Exam 2: Chapter 5 - Catecholamines

name the catecholamines

• dopamine (DA): dopaminergic

• Noepinephrine (NE): noadrenergic

• Epinephrine (EPI): adrenergic

T or F: DA, NE, and EPI serve only as neurotransmitters

F: they serve as neurotransmitters, neuromodulators, and hormones

dopamine functions

executive functioning (attention, inhibition, working memory, behavioral flexibility), motor control, arousal, reward

Noepinephrine functions

• alertness, arousal, attention, feeding behavior, sleeping behavior, mood, learning and memory

• reduce background noise and increase response to strong stimulation

epinephrine function

• fight or flight response, regulates cardiac and respiratory function

• present in few neurons (more involved in PNS than the CNS)

what umbrella are catecholamines under

monoamines

structure of catecholamines

• core structure is catechol

• has an amine group attached

catecholamine synthesis

1. tyrosine (amino acid) is converted by enzyme tyrosine hydroxylase (TH) into L-DOPA

2. L-DOPA is the precursor to DA. It is converted to DA via AADC enzyme.

3. DA is converted to NE via dopamine B-hydrozylase enzyme (DBH)

4. NE is converted into EPI via PNMT enzyme

what enzymes do DA neurons contain

TH and AADC

what enzymes do NE neurons contain

TH AADC and DBH

what enzymes do EPI neurons contain

TH, AADC, DBH, and PNMT

where is NE synthesized?

in synaptic vesicles

what is the rate-limiting enzyme in the catecholamine synthesis pathway?

• tyrosine hydroxylase (TH) since it is the first enzyme in the production of catecholamines (converts tyrosine into LDOPA)

• means that this step occurs at a slower rate than subsequent reactions in the pathway

how do high levels of DA or NE in the nerve terminal impact tyrosine hydroxylase

TH is inhibited to stop production of these NTs

how does a high rate of cell firing impact TH activity?

high rates of cell firing stimulates TH activity to produce more DA/NE

how are catecholamines stored?

in synaptic vesicles; they are packaged into the synaptic vesicles by passing through vesicular monamine transporters (VMAT)

where is VMAT1 located?

adrenal medulla

where is VMAT2 located?

CNS

if a drug is an antagonist to VMAT it would increase/decrease the amount of NT in the brain

decrease

Neurons release a ___________ amount of catecholamine neurotransmitter

predetermined; this protects the NT from being degraded by enzymes outside the vesicles in the neuron terminal

why would we want to inhibit the amount of DA we release?

without inhibition of DA release, we would be extremely irrational and impulsive; shown by mice that were too hyperactive when they had DAD2 receptor knocked out

how are catecholamines released?

• usually via exocytosis (requires an action potential)

• exception: amphetamine and methamphetamine can cause the release of catecholamines independent of nerve cell firing (AP)

how is catecholamine release inhibited?

via terminal and somatodendritic autoreceptors

terminal: reduce amount of Ca2+ that enters the terminal (less NT packaged into vesicles) and enhances opening of voltage-gated K+channels causing hyperpolarization of the terminal

somatodendritic: reduce the cell firing rate

which receptor subtype is the DA autoreceptor?

D2 receptor subtype

which receptor subtype is the NE autoreceptor?

a2 receptor subtype

how is extracellular DA modulated in the brain?

phasic and tonic transmission

what is tonic transmission?

• 4-5 Hz

• when small amounts of DA are released without being preceded by presynaptic action potentials

• picks up activity of other neurons, neurotransmitter reuptake

• categorized by spontaneous firing at low rates

what is phasic transmission?

• 20 Hz (firing at high rate)

• driven directly by APs in DA-containing cells

• caused by events of motivational significance (unexpected primary rewards) and stimuli that predict reward

• Extra spikes that occur in bursts

what is a varicosity?

bulge along an axon, cell body or dendrite of a DA or NE neuron filled with synaptic vesicles that releases NT

how are catecholamines inactived?

1. reuptake: NT is taken up into nerve terminal via a transporter (DAT for dopamine or NET for NE)

2. NT is repackaged into a synaptic vesicle or broken down by an enzyme to prevent excessive NT accumulation/avoid neurotoxic event

what is a DAT?

dopamine transporter for reuptake

what is a NET

NE transporter for reuptake

what enzymes metabolize catecholamines to inactivate them?

• catecholamine-O-methyltransferase (COMT)

• Monoamine oxidase

  • MAO-A (breaks down NE)

  • MAO-B (brekas down DA)

what is the flow of excretion for metabolites after DA/NE are broken down?

metabolites move from CSF to the bloodstream to the urine (so the highest concentration of metabolites is in the CSF)

what are the metabolites you can test for to give idea of NE/DA brain activity?

• DOPA-C (metabolite for DA)

• HVA (metabolite for DA)

• MHPG (metabolite for NE)

how is task performance affected when amount of DA is too low/high?

when too low: subject has cognitive impairment, inattention, drowsiness

when too high: subject has cognitive impairment, anxiety, and dysphoric psychosis

how is task performance affected when amount of NE is too low/high?

too low: subject shows sedation

too high: subject has stress

what are the four DA pathways?

1. nigrostriatal

2. mesolimbic

3. Mesocortical

4. tuberinfundibular

DA pathways: nigrostriatal

• control of voluntary movement; damage to this pathway results in Parkinson’s

• cell bodies are in the substantial nigra and axons end in dorsal striatum

DA pathways: mesolimbic

• mediation of stimuli (rewarding and aversive)

• dysfunction: addiction

• cell bodies are in the ventral tegmental area and axons stretch to the nucleus accumbens

DA pathways: mesocortical

• cognitive functions (attention, working memory, decision making)

• neurons originate in the ventral tegmental area and axons stretch to the prefrontal cortex and continue into motor areas

DA pathways: tuberoinfundibular

• regulates prolactin secretion by the pituitary gland

• neurons originate in the pituitary and axons stretch to the hypothalamus

due to its extensive projections, DA acts as a _________

neuromodulator; influences the function of local neuronal populations by moving outside the synapse

What does DA do outside the CNS?

• used as a paracrine messenger (molecules secreted by a cell that act on nearby cells)

• ex: when DA is present in the blood vessels it inhibits NE release

how does NE act as a neuromodulator

it is often released steadily so that it can prepare supporting glial cells for calibrated responses (keeps brain awake/attentive)

which DA receptors are in the D1-like family?

D1, D5

which DA receptors are in the D2-like family?

D2, D3, D4

which dopamine receptors are excitatory?

D1-like family (D1, D5)

stimulates adenylyl cyclase which causes more cAMP to be synthesized and subsequently activation of PKA

which dopamine receptors are inhibitory?

D2-like family (D2, D3, D4)

inhibit adenylyl cyclase which decreases cAMP levels

are DA receptors metabotropic or ionotropic?

metabotropic

which dopamine receptor is a common autoreceptor?

D2

vesicular transporters rely on what to get neurotransmitters packaged into the vesicle?

• they rely on a proton gradient created by the hydrolysis of ATP

• v-ATPase hydrolyzes ATP, causing protons to be pumped into synaptic vesicles. This creates a proton gradient. The movement of H+ ions out of the vesicle back into the synapse is favorable and provides energy to bring NT into the vesicle through the VMAT transporter

where do neurotransmitters get their energy to enter /leave the synapse

• electrochemical gradients

• glutamate uses energy obtained by the cotransport (symport of Na+) to enter the cell

how do monoamine transporters (DAT and NET) work?

• DAT brings dopamine back into the nerve cell and NET brings NE back into the nerve cell

• this transporter is a symporter that requires 2 Na+ ions and 1 Cl- ion to sequentially bind with the DA substrate to cause a conformation change

• specifically, Na+ ions must bind to the transporter intracellularly before DA can bind and cause conformation change

DAT couples to ___ channels

Ca2+ channels; DAT activation can open Ca2+ channels

NE pathway in the CNS

cell bodies of NE neurons are in the nucleus coeruleus; their axons are lined with varicosities to release NT and project to all areas of the forebrain, cerebellum, and spinal cord

NE in the PNS

• NE is main NT used by SNS

• located in ganglia on the sympathetic chain (activates all organs at once in sympathetic NS during fight or flight)

• hormone secreted by the adrenal glands

T or F: blood borne NE can cross the BBB

false it cannot

which catecholamine mediates the sympathetic NS?

NE

NE receptors (alpha and Beta) are metabotropic/ionotropic

metabotropic

NE receptor subtypes

• Alpha (a1, a2)

• Beta (B1, B2)

a1 receptor is _____ (excitatory/inhibitory)

• excitatory in response to NE/EPI binding

• stimulates phospholipase C which increases free Ca2+

• metabotropic

a2 receptor is _____

• inhibitory in response to NE/EPI binding

• inhibits adenylyl cyclase

• enhances opening of voltage-gated K+ channels causing hyperpolarization of the terminal

Beta receptors (B1 and B2) are ______

• excitatory in response to NE/EPI binding

• stimulate adenylyl cyclase, causes cAMP to be synthesized, activation of PKA

T or F: EPI also uses alpha and Beta receptors

true EPI uses the same receptors as NE

______ (EPI/NE) is primarily a NT while ______ (EPI/NE) is primarily a hormone

NE; EPI

EPI neurons (those containing PNMT enzyme) are found where?

brain stem regions, hypothalamus, spinal cord

what specific brain stem regions are EPI neurons found in?

1. area postrema (not enclosed by BBB so things can directly diffuse in)

2. nucleus of the solitary tract

Difference in involvement of NT’s between parasympathetic and sympathetic NS

• in sympathetic NS, the NT released from the preganglionic neuron onto the ganglion is ACh but the NT secreted by the ganglion onto the target is EPI/NE

• in parasympathetic NS, ACh is the only NT released (released by preganglionic fiber AND released on to target by ganglion)