Cognitive enhancers Flashcards
nootropic drugs
enhance cognition in healthy brains
Can drugs increase IQ?
No, but they can improve attention
What NTs are involved in the arousal system, i.e. promoting activity of which NTs promotes wakefulness?
Acetylcholine, histamine, NE, 5 HT, orexin
HANSO
reticular formation
arousal system
which NT promotes sleep
adenosine
- accumulates when brain is awake (from ATP use) and clears during sleep
What does the viPOA (slow-wave-sleep-on) region inhibit?
viPOA inhibits:
- the arousal system (and vice versa the arousal system inhibits the viPOA)
- orexinergic neurons in the LH
What signals modulate the LH orexinergic neurons?
biological clock (time of day, light) - activates
hunger signals - activate
satiety signals - inhibit
orexin
Regulates arousal and hunger
Psychostimulants
drugs that promote wakefulness and attention
- often increase motor activity as well (undesired)
what kind of drug is caffeine
psychostimulant
how does caffeine work
- blocks adenosine receptor which stops adenosine from signalling that you’re sleepy
- also inhibits phosphodiesterase which indirectly increases NE and E
Phosphodiesterase
enzyme that breaks down cAMP
- inhibited by caffeine
Why are NE and E signalling levels increased with caffeine intake
NE and E act through Galpha-s protein which increases cAMP (when they bind to their receptors, cAMP is increased)
- preventing breakdown of cAMP by inhibiting phosphodiesterase works in same direction as NE and E (more cAMP) so their signal is amplified
dependence vs addiction
dependence: body performs best with the drug, would prefer to have it
addiction: compulsion to take drug despite adverse consequences
caffeine adverse effects
dry mouth, heart burn, agitation, nausea, diarrhea, insomnia, racing heart
- a lot of these similar to adrenaline because cAMP (dry mouth, rapid HR)
fatal doses rare but have happened (cardiac arrest)
What happens during slow wave sleep
brain increases pumping of fluid - metabolites washed away
Most psychostimulants are…
DAT and NET blockers
- ex. cocaine, methamphetamine, amphetamine, and methylphenidate
adderall vs ritalin
adderall = amphetamine
ritalin = methylphenidate
are psychostimulants addictive?
they can be:
cocaine is a psychostimulant and so is meth, but something like ritalin (methylphenidate) isn’t.
Depends on the route of admin and dose (also is individual variation though)
Effects of psychostimulants
wakefulness, euphoria, suppressed appetite, insomnia, agitation, restlessness, dry mouth, racing heart, GI upset, constipation, grandiosity, paranoia, psychosis
Dopamine recycling:
- normal
- on cocaine
- on amphetamine
bonus: which drugs act same way as last two on DAT?
normal
- VMAT (vesicular monoamine transporter) packages DA
- DAT takes up DA from synapse to be repackaged
cocaine
- DAT is plugged so DA is accumulated in synapse and activates more DRs
Amphetamine
- reverses the DAT, DA from cytosol actually goes into synapse
- amphetamine also displaces DA from the vesicles which pushes DA into cytosol (this flips the conc gradient and allows VMAT to reverse)
BONUS: methylphenidate does same as cocaine and plugs DAT, methamphetamine does same as amphet
drugs like amphet, cocaine, methylphen act on which transporter(s)?
mostly act on DAT but also do the same thing to SERT and NET, just to a lesser extent
Neuropathology of Alzheimer’s Disease (AD)
- amyloid plaques and neurofibrillary tangles are clearly visible in microscopy
- gross diffuse atrophy of brain and loss of neurons, neuronal processes, synapses
- degeneration in temporal and parietal lobes, as well as part of frontal cortex
Which NT reduced in AD? Elevated?
Acetylcholine is reduced as well as 5HT and NE
glutamate usually elevated
Debate with beta amyloid plaques?
Are these biomarkers causative or correlational?
- shown that reducing beta amyloid plaques doesn’t work
Pharmacotherapy for AD
- cholinesterase inhibitors (prevent breakdown of Ach)
- low-affinity NMDA receptor antagonists (to slightly reduce glutamate signalling)
why are cholinesterase inhibitors prescribed for AD?
reduction in acetylcholine (ACh) by loss of cholinergic neurons throughout brain associated with AD:
- cholinesterase inhibitors elevate Ach levels, allows more to bind (doesn’t actually fix prob which is loss of cholinergic neurons)
Types of cholinergic receptors
`muscarinic receptors - are GPCRs
nicotinic receptors - are sodium channels
Unique characteristic of acetylcholine
only NT whose actions are terminated by enzyme degradation in the synaptic cleft
- acetylcholinesterase in synapse rapidly metabolizes Ach to choline which is retaken up and used to produce more
Acetylcholine signalling (major systems)
- ACh is the NT at the neuromuscular junction
- ACh is NT of the parasympathetic NS
(ACh is also used by sympathetic NS at the sympathetic ganglia but then secondary neurons use NE and E)
Reversible vs irreversible cholinesterase inhibitors
- reversible ones are cholinesterase drugs prescribed that increase cortical Ach
- irreversible inhibitors are POISONS (sarin gas, organophosphate insecticides)
Examples of cholinesterase inhibitors
- donepezil
- galantamine
- rivastigmine
How is efficacy of cholinesterase inhibitors tested
objective/subjective measures
activities of daily living: bathing, dressing, eating, moving from car to bed, voluntary urinary and fecal discharge, using toilet, walking
looks at disturbances in memory, language, and attention
Adverse effects of cholinesterase inhibs
nausea, GI cramping, vomiting, diarrhea, bradycardia, anorexia, vivid dreams
Do cholinesterase inhibitors help healthy people?
no - they help memory recall in AD patients but not healthy brains
Five receptor types for glutamate
- AMPARs (Na channels) MAJOR ONE
- Kainate Rs (Na channels)
- NMDARs (Na and Ca channels)
- mGluRs (GPCRs)
- delta receptors (Na channels)
Learning = forming a memory = _____
strengthening the connections between those neurons that together make the memory
NMDARs are required for…
LTP
- calcium influx triggers cascades that lead to increased AMPA receptors at synapse (more sensitive)
What’s special about NMDARs
- they let in sodium - to depolarize the neuron -
and calcium - allows for intracellular changes - requires glutamate AND coagonist glycine to open
- has a magnesium ion in its pore which has to be expelled by prior depolarization of membrane
competitive antagonists for NMDARs bind at____ and non-competitive antagonists are ___
- the glutamate binding site
- NMDAR channel blockers
Memantine
- low-affinity, non-competitive NMDAR antagonist (so blocks the pore)
- binds at the PCP site
- has VERY fast on and off which is how it doesn’t impair cognition but still reduces glutamate signalling slightly
- Memantine has been associated with reduced rate of deterioration on global, cognitive, and functional measures (also behavioural improvements)
- safe for use with AChIs
How does memantine reduce cognitive decline?
Might seem counterintuitive because NMDARs needed for learning and memory, HOWEVER excessive activation leads to excitotoxicity
- neurons trigger glutamate as they die
- surrounding neurons overexcite and die
memantine has neuroprotective effects - blocks enough NMDA to prevent excitotoxicity but leaves enough for learning and mem
adverse effects of memantine
(recall this is a drug for AD - NMDAR antagonist at PCP site)
- headache, body ache, fatigue, dizziness
