PSYC 383 Midterm 2

What is a catecholamine? Name some examples.

Catecholamines are monamines: catechol + amine group

• Dopamine (DA)

• Norepinephrine (NE)

• Epinephrine (EPI)

They act as neurotransmitters and neuromodulators

Catecholamines are synthesized from ______

Tyrosine

How can catecholamine synthesis be increased?

By administering precursors such as tyrosine or L-DOPA, which is used to treat Parkinsons

What does the enzyme Tyrosine hydroxylase (TH) do?

• Converts Tyrosine: It changes the amino acid L-tyrosine into L-DOPA

• Creates Catecholamines: L-DOPA then turns into dopamine, which can further change into norepinephrine (noradrenaline) and epinephrine (adrenaline)

• Acts as a Rate-Limiter: It is the slowest, most crucial step in this production line. By setting the pace, it dictates how much of these vital brain signals get made

How would one reduce the synthesis of catecholamines?

The drug α-methyl-para-tyrosine (AMPT) blocks TH from doing its thing

What are 2 factors that affect TH activity?

• Dopamine and Norepinephrine levels in the nerve terminal (negative feedback)

• Cell firing stimulates TH activity through phosphorylation of the enzyme by protein kinases

Can you go through catecholamine synthesis step by step?

Tyrosine hydroxylase (TH) synthesizes Dopa from tyrosine by removing a hydroxide ion, Dopa is inactive so then aromatic amino acid decarboxylase (AADC) converts it into dopamine by removing a carboxyl group, then dopamine β-hydroxylase hydrolyzes dopamine, converting it to norepinephrine

Catecholamines are loaded into synaptic vesicles by ________

vesicular monoamine transporters (VMAT)

Vesicular monoamine transporters (VMAT) can be blocked by _______ which is an _________; causes sedation and depressive symptoms

reserpine, irreversible inhibitor

Reversible inhibitors of VMAT are used to do what?

Reduce uncontrolled movements in Huntington’s disease

Psychostimulants like ________ and _________. cause release of catecholamines without neuron firing. What effect can this have on humans?

amphetamine and methamphetamine

Drug effects include increased alertness, high energy levels, euphoria, insomnia

How does methamphetamine cause the release of catecholamines?

Methamphetamine causes the massive release of catecholamines (like dopamine, norepinephrine, and epinephrine) by entering presynaptic nerve terminals, the basic state of meth disrupts the acidic environment of the vesicle and causing the neurotransmitters to be released into the cytosol of the terminal. Meth also binds onto monoamine oxidase (MAO) to inhibit it from degrading the excess catecholamines

As catecholamines accumulate rapidly in the cytoplasm, the concentration gradient across the cell membrane completely flips. This high internal pressure forces the cell membrane transporters (DAT and NET) to operate in reverse. Instead of clearing neurotransmitters out of the synaptic cleft (reuptake), the transporters act as open gates, continuously pumping dopamine and norepinephrine out into the synapse

Dopamine release is inhibited by autoreceptors, what channels influence this?

The inhibition of voltage-gated Calcium channels, and activating voltage-gated Potassium channels

Dopamine is always firing at a ______ release

tonic (single-spiking mode; action potentials appear at irregular intervals)

The breakdown of Catecholamines involved _______ and _______

monoamine oxidase (MAO) and Catechol-O-methyltransferase (COMT)

Why are nonselective MAO inhibitors dangerous for the treatment of depression?

If you take MAO inhibitors, your body then can’t break down Tyramine, which will increase the risk of hypertension due to excess norepinephrine release

Dopamine metabolites into:

homovanillic acid (HVA)

Norepinephrine metabolites into __________ in the brain and ______ in the PNS

3-methoxy-4-hydroxy-phenylglycol (MHPG); vanillymandelic acid (VMA)

The ________ pathway originates in the substantia nigra and innervates what?

nigrostriatal; innervates the caudate putamen

The _______ pathway originates in the ventral tegmental area and innervates what?

mesolimbic; innervates various limbic system structures such as nucleus accumbens, hippocampus, lateral septum, and amygdala

The mesolimbic pathway lacks _____ but has dopamine transporters

COMT

The ______ pathway also originates in the ventral tegmental area and innervates what?

mesocortical; innervates the cerebral cortex

The mesocortical pathway lacks ______ but can metabolize with COMT

dopamine transporters

How do you kill a dopamine neuron?

6-hydroxidopamine acts as dopamine and when it gets metabolized theres lots of oxidizing activity which the cell can’t handle so it dies

Describe the cool little spinning trick

a 6-OHDA lesion destroys nigrostriatal dopamine neurons on example the left side of the brain. the rat is now sensitive to dopamine and receptors are up regulated.

if you inject apomorphine (a D2 like agonist), it stimulates D2 receptors on the lesioned side which is now supersensitive and it produces a contralateral rotation

if you inject amphetamine, it increases dopamine release from the remaining terminals on the intact side which causes an ipsilateral rotation

___________ mice exhibit severe aphagia (lack of feeding behaviour, adipsia (lack of drinking) and hypoactivity

Dopamine-deficient (DD)

Mesolimbic dopamine pathways activates _____ and ______

arousal and locomotor behaviour

The mesocortical pathway helps regulatem______

cognitive functions like attention and working memory

D1 receptors do what?

Stimulate adenyl cyclase - increasing the rate of cAMP synthesis

D2 receptors do what?

they inhibit adenyl cyclase which decreases the rate of cAMP synthesis. (they also regulate membrane ion channels for potassium)

__ receptors have a higher affinity for DA than __ receptors

D2; D1

Norpinephrine neurons are located in the pons and medulla, but especially in the ______

locus coeruleus

NE has the same pharmacodynamic profile as ____

dopamine

Compare motor impulsivity vs Cognitive impulsivity

motor impulsivity is an impulsive action; impaired response inhibitory control (ex: shouting out the answer)

cognitive impulsivity is an impulsive choice; without forethought — immediate rewards (ex: spending not saving)

which prefrontal brain regions are involved in motor impulsivity and cognitive impulsivity?

Motor impulsivity → dorsolateral/dorsomedial PFC (humans)/medial PFC (rodents)

Cognitive impulsivity → orbitofrontal cortex

name some subcortical regions involved in impulse control

the striatum is involved in both choice and motor impulsivity;

Caudate/putamen (humans); dorsal striatum (rat) is in charge of action initiation/inhibition

Nucleus accumbens is in charge of motivational drive and catecholamine regulation of motor impulsivity

In ADHD, prefrontal catecholamine function is ____

low

Explain how Ritalin and Adderall works to help with ADHD

Ritalin: it is a reuptake inhibitor. it blocks DAT and NET so dopamine and norepinephrine aren’t “vacuumed up” back into the presynaptic terminal, leaving them in the synapse longer, increasing receptor activity in the PFC

Adderall: it is a reuptake inhibitor and a releasing agent. Like Ritalin, it blocks DAT and NET to prevent reuptake. However, Adderall also enters the presynaptic neuron. It enters storage vesicles via the vesicular monoamine transporter (VMAT) and displaces dopamine and norepinephrine, causing a direct release of these chemicals into the cell and out into the synaptic cleft.

Serotonin is an _____ meaning it is synthesized by _______

indoleamine; tryptophan

Explain the synthesis of Serotonin from tryptophan

Tryptophan is catalyzed by tryptophan hydroxylase (TPH), product: 5-hydroxyl-tryptophan (5-HTP) (this is a rate limiting step—can only convert into 5-HTP depending how much TPH is available)

5-HTP is catalyzed by aromatic amino acid decarboxylase (AADC) to form 5-HT (Serotonin)

What are the 2 forms of TPH?

TPH1 in your non-neuronal cells like gut and pineal gland

TPH2 only in serotonergic neurons

What does Telotristat do?

if you have a tumor in your intestines that are releasing too much serotonin you can get carcinoid syndrome. telotristat is a nonselective TPH inhibitor that blocks TPH1 in your peripheral system (acts outside CNS, can’t access BBB)

What does a high protein diet mean for tryptophan levels? how does insulin affect this?

High protein consumption = low tryptophan in your brain because of all the competing amino acids, this means lower serotonin synthesis

insulin stimulates the uptake of amino acids (except tryptophan) in your skeletal muscle, so tryptophan no longer has to compete for entry into the brain

______ irreversibly inhibits TPH which blocks 5-HT synthesis

Para-chlorophenyalanine (PCPA)

________ loads the body with large doses of amino acids minus tryptophan so the gate to the BBB is too crowded

Acute tryptophan depletion (ATD)

Name 2 ways to deplete 5-HT

Para-chlorophenylalanine (PCPA) and Acute tryotpphan depletion (ATD)

Name a dietary way to elevate tryptophan levels

consume a diet rich in carbohydrates but low in protein

5-HT is transported into synaptic vesicles by _______

VMAT2

Blocking ______ directly inhibits 5-HT release, while activation of _____ inhibit release by slowing the rate of nerve firing

Ca²⁺ channels; K⁺ channels

Sertotonergic neurons in the CNS are found along the midline of the brain stem, loosly associated with the _________

Raphe nuclei

Which stage in the sleep cycle has the lowest level of serotonin activity?

REM sleep

The serotonin receptor 5-HT_1A are concentrated in ______________ and what do they do?

hippocampus, amygdala, and dorsal raphe nucleus; the receptor inhibits adenyl cyclase to decrease cAMP synthesis and increase opening of K⁺ channels and membrane hyperpolarization (decreasing the excitability of the cell)

The serotonin receptor 5-HT_2A are in the _____ and other brain areas. What do they do?

Cortex; they increase Ca²⁺ levels in the postsynaptic cell; also activate protein kinase C (PKC) (increases excitability)

Describe the IP₃ signalling pathway

• A ligand binds to a GPCR

• The receptor activates PLC (phospholipase C)

• PLC breaks PIP₂ into:

  • IP₃

  • DAG

• IP₃ moves through the cytosol into the ER and binds to an IP₃ receptor there

• This opens a Ca²⁺ channel

• Ca²⁺ is released from the ER into the cytosol

• DAG + Ca²⁺ activate PKC

• PKC triggers a cellular response

Hallucinogenic effects of ________ may stem from its ability to stimulate 5HT_2A receptors

Lysergic acid diethylamide (LSD)

Several drugs used to treat ______ with reduced motor side effects act as inverse agonists at 5-HT_2A and/or 5-HT_2C receptors

schizophrenia

Receptor 5-HT_3A is _____, meaning:

Ionotropic; sodium goes in, potassium goes out

5-HT3 antagonists such as _______ can counteract nausea and vomiting associated with chemotherapy and radiation treatments

Ondansetron (Zofran)

____ and _____ receptor agonists are used to treat anxiety disorders

SSRIs and 5-HT_1A

Acetylcholine (ACh) is synthesized in one step from ______ and _______. catalyzed by __________ (no inhibitors of this)

choline, acetyl coenzyme A; choline acetyltransferase (ChAT)

ACh is loaded into synaptic vesicles by _______

Vesicular ACh transporters (VAChT)

VAChT can be blocked by _______ which reduces the amount of ACH released when neurons fire

vesamicol

ACh release is affected by _____

toxins

______ toxin blocks ACh release by preventing fusion of synaptic vesicles with nerve terminal membrane; causes what?

Botulism; muscular paralysis

Acetylcholine is broken down into _____ and ______ by __________

choline and acetic acid; acetylcholinesterase

What happens to the byproducts of ACh catabolism?

Choline is taken back up by choline transporters

What blocks the choline transporters?

hemicholinium-3. declines ACh production

a parasympathetic branch of cholinergic neurons send ___ to the target organ while in the sympathetic branch, ____ is the final neurotransmitter to the target organ

ACh, Norepinephrine

Where do nicotinic acetylcholine receptors lie?

the neuromuscular junction

The Basal forebrain cholinergic system (BFCS) projects to where?

its the the origin of cholinergic innervation of the cerebral cortex, projects to the hippocampus, and other limbic system structures

Where do cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei project to?

the basal ganglia and thalamus

From the interneurons in the striatum, regulation of movement depends in part on the balance between ___ and _____

ACh and DA

In Parkinson’s disease, low _____ levels cause transmitter imbalance; _______ drugs may be used for treatment

dopamine; anticholergic

Name and describe 2 subtypes of acetylcholine receptors

1. Nicotinic receptors → respond to the agonist nicotine. ionotropic, mediate fast, excitatory responses in both CNS and PNS. When ACh binds, the channel opens and Sodium and Calcium enter the neuron or muscle cell, which depolarizes the membrane.

2. Muscarinic receptors → respond to muscarine (an alkaloid in fly agaric mushrooms). metabotropic — operate va second messangers. M1, M3,and M5 excite the second messanger system. M2 and M4 inhibit cAMP synthesis, stimulate potassium channel opening, and inhibit nerve terminal calcium channel opening (inhibitory)

Describe the cholinergic interneurons of the striatum

Local cholinergic interneurons form a microcircuit with dopamine neuron terminals in the striatum. dopamine terminals have a beta-2 subunit containing nicotinic acetylcholine receptors. acetylcholine binding causes Calcium influx and vesicular release of dopamine. (this is thought to maintain TONIC DA levels)

What is the PIT test?

the conditioned cue is presented while the lever is available. the conditioned cue invigorates instrumental responding. there is an increased response rate of lever pressing when conditioned cue is present

Glutamate and apartate are ________ neurotransmitters (inhibitory/excitatory)

excitatory!

Vesicular glutamate transporters move glutamate into synaptic vesicles: ____, _____, ______

VGLUT1 OR VGLUT2 OR RARELY VGLUT3

In some neurons, the VGLUT are expressed with markers for 5-HT, DA, ACh, or GABA, indicating that glutamate is a _________

co-transmitter

For glutamate uptake, there are 5 different excitatory amino acid transporters that occur in different locations, give an example

EAAT3 is located on the postsynaptic cell, while astrocytes express EAAT2/EAAT1 (accounts for 90% of glutamate uptake in the brain)

EAAT2 knockout mice develop ____ and have _____ due to dangerously high glutamate levels

seizures; short life spans

Where can you find each EAAT?

EAAT1/EAAT2 → highly expressed in astrocytes in the cerebellum

EAAAT3 → postsynaptic localization

EAAT4 → expressed primarily by Purkinje cells in the cerebellum

EAAT5 → present in bipolar cells in the retina

Astrocyte transporters convert the glutamate they take up to glutamine using ______.

Glutamine is then transported out of astrocytes and picked up by neurons, where it can be converted back into glutamate by _______.

glutamine synthase; glutaminase

why are astrocytes involved in the uptake of glutamate

to protect brain function and enable normal nerve signalling. High levels of glutamate over-activate neuronal receptors, causing a toxic influx of calcium into neurons that can lead to cell death

Glutamatergic pathways in the brain include:

• parallel fibres of the cerebellum

• excitatory pathways in the hippocampus

the most fast excitatory responses to glutamate are mediated by stimulation of ______ receptors (let Na⁺ in)

AMPA

Which ionotropic glutamate receptors let in sodium, and which calcium?

Na⁺ → AMPA, Kainate, NMDA

Ca²⁺ → NMDA

NMDA receptors are activated by ________ and what does this do?

the simultaneous binding of glutamate and glycine or D-serine released by astrocytes. this allows sodium and calcium to come in, depolarizing it, which then allows the Mg²⁺ lodged in the channel to dissocate and open up the channel

NMDA receptors have another binding site for antagonists, which drugs abuse this?

PCP and Ketamine which block the channel. causes a surge of extracellular glutamate in regions like the prefrontal cortex because they block the inhibitory GABAergic inhibitory interneurons. Memantine is used to treat alzheimers with this.

There are 3 groups of metabotropic glutamate receptors, what do they do and where are they located?

Group 1 → located postsynaptically, use second messanger system

Group 2 → located presynaptically, inhibit cAMP formation

Group 3 → same as group 2

Describe long-term potentiation

a process that leads to long-lasting increases in synaptic strength. the larger the EPSP, the greater the synaptic strength

How do you measure LTP in the lab?

1. stimulate presynaptic axons @ low frequency to get a sub-threshold EPSP (no AP)

2. stimulate axons @ higher frequency (tetanus) and get lots of action potentials in postsynaptic neuron

3. stimulate axons @ low frequency again…do you see action potentials this time?

Describe AMPA and NMDA in short-term potentiation

Both ionotropic glutamate receptors that allow Na+ to flow through. Glutamate can always bind to AMPA, but NMDA has a Mg²⁺ ion blocking the flow of sodium and calcium. AMPA needs to depolarize the neuron first enough to remove the Mg²⁺ block. NMDA receptors can then be activated and allow both Na⁺ and Ca²⁺ into the cell

Calcium sets off long-term potentiation, describe it.

Calcium enters the cell through NMDA and activates protein kinases, which in turn activate other proteins through a cascade. Calcium-calmodulin kinase II (CaMKII) leads to more AMPA receptors being inserted into the membrane. Protein Kinase C (PKC) and CaMKII increase the conductance of AMPA. PKC activates the transcription factor CREB, which that can lead to the formation of retrograde messanger Nitric Oxide (NO). NO travels from the postsynaptic cell to presynaptic axon and triggers greater release of presynaptic glutamate. CREB also activates protein synthesis which can lead to long-lasting structural changes.

Excitotoxicity

excessive exposure to glutamate kills neurons

Why is cell death by necrosis bad?

because genetic material is compromised and inflammatory factors harm nearby cells (cancer)

Why is cell death by apoptosis good?

because the dead cell is safely disposed of by phagocytosis

Infarct

area of dead or dying tissue surrounded by penumbra

Glutamate toxicity can lead to _____ brain damage

ischemic (a condition where reduced or restricted blood flow deprives cells and tissues of vital oxygen and nutrients)

GABA, a major inhibitory amino acid transmitter, is synthesized from glutamate in one step by ________ in astrocytes

glutamic acid decarboxylase