ACTH bc gets more stable thru more sequences (its a 7hepatopeptide)

• treats stroke, neurodeg disease

• intranasal admin OR subq

• nootropic! = enhances brain function + no side effects

ACTH + vassopressin

hormones, involved in
fluid balance, stress, metabolism

• VP enhances learning / memory mostly, improves psychometric tests in AD or Korsakoff psychosis.

• ACTH improves performance on neuropsychological tests