CH 5 Flashcards
NE and EPI are released from the ____ _____, and EPI transmission in the brain is _____
adrenal medulla, minor
DA and NE subserve important behavioural functions (5)
- motor, 2. learning and memory, 3. attention, 4. reward, 5. motivation and emotions
Dysfunctional catecholamine transmission has been linked to numerous diseases such as _____, ____, _____, _____ and _____ ____
Parkinson’s, Schizophrenia, Depression, ADHD, drug addiction
the amino acid that is the precursor to DOPA
tyrosine
then enzyme that converts tyrosine to DOPA; is slow
tyrosine hydroxylase
TH is the _____ enzyme in the pathway that determines the overall ________ synthesis
rate-limiting, DA/NE
TH and ____ _____ are found in neurons that make ______.
dopamine decarboxylase, DA
the enzyme that converts DOPA to dopamine; is fast
dopamine decarboxylase
the enzyme that converts dopamine to norepinephrine
dopamine beta-hydroxylase
____ catecholamine levels inhibit TH activity through ____ _____. Increased ___ of firing during times of ____ stimulates TH to accelerate catecholamine synthesis
high, negative feedback, rate, stress
a drug that is a precursor to dopamine and quickly taken up; increases DA levels
L-DOPA
a drug that blocks TH, preventing synthesis of DA and NE
alpha-methyl-para-tyrosine (AMPT)
AMPT induces _____, depression, reduced ____ _____, and its effects can be reversed with ______
sedation, blood pressure, L-DOPA
transporter that packages DA/NE into vesicles
vesicular monoamine transport (VMAT)
Drug that blocks VMAT, preventing DA and NE from being packaged, and making transmitter levels drop
reserpine
reserpine causes sedation and _____ as well as ___ effects - this effect led to the ______ theory of depression
depression, systemic, monoamine
the enzymes that metabolize catecholamines
monoamine oxidase (MAO), catechol-O-methyltransferase (COMT)
the main DA metabolite
homovanilic acid
the main NE metabolite in the brain
3-methoxy-4-hydroxy-phenylglycol (MHPG)
Metabolites enter the ____ and ____ and are eliminated via _____
CSF, bloodstream, urine
a MAO inhibitor used to treat clinical depression
phenelzine (Nardil)
A COMT inhibitor that enhances the effectiveness of L-DOPA in treating Parkinson’s disease
tolcapone (tasmar)
Many DA and NE terminal are _____ ___ with no direct connection. Their axons exhibit repeated swellings / _______ filled with synaptic vesicles that form ____ _____ synapses. Some form tight synapses onto ____, but many do not. This allows for ______ transmission
free floating, varicosities, en passant, dendrites, volume
DA membrane transporter protein that removes DA from the synaptic cleft
DAT
NE membrane transporter protein that removes NE from the synaptic cleft
NET
NET and DAT can also take up _____ and ____ respectively, because of similar structure of the two molecules
DA, NE
Blocking NET or DAT leads to greater ______ NT levels; transmitter levels build up with each _______. If catecholamine neurons are not firing, blocking NET or DAT ________ increase transmitter release.
extracellular, impulse, do not
drug that inhibits reuptake of all monoamines (DA, NE, 5-HT)
cocaine
drugs that inhibit reuptake of both NE and 5-HT
tricyclic antidepressants
Drug that selectively inhibits reuptake of catecholamines
methylphenidate (ritalin)
a drug that selectively inhbits reuptake of NE transporters
statera
drugs that reverse the DA/NE transporter so that molecules from inside the terminal are pushed out into the synapse
amphetamines
amphetamines increase transmitter release _____ of cell firing, and are relatively _______, acting on _____, ____ and also ____ terminals
independent, non-selective, DA, 5-HT, NE
Amphetamines that enter the brain increase _____ activity. This is primarily driven by increased ___ in the _____. At higher doses, this is replaced by _____ behaviours such as intense sniffing, repetitive ____/____ movements, licking, and biting.
locomotor, DA, NAcc, stereotyped, limb/head
Lower doses of amphetamine ____ DA release in the accumbens, while at higher doses, more DA activation occurs throughout the ____ ______
saturates, dorsal striatum
when repeated exposure causes increase in sensitivity to effects of the drug at the same dose
Sensitization
Involves two groups getting the same starting dose of amphetamine, then daily injections of either saline, or high doses of amphetamine for 5 days. On test day, both groups get the same dose of amphetamine, but only the amphetamine group will have a greater locomotor response
amphetamine induced locomotion
Drugs have multiple _____, some can develop tolerance, while others _____ in parallel. Most drugs of abuse with high addictive potential can produce ______ of some effects with repeated exposure
actions, sensitize, sensitization
At lower doses, drugs like _____ have a number of therapeutic effects such as working as a powerful _____ to promote wakefulness. However, one key side effect is that it reduces ____ sleep. It can also work as a cognitive enhancer for _____, ____ ____ and ____ ____, in healthy humans and in those with certain psychiatric disorders. This is thought to be mediated by enhancing catecholamine activity in the ____ _____. However, enhancement of these functions comes at the sacrifice of other functions such as _____ _____. Prolonged use at higher doses may lead to longer-lasting, _____ alterations in brain systems
amphetamine, stimulant, REM, attention, working memory, memory encoding, frontal lobes, creative thought, detrimental
Monoamine _______ reside on axon terminals and cell bodies. Activation enhances opening of ______ K+ channels and shortens duration of _______ _______. On terminals, this reduces _____ influx and transmitter exocytosis. On cells bodies, this reduces neural ______.
autoreceptors, voltage-gated, action potentials, Ca2+, firing
Firing at a cell body causes ______ release which acts on _______ _____ to reduce neural firing
local, somatodendritic autoreceptors
DA receptor that is an autoreceptor and also postsynaptic receptor
D2 receptor
NE receptor that is an autoreceptor and also a postsynaptic receptor
alpha-2 subtype
Lower doses of a D2/alpha2 _____ can have one effect (e.g. reducing catecholamine release via the ______), while a higher dose has the opposite effect by activating _____ receptors
agonist, autoreceptor, postsynaptic
Selective knockout of D2 autoreceptors in animals leads to greater DA-mediated ______ confirming that these receptors _____ DA transmission
locomotion, attenuate
cell groups that are noredrenergic
A1-A7
cell groups that are dopaminergic
A8-A16
_____ DA neurons originate in the substantia nigra and extend to the _____ _____ (dorsal striatum). This pathway facilitates ______ ________. Parkinson’s disease involves the loss of DA neurons in the substantia nigra and denervation of the _____. Neurotoxins _____ and ____ have been used to damage this pathway in animal models for PD
A9, caudate putamen, voluntary movement, striatum, 6-OHDA, MPTP
Dorsal striatum DA aids in ____ _____, promoting the best action while ____ others. Loss of DA may cause _____ movements because the striatum cannot select the best action
action selection, suppressing, rigid
the _____ cell group is in the VTA, and gives rise to the ____ and ____ pathways
A10, mesolimbic, mesocortical
The mesolimbic pathway, extends to various ___ ______ nuclei such as the NAcc and _______. DA input to the accumbens facilitates forward ______. This pathway is linked heavily to _______ and ____ functions. It is critical for facilitating ____ of rewards and other goals, but does not mediate _____
limbic, system, amygdala, locomotion, reward, motivational, obtainment, pleasure
The mesocortical pathway involves projection to the ____ _____. These DA terminals have few DA ______, and most of the DA clearance in the cortex is done by _____ and _____. This pathway is linked to _____ ____ (working memory, attention, cognitive flexibility). _______ receptors are more heavily expressed in PFC regions than _____.
frontal cortex, transporters, COMT, NET, executive function, D2, D1
DA and NE modulation of some cognitive functions such as ___ _____ takes the shape of an inverted U shaped curve. Too little or too much DA can result in _____, _____, _____ and ____ ______, as well as _____ ______. Just right DA modulation results in optimal ____, focus and attention, as well as good _____.
working memory, hyperactivity, distractibility, impulsivity, poor judgment, cognitive inflexibility, cognition, judgment
There are _____ dopamine receptor subtypes. All are _____. ____ and ____ receptors are similar in structure and pharmacology, while ____, ____ and _____ are a separate family.
five, metabotropic, D1, D5, D2, D3, D4
D1 receptor activation stimulates ___ ____ and ____ synthesis, while ____ has the opposite effect.
adenylyl cyclase, D2
D1 and D2 receptors are found in all brain regions that receive DA _____, while ____ and ____ receptors show more regional variations. In many brain regions, such as the ___ ___, there are separate populations of neurons that express only ___ or ____ receptors
innervation, D3, D4, dorsal striatum, D1, D2
D2 receptors have a _____x higher affinity for DA compared to ____ receptors. Typically ____ concentrations of DA are required to activate D1 receptors
5, D1, higher
Some DA receptors are heteroreceptors on ______ terminals that modulate ____ ____ presynaptically. For example, PFC cortical ____ terminals in the striatum contain ____ receptors, and activation of these _____ glu release
glu/GABA, fast transmission, glutamate, D2, attenuates
an agonist that sitmulate both D1 and D2 receptors causing behavioural activation similar to that seen with cocaine and amphetamine
apomorphine
DA receptor agonists are used for treatment of ___ symptoms, when L-DOPA is less effective
parkinson’s disease
an antagonist that blocks both D1-D2 receptors, reducing motivation and at higher doses, producing catalepsy
flupenthixol
lack of spontaneous movement
catalepsy
There are DA receptor drugs that show good selectivity between _____ families, but poorer selectivity ____ a family
D1/D2, within
an antagonist that has >1000x affinity for D2 like vs D1 receptors, but binds with D2, D3 and D4 with similar affinity
haloperidol
When initially, an antagonist blocks the effects of a DA agonist, but after chronic treatment, it is no longer effective, and when treatment is stopped, a DA agonist causes a greater locomotor response
dopamine supersensitivity
dopamine supersensitivity may underlie why some _____ stop working over time.
antipsychotics
greater sensitivity to a DA agonist after chronic antagonist treatment may be caused due to increased ____ of D2 receptor (receptor ____)
density, upregulation
most NE neuron cell bodies are found in the ___ and _____, in the brainstem. NE has more ____ innvervation than DA, and axons extend to nearly all of the ____ as well as the ____ and ___ ____
pons, medulla, diffuse, forebrain, cerebellum, spinal cord
The A6 cell group is a dense collection of NE neurons in the _____ ______ (pons)
locus coeruleus
the ____ nervous system uses NE that reaches its target organs by release from sympathetic noradrenergic neurons at _______ contacts onto the heart, lungs, and ____ ___, and release from___ ____ that travel in the bloodstream to target organs but cannot cross the _____. Both paths are turn on in ____ situations but are kept separate
sympathetic, synapse-like, gastrointestinal tract, adrenal glands, blood brain barrier, stressful
There are two families of adrenergic receptors, ____ and ____, both of which are ____ and distributed widely across cortical and ____ sites
alpha, beta, metabotropic, subcortical
alpha-1 receptors operate via the _____ 2nd messenger system and are _____. They exert _____ effects on organs or neurons by increasing intracellular ____.
phosphoinositide, postsynaptic, excitatory, Ca2+
an alpha-1 receptor agonist
phenylephrine
an alpha-1 receptor antagonist
prazosin
alpha-2 receptors reduce _____ synthesis and serve as both _____ autoreceptors and _____ receptors. they reduce NE transmission by reducing firing of ___ ___, or by ____ the cell
cAMP, presynaptic, postsynaptic, cell bodies, hyperpolarizing
alpha-2 receptor agonist that reduces NE release in both the brain and body, slowing heart rate
clonidine
an alpha-2 receptor antagonist that blocks both postsynaptic and autoreceptors, leading to an anxiogenic type response
yohimbine
beta-1 and beta-2 receptors stimulate ___ ____ and enhance synthesis of _____. In the periphery, beta-1 receptors are on ____ cells.
adenylyl cyclase, cAMP, cardiac
an agonist for beta-1 or beta-2 receptors
isoproterenol
an antagonist for beta-1 or beta-2 receptors
propranolol
NE is key for maintaining _____. LC neurons fire more rapidly during waking vs ______, and they are almost completely silent during ______. NE projections to the medial _____ and medial ____ areas promote wakefulness. Intracranial injections of alpha-1 or beta receptor _____ increase _____ times. Pharmacological reduction of NE activity typically cause ____ at higher doses
arousal, sleep, REM, septal, preoptic, agonist, awake, sedation
Pharmacological increases in NE can promote _____ feelings of anxiety in animals and humans. Humans tested on the virtual version of the _____ ____ _____, spend ____ time in open arms. This is increased with administration of _____, whereas an _____ ______ has the opposite effect.
stress-like, elevated plus maze, less, yohimbine, anxiolytic benzodiazepine
NE regulates cognitive functions mediated by the ____ such as attention, and working memory. Reserpine ______ performance in the delayed object recognition task. Experimental or _____ depletion of PFC NE is detrimental for these functions. Aged monkeys given a _____ during a task show greater _____ than younger monkeys If NE signalling is boosted during the distractor, performance returns to ____
PFC, decreases, age-related, distractor, impairment, baseline
activation of PFC _____ receptors by ______ relieves working memory impairments likely via activation of ______ receptors, suggesting that under normal conditions, NE facilitates PFC function via activation of these receptors.
alpha-2, guanfacine-GFC, postsynaptic
Stress can cause ____ increases in PFC NE levels and impair ____ _____. It is proposed to take the PFC ____ so that sensory-motor / affective regions have greater ____ over behaviour. Stress induced impairments in PFC function are driven in part by _____ receptors. Stimulating PFC ____ receptors impairs cognition. Antagonizing them can ____ stress-induced impairments.
excessive, cognitive function, offline, control, alpha, alpha-1, ameliorate
NE has a lower affinity for _____ receptors vs ____ receptors. ______ concentrations of NE activate _____ receptors and start counteracting the effects of activation by alpha-2 receptors
alpha-1, alpha-2, higher, alpha-1
An alpha-1 receptor _____ by itself, does not have any effect, while in combination with ____ it ameliorates stress induced cognitive impairment. Stress induced increase in NE may increase ____ receptor activation, which leads to cognitive impairment
antagonist, stress, alpha-1
NE may mediate ____ ____ that is enhanced by strong ___ ____. ______ receptor antagonists disrupt the enhancement of memory for _____ but not _____ content without disrupting the ____ ______. Emotional events increase NE release in the ____, which can enhance consolidation of memories. This may be the type of memory modulation underlying _____
memory consolidation, emotional states, beta-adrenergic, emtoional, neutral, emotional response, amygdala, PTSD
