Neuropharmacology Flashcards
exam
alpha1-R
stimulatory
alpha2-R
inhibitory
GABAA-R
inhibitory
NMDA-R and nACh-R
excitatory
potency
activity of drug in terms of concentration of drug required
thalamus is associated with
pain, altertness
Basal ganglia (striatum) associated with
movement
hippocampus associated with
long term memory and episodic memory, stress response
amygdala associated with
emotional memories
Nucleus accumbens (striatum) associated with
reward and motivation
Dorsolateral PFC
executive function, problem solving
orbitofrontal PFC
emotions, impulsivity, decision making
cingulate PFC
formation, processing of memories
hypothalamus associated with
sleep, appetite
spinal cord associated with
pain
inhibitory neurotransmitter
GABA
Effect of GABA
sedation
Effect of NE
mood, arousal, cognition, wakefulness
Effect of 5HT
mood, arousal, cognition wakefulness, anxiety, impulsivity
Effect of DA
arousal, cognition, reward, movement, impulsivity, addiction
Dopaminergic pathways
Mesolimbic, VTA to striatum
Mesocortical, VTA to PFC
Nigrostritial, Substantia nigra to striatum
Mesolimbic dysregulation
Addiction , reward pathway
Mesocortical dysfunction
negative symptoms in schizophrenia
Nigrostriatial dysfunction
movement control, EPS
Effect of histamines
wakefulness, executive function
Effect of ACh
arousal, sleep, learning, memory
CSTC loop modulates
attention, emotion, impulsivity, motor activity
Positive symptoms of schizophrenia
characteristics that should not be there eg delusions, hallucination.
Negative symptoms of schizophrenia
lack of normal characteristics
symptoms of schizophrenia
positive- and negative symptoms, affective symptoms, cognitive function, aggressive symptoms
Hyperactive mesolimbic pathway in schizophrenia according to DA hypothesis
positive symptoms
Hypoactive mesocortical pathway in schizophrenia according to DA hypothesis
cognitive, affective, negative symptoms
Dopamine hypothesis of schizophrenia
disturbed and hyperactive DA transmission
Positive symptoms glutamate hypothesis of schizophrenia
Hyperactive mesolimbic DA transmission, due to insufficient GABA feedback to VTA leading to excessive glutamate in VTA, excessive DA in N-Acc
Negative symptoms glutamate hypothesis of schizophrenia
Hypoactive mesocoritcal DA transmission
Hypoactiva tuberofudibular pathway
Hyperprolactinemia
Glutamate hypothesis
NMDA-R dysfunction, compromises GABA feedback causing increased glutaminergic neuron activity. Too much uncoordinated information
Glutamate hypothesis : positive symptoms
Hypoactive NMDA-R on GABA neurons leads to increased glutamate in VTA, leading to excessive DA stimulation in mesolimbic DA pathway
Glutamate hypothesis: negative symptoms
Hypoactive NMDA-R on GABA neurons leads to increased glutamate in VTA, this leads to excessive stimulation on pyramidal neurons which inhibits mesocortical DA neurons
Nigrostrial pathway (substantia nigto to striatum)
EPS
Serotonin hypothesis of schizophrenia
increased 5HT in striatum and PFC
Conventional anti psychosis
D2 antagonists eg haloperidol.
Dampens positive symptoms (limbic), do not alleviate negative systems.
Side effects of conventional psychotics:
Hyperprolactinemia, EPS
Types of EPS:
Parkinsonism = parkinson like symptoms like tremor
Akathasia: inability to remain motionless
Dystonia: sustained muscle contractions
Dyskinesia: involuntary movements
Role of 5HT-R
5HT1A: depression, anxiety, cognition
5HT2A: sleep, hallucinations, inhibits DA release in nigrostriatal pathway
5HT2C: obesity, mood, cognition
5HT2A-R
on GABA neurons inhibit DA transmission in nigrostrial pathway,
stimulate mesolimbic DA transmission by stimulating glutamate neurons
5HT1A-R
autoreceptor inhibits 5HT release, less 5HT2A stimulated DA release. Stimulate striatal DA by decreasing 5HT transmission
Atypical antipsychotics
reduced EPS tendency, 5HT2A-antagonism, 5HT1A antagonism, D2 rapid dissociation , D2-R partial
only partially normalize negative, cognitive and affective symptoms
side effects atypical antipsychotics
Broad antagonism:
alpha1: sedation, dizziness, orthostatic hypotension
H1: weight gain
M1: blurred vision mouth
5HT2C antagonism
weight gain, increased cortical DA and NE, mesolimbic DA disinhibition
Symptoms of depression
depressed mood, apathy, weight changes, sleep disturbance, guilt, psychomotor, fatigue
reduced positive affect
depressed mood, anhedonia, apathy, decreased enthusiasm
= DA and NE deficits
increased negative affect
depressed mood, ruminative thoughts, guilt, disgust
=5HT deficits
Monoamine hypothesis
depression due to deficient brain monoamine transmission
Activity in different brain regions in depression
increased in amygdala, acc, ofc
decreased in striatum
Anhedonia
due to reduced response of N.Acc to positive stimuli
Dysregulated HPA axis in depression
decreased negative feedback by GR, increase CRH and ACTH and thereby cortisol. Cortisol facilitate mesolimbic DA release which leads negative bias and cognitive deficits
default mode network
active during passive rest and mind wandering
self-appraisal, self-evaluation
hyperactive in depression
task positive network
active during tasks
SNRI and NRI effect
SNRI decrease negative affects
NRI increase positive affects
VMPFC involved in
emotional response, self-confidence, self-criticism
DLPFC involved in
problem solving, sustained attention, cognitive flexibility
Acc
selective attention
amygdala
associative emotional memory
hippocampus
conscious long term memory, attribute context to stimuli
Neuroinflammatory hypothesis of depression
increased production of inflammatory markers
Neurogenesis hypothesis
antidepressants increase BDNF production which leads to neurogenesis
GABA-glutamate hypothesis of depression
depressed has Reduced GABA, increased glutamate in CSF
NMDA-R inhibition disinhibit glum release causing more AMPA transmission
Reboxetine (NRI)
normalize impaired memory of positive words
NE regulate 5HT transmission through
alpha1 and alpha2 receptors
adrenergic autoreceptor
alpha2
5HT regulate NE through
5HT2A (increase DA and NE in PFC) and 5HT2C receptors (reduce DA and NE in PFC)
TCAs
effective,
side effects due to alpha1 (orthostatic hypotension), M1/M3 (blurred vision, dry mouth constipation) and H1 antagonism (sedation, weight gain), voltage gated Na+ channels (cardiac arrhythmia, seizures)
SSRI
fluoxetine, setraline, citalopram
may cause apathic recovery by increasing 5HT, the negative affect is improved but positive affects isn’t.
SNRI
venlaflaxine
improves positive affects better than SSRI
NDRI
methylphenidate, amphetamine
less sexual side effects
may be nAchR-antagonist
NRI
reboxetine, amoxetine
Other targets
melatonin-R agonists (agomelatine), NaSSA (mirtazapine)
MAO-I
inhibits MAO enzymes
reversible or irreversible
tyramine risk of hypertensive crisis
if given with SERT can cause serotonin syndrome
5HT reduce mesolimbic and cortical DA
through 5HT2C-R in Acc (GABA, descending glutamate)
Delayed action of ADs
due to autoreceptor desensitization:
- chronic NET inhibition can desensitize terminal alpha2-R
- chronic SERT can desensitize 5HT1A and 5HT1B/D autoreceptors. 5Ht transmission is attenuated by increased 1A stimulation, chronic stimulation leads desensitized 1A-R causing firing to normalize.
AMPA and NMDA ratio
chronic AD treatment cause decrease in NMDA-R sensitivity, which increase AMPA expression. ADs shifts toward AMPA
side effects of SERT inhibition
anxiety: 5HT2A/C overactivation
suicidal: changes in 5HT2A transmission
sexual: 5HT1B/C
nausea: 5HT3
psilocybin in despression
fast acting, long lasting, blast 5HT2A-r stimulation
symptoms of anxiety
Fear and worry (sleep, concentration, fatigue, arousal, panic attacks)
Regulation of fear
overreactive connections between amygdala and Acc+OFC
Fear expression
expressed by motor avoidance (amygdala and PAG), increased cortisol (heart disease, diabetes), increasing respiration rate (PBN via amygdala), increased HR and BP (LC and amygdala)
characterization of anxiety disorders
excessive and aberrant responding under conditions of threat. Inflated estimates of probability and consequences = judgement bias
can be triggered by traumatic memories hippocampus activating amygdala
Fear is amygdala centered
emotional response to actual threat/stressor, quick, on-set, brief
panic, phobia
anxiety is CSTC centered
sustained emotional response to unpredictable threat
anxious misery, obsessions
Cause of fear and worry
amygdala hyperactivity causing glutamate release
BDZ, alpha2delta, SERT, 5HT1A-R reduce this
GAD (anxiety based)
generalized and persistent anxiety - not restricted to particular circumstances.
symptoms are nervousness, sweating, trembling
intolerance of uncertainty
dysregulated HPA axis, elevated cortisol, low GABAA-R
treated with: SSRI, SNRI alpha2delta ligands, 5HT1A-R partial agonist
PD (fear based)
recurrent panic attacks not restricted to particular circumstances
chest pain, choking, dizziness
No HPA dysregulation
SSRI, SNRI, alpha2delta ligands
avoidance maintained by cognitive appraisal
Phobia (fear based)
anxiety evoked in well-defined situations
focused on individual symptoms
SSRI, SNRI, alpha2delta ligands
beta-blockers may dampen blushing, tremor, nausea
PTSD (anxiety based)
reexperiencing and avoiding traumatic memories
traumatic stressor is criteria
due to decreased alpha2R sensitivity leading to increased cortical NE
sensitized HPA -> low cortisol
SNRI, SSRI, alpha-delta ligands, alpha1 antagonists prevents nightmares
OCD
recurrent obsessive thoughts, compulsive rituals, if resisted anxiety gets worse
buspirone is partial 5HT1A agonist
-
NE hyperactivation in anxiety
= anxiety, panic, tremor,
treat with alpha1 or beta blockers
Fear extinction
progressive reduction of response to stimuli as VMPFC learns new context for feared stimuli. Produces GABA inhibition by activating glutamate neurons
fear conditioning
stressfull stimuli is relayed to amygdala and integrated with input from VMPFC and hippocampus. Amygdala may remember stimuli and increase efficiently of glutamate neurontransmission making future response more efficiently triggered.
MDMA in anxiety
reduce sense of fear by increasing 5HT2A-R, Ne, DA, alpha2 activation
Rem sleep is characterized by
motor atonia = due to sleep specific ACh activated inhibitory circuit
brain region allowing sleep
hypothalamus filtering out sensory transmission
wakepromoting neurotransmitters
5HT, NE, Ach, histamine
sleep promoting neurotransmitters
MCH, GABA, ACh, adenosine
high firing neurotransmitters in REM
ACh
high firing neurotransmitters in awake
ACh, 5HT, NE, H
Adenosine hypothesis
increases sleep. Accumulating extra cellular concentration during wakefulness. The increased concentration inhibits waker,oyinh cells, when this activity is sufficiently decreased sleep is induced. Concentration decrease during sleep.
Orexin neurons
located in lateral hypothalamus. fire in awake, silent in asleep. induce behavioral arousal excites Ach neurons in wakefullness, 5HT, H, Ne all involved in wakefullness = Arousal
MCH (melanin concentrating hormone)
in lateral hypothalamus
increase REM duration, release GABA
wake promoting regions
LC, TMN, raphe
melatonin
SCN passes information onto pineal gland which synthesize and secrete melatonin, inhibited by light exposure
increases sleepiness, master clock for timing
insomnia
disruption of thalamic filters i CSTC loops
-> local thalamic GABA transmission deficient at night = massive sensory input
OR
stress activating HPA axis, increasing cortisol blocks sleep
consequences of sleep deprivation
increased BP, mood changes, elevated metabolic rate hyperalgesia
Sleep wake switch
in hypothalamus.
VLPO is sleep switch mediated by GABA
TMN is wake switch mediated by Histamine
Drugs for insomnia
GABAA-PAMs (BDZ, barbiturates, z-drugs), histamine drugs (H1 antagonism), melatonin (M1/M2 agonism)
EDS
problem with sleep/wake switch
treated with wakefulness drugs like orexin agonists
Drugs causing sedation
histamine, anticholinergic, alpha adrenergic, 5Ht enhancers, melatonin-R agonists
Restless leg syndrome,e
cause of insomnia
urge to move legs, relieving pain, worsening at rest
ion deficiency
alpga2 agonistst, Da agonists, opioids, BDZ
sleep disturbance indicators
high NE and CRH
REM sleep behavior disorder
vigorous and injurious behavior in REM sleep,
Narcolepsy treatment
treated with GHB, midnafinil, amphetamine,
function of sleep
maintain healthy immune system (comprises immune system), metabolism (risk of metabolic syndrome), healthy cognition.
function of sleep
maintain healthy immune system (comprises immune system), metabolism (risk of metabolic syndrome), healthy cognition.
symptoms of ADHD
hyperactivity, impulsivity, sustained attention, selective attentive
selective attention in ADHD due to
unability to activate ACC this recruiting other regions (dysfunctional CSTC-loop)
Motor activity in ADHD due to
regulation by PFMC
dysfunctional CSTC-loop
Sustained attention in ADHD due to
regulation by DLPFC
dysfunctional CSTC-loop
Impulsivity in ADHD due to
regulation by OFC
dysfunctional CSTC-loop
Insufficient NE/DA in ADHD
distracted, impulsive, poor judgement, impaired working memory,
Excessive NE/DA in ADHD
stressed, hyperactive, distractible, inattentive
Fine tuning signal-to-noise ratio in ADHD
hypofrontality in PFC for executive functioning.
NE increase sensitivity for relevant stimuli, DA decrease sensitivity for irrelevant stimuli
alpha2 and D1 receptors on dendritic spines gate incoming signals.
If HCN channel is open, signal leaks and is lost.
NE keeps channel closed, DA opens channel.
default mode network in ADHD
interrups task positive network during attention tasks
treatment of ADHD
methylphenidate, ampetamine, amoxetine, guanfacine, stimulants (normalize mesolimbic DA, reduce amygdala)
Reuptake transporters in PFC
low DAT, high NET
Reuptake transporters in NAcc
low NET, high DAT
Gate control theory
Abeta-fibers can disrupt sensation of pain, by exciting neurons that can inhibit pain carrying neurons by releasing GABA
Neuropathic pain
pain caused by lesion or disease of somatosensory nervous system
Abeta fibers
non-noxious, mechanical stimuli (myelinated)
Adelta fibers
noxious, chemical stimuli (myelinated)
C fibers
noxious, heat and chemical stimuli (unmyelinated)
Delaying discount in ADHD
decay of subjective experience of reward value, if reward delivery is delayed
- delays faster in impulsive
- challenges ability to tolerate delayed gratification.
lack of DA response to stimuli can cause distress and delayed gratification.
(less striatal response to reward anticipation in DA, more to reward delivery)
segmentral central sensitization
can increase pain as chronic firing in dorsal horn leads to exaggerated or prolonged response to inputs
suprasegmentral central sensitization
from peripheral injury
- thalamus or cortex amplifies pain
- pain can occur without peripheral input
Desccending NE and 5HT
can inhibit pain
treatment of neuropathic pain
TCA, SSRI, SNRI, anticonvulsants
inherent reward
intrinsic
not inherent reward
extrinsic
Intensifying hedonic experiences
DA release in NAcc
can be stimulated by coke, my-opioid R
repeated opioid use
cause down regulation of my-opioid-R leading my tolerance and dependence
BDZ in addiction
disinhibit reward circuit, chronic use down regulate GABAA-R = tolerance and dependence
Alcohol
PAM at GABAA-R, chronic intake down regulate expression extrasynaptically -> leading to decreased excitability of neurons, chronic reduce baseline GABA transmission and increase glutamate,
stimulate my-opioid-R, Cb1 activation
Gateway hypothesis
alcohol, nicotine, cannabis are gateway drugs increasing risk of moving on to harder drugs
diagnostic criteria for addiction
impaired control, social impairment, risky use of substance, pharmacological criteria
Tolerance
reduction in drug effect, requiring increased dose to maintain effective dose
Dependence
response to a drug whereby removal gives unpleasant symptoms
Addiction
drug taker feels compelled to use drug and suffers from anxiety when separated
