Chapter 11: ADHD Flashcards
what CSTC pathway modulates the ability to sustain attention
from the DLPFC to the striatal complex
what causes symptoms of inattention in ADHD such as inability to finish tasks, disorganization, and trouble sustaining mental effort
inefficient information processing in the DLPFC
what CSTC loop pathway modulates selective inattention and inability to focus
CSTC loop from dorsal anterior cingulate cortex to striatal complex, then thalamus, back to dorsal anterior cingulate cortex
inefficient activation of which pathway leads to deficits in selective attention like not listening, losing things, focusing, making careless mistakes
CSTC loop from the dorsal anterior cingulate cortex to striatal complex, thalamus, and back to dorsal anterior cingulate cortex
which CSTC pathway modulates hyperactive symptoms
from prefrontal motor cortex to the putanem, thalamus, and back to prefrontal motor cortex
which CSTC loop pathway is associated with impulsive symptoms such as talking excessively, blurting out things, interrupting, and not waiting for one’s turn
CSTC loop from the orbital frontal cortex to the striatal complex, thalamus, and back to orbital frontal cortex
what area of the brain is associated with impulsive symptoms
orbital frontal cortex
what other psych conditions (common comorbidities) are also associated with the orbital frontal cortex
conduct disorder
ODD
bipolar
which areas of the brain are most associated with sustained and selective attention deficits
DLPFC and dACC
what area of the brain is most associated with symptoms of impulsivity and hyperactivity
alterations in the orbital frontal cortex
what neurotransmitters are associated with regulation of attention and behavior
dopamine and norepinephrine
what happens if tonic firing of norepinephrine neurons innervating the PFC is too low
problems with cognitive functioning
what happens when norepinephrine levels are too high
anxiety, substance abuse, mania, and problems with working memory
what happens with dopamine receptors when tonic firing of dopamine neurons is too low
sensitive postsynaptic D3 receptors are stimulated but there is inadequate dopamine to stimulate D1 which causes inadequate downstream neuronal signaling resulting in cognitive dysfunction
How does methylphenidate block NETs and DATs
allosterically with no action at VMAT2
how does amphetamine block NET and DAT
it is a competitor and pseudo substrate for them. So they bind at the same transport site, preventing the monoamines from binding there
which isomer is more potent for DAT binding
D
How does atomoxetine work
blocks NETs in the PFC which increases both dopamine and norepinephrine
what is the minimum threshold of DAT occupancy required for therapeutic action in ADHD
50-60%
what medication is good for augmenting stimulants when there are oppositional symptoms
clonidine
what receptors, located on the spines of cortical pyramidal neurons, can gate incoming signals
a2A and D1 in the PFC
how are a2A receptors in the PFC linked to cAMP molecules
via an inhibitory G protein (Gi)
how are D1 receptors in the PFC linked to cAMP molecules
stimulatory G proteins (Gs)
which type of channel strengthens incoming signals
closed
what does stimulation of D1 receptors in the PFC lead to
weakening of incoming signals
how does stimulation of D1 receptors in the PFC open channels to weaken incoming signals
when dopamine/agonist binds to D1 it activates the Gs-linked system that results in HCN channel opening leading to signal leakage and shunting input out of the spine
what does stimulation of a2A receptors in the PFC do to incoming signals
when NE/agonist binds to a2A it activates the Gi-linked system that results in closing the HCN channel allowing the signal through to strengthen connectivity to similar neurons
what if the same neuron receives NE input at an a2A receptor on one spine and DA input at a D1 receptor on another spine
D1 stimulation can turn down the noise while a2A stimulation can increase the signal resulting in proper PFC functioning
what if there is not enough stimulation of both a2A OR D1 receptors
increased noise and decreased signal
what is the gist of pruning
synapses rapidly increase in the PFC until age 6 and then half are eliminated by adolescence (over-produced or weak synapses are eliminated to allow for cognitive maturation)
order of comorbid symptom treatment with ADHD
- substance abuse disorder
- mood disorders
- anxiety disorders
- ADHD
- nicotine dependence
ADHD can result from what type of levels of NE and DA
too high or too low
MOA of methylphenidate
blocks NETs and DATs allosterically with no action at VMAT2
common brand names for methylphenidate DL
ritalin
concerta
common brand name for methylphenidate D
focalin
of D and L, which isomer of methylphenidate is more potent for both NETs and DATs
D
MOA of amphetamine
competitive inhibitor and pseudo-substrate for NET and DAT
-binds to the same transporter sites as monoamines, thus inhibiting their reuptake
how does amphetamine abuse cause euphoria
after competitive inhibition of DAT, amphetamine is transported to presynaptic DA terminals where it is also a competitive inhibitor of VMAT2 for both DA and NE. Once in the synaptic vesicles DA there is displaced causing a flood of DA release. As it accumulates in the presynaptic neuron the direction of DATs is reversed spilling intracellular DA into the synapse. This opens presynaptic channels to further release dopamine into the synapse
which amphetamine isomer is more potent for DAT binding
D
which type of amphetamine has more action on DATs than NETs
D-amphetamine
D and L amphetamine isomers action on NETs
about equal for NET binding
DAT and NET binding of mixed salts over D-amphetamine
mixed salts have more action on DATs than NETs but still more action at NETs that D-amphetamine
how do you attain immediate therapeutic actions by inhibiting DAT
DAT occupancy levels above a critical threshold
Minimum threshold for action is 50-60%
how does atomoxetine work
selective NE reuptake inhibitor
blocking NETs in the PFC versus the Nucleus accumbens
blocking NET in the PFC increases both DA and NE there. Blocking NET in the nucleus accumbens does not increase DA and NE as there are relatively few NE neurons there. This is why NET inhibitors do not have abuse potential
what are some other medications with notable norepinephrine reuptake inhibition
wellbutrin
desipramine
nortriptyline
where is the highest concentration of a2A receptors
cortex
locus coeruleus
what do a2A receptors mediate
NE effects in the PFC (regulates sx of inattention, hyperactivity, and impulsivity)
location with the highest concentration of a2B receptors
thalamus
which receptor is important in mediating the sedating effects of NE
a2B
where are a2C receptors densest
striatum
opposing actions of a2 and a1
-when NE is low a2 mechanisms at the synapse predominate
-when NE is high a1 mechanisms at synapses predominate
which adrenergic receptors are guanfacine most selective for
a2A
guanfacine v. clonidine for sedation and BP reduction
10x weaker than clonidine for sedation but more potent at enhancing PFC function
what else is guanfacine approved for
augmentation for patients with oppositional symptoms
clonidine selectivity for a2 receptors
relatively nonselective with action at a2A, a2B, and a2C
off label indications for clonidine
conduct disorder
ODD
tourette’s
when is clonidine good for augmenting stimulants
when there are oppositional symptoms
