Acetylcholine is broken down into choline and acetate by acetylcholinesterase.

AChE can hydrolzye up to 1000 molecules of ACh per second

1. Nicotinic: these are ionotropic and let Na and Ca in
2. Muscarinic: these are metabotropic

5

1, 3, and 5 are Gq/11

2 and 4 are Go

1 and 4 are in the striatum. They are involved in extrapyramidal motor circuits and reward responses.

Disrupting these can enhance DA signaling, improving PD-like side effects.

Tacrine (used to treat Alzheimer's) and physostigmine.

Phsyostigmine cannot cross the BBB, so it has not good long lasting effect, but tacrine can. 

Acetylcholine, mascarine (mushrooms), carbachol, oxotremorine, pilocarpine.

Carbochol and oxotremorine are full, while pilocarpine is partial.

Through alternative splicing. Location and order of cleaving determines what neuropeptide will be made.

All produce substance P, but only some produce neurokinin A (a, b, and gamma).

They are packaged into large dense core vesicles on the periphery cell. 

The require a train of action potentials and a persisten influx of calcium to cause them to fuse and dump.

1. μ - targeted by β-endorphins
2. δ (delta) - traged by enkephalins
3. κ - targeted by dynorphins

Morphine targets u receptors

1. It activates analgesic pathways in the medial thalamus and dorsal horn of the spinal cord
2. It activates reward/addiction behaviors in the VTA and NA
3. It acts in the dorsal striatum and locus ceruleus to affect dependence and withdrawal

It acts in the kidneys to retain water, lessening blood pressure. Alcohol can block this.

In the brain, it can increase or decrease affiliative behavior and can increase anxiety/fear in the amygdala

"The Trust Hormone"

It can decrease fear/anxiety. It is known for building the bond between a lactating mother and their infant.

1. Substance P - NK1 receptor
2. Neurokinin A - NK2 receptor
3. Neurokinin B - NK3 receptor

They are used to block nausea and vomiting caused by chemotherapeutic agents - they act in the medulla/area postrema

Aprepitant

Activation of Y1 in the amygdala decreased anxiety

Activation of Y5 in the hypothalamus stimulates appetite (opposite of leptin)

A2a. It is in the striatum and inhibits DA D2 receptor mediate behaviors, causing PD like effects.

Antagonists for A2a are much like D2 agonists (bromocryptine)

Certain gases can also suppress NT release.

Example: When Ca binds to calmodulin, it can active mNOS, which generates NO from L-Arg. It goes to the presynaptic cell and activates sGC which converts GTP to cGMP, which suppresses N release.

Example: PKC can activate CK2, which can phosphorylate HO2, which can break down heme into CO, which activates sGC, and so on.

They stimulate neural growth and survival.

1. Neurotrophins
2. GDNF family
3. CNTF family
4. EGF family
5. VEGF

Cytokines and interleukins are involved in inflammation.

Chemokines attract microglial cells to injured neurons

1. Retrograde: post to pre (e.g., CBs, CO, NO)
2. Anterograde: pre to post (e.g., glutamate)
3. Paracrine: astrocytes release NGF to neuron, promoting growth
4. Autocrine: neuron produces and releases NFG to self, promoting growth

NGF --> TrkA

BDNF and NT-4 --> TrkB

NT-3 --> TrkC

P75 NTR is a low affinity (will only bind at high concentrations) receptor involved in apoptosis. Too much activation is toxic

1. Ras/MAPK
2. PI3K/AKT
3. PLCy/PKC/Ca2+

It plays a role in LTP, learning and memory, adult hippocampal neurogenesis, epilepsy, and many disorders.

Major growth factor for hippocampal parietal cells

It binds on two domains as a dimer, but functions the same.

Yes, too much GDNF is not good for perkinje neurons because they become dependent on it.

Glial cells secrete it, along with LIF, and IL-6.

It is expressed on the surface of motor neurons- it helps repair some motor neuron connections after the axons have been cut.

1. VEGFR1 --> flt-1
2. VEGFR2 --> flk-1

Vascular endothelial growth factor is a neurotrophic factor for motor neurons and promotes polymophisms that are associate with ALS.

It can also protect cortical neurons after breaking the clot from stroke

Epidermal growth factors are primarily used to treat cancers that create glioblastomas in the nervous system.

Gefitinib and erlotinib

• Eye lids contract
• Blood vessels on skin and gut diver blood to muscles
• Hairs stand up
• Bronchi dilate (better oxygenation of blood)
• Cardiac contraction is enhanced
• Digestive and other vegatative functions are slowed

• Blood flow
• Cardia output
• Kidneys
• Glucose level
• Digestive function
• Temperature
• Gender orientation

Preganglionic neurons are cholinergic and fire to nicotinic receptor. 

Postganglionic neurons are cholinergic and fire to muscarinic receptors

Preganglionic neurons are cholinergic and fire to nicotinic receptors. 

Postganglionic are noragrenergic and fire to NE receptors

Nicotine (along with lobeline)- it increases heart rate, blood pressure, salivation, and contraction in the gut.

Tetramethylammonium: very potent and synthetic

Succinlcohline is used at the NMJs and is a paralytic used in anesthesia

1. Tetraethylammonium: blocks voltage gated potassium channel
2. a-bungarotoxin: nicotinic, automatic ganglia, and somatic NMJ
3. Mecamylamine: treats severe hyptertension

Whenever you use a blocking agent, whatever system is predominant in the current state, the blocking agent will switch it to the other state.

Ex: In the heart, the predominant tone is the parasympathetic system. A blocking agent would block the parasympathetic receptors more, causing it to go into the sympathetic state.

Agonist = sympathomimetics (because they mimic the sympathetic nervous system)

Antagonist = sympatholytics (they block the sympathetic nervous systhem)

1. Dobutamine
2. Isoproterenol

They are used to treat heart failure because they stimulate the heart

1. Terbutaline

They are put in inhalers for asthma because they cause bronchi to dilate in the lungs

• Phenylephrine

They are used in decongestents for nasal congestion.

• Clonidine

They are used as a central antihypertensive for people with very low blood pressure.

• Atenolol
• Propanolol
• Carvedilol

They calm you down and are used for hypertension and ischemic heart disease

• Prazosin

Used for hyptertension

• Yohimbine

It induces fear and anxiety

• M1 is paired with Gq on smooth muscles and gut glands
• M2 is paired with Gi on smooth and cardiac muscle in CVS
• M3 is paired with Gq on smooth muscles and glands

• Muscarine
• Pilocarpine
• Carbachol

They decrease heart rate and blood pressure, causing bladder emptying.

• Atropine
• Scopolamine

They are used to treat bradycardia and to dilate pupils; all used for nausea and motion sickness

• Physostigmine: treats people with bladder problems and lazy eyes
• Pyridosdtigmine: improves blood pressure when standing up and lying down
• Neostigmine
• Nerve gases like sarin, soman, and VX: enhance permanent functiton of cholinergic synapses

Signaling molecules that reach targets through the blood stream. They can be peptides, small molecule NT, or steroid-like molecules.

The are secreted by neuroendocrine neurons.

It acts with the corticotropin release hormone (CRH) to stimulate ACTH release from adrenal glands.

It can also increase reabsorption of water in distal nephron.

Lithium inhibits the renal V2 receptor-linked AC leading to the diabeetus

They are hormones released by the hypothalamus that go to the anterior pituitary and trigger the release of other hormones.

• CRH
• TRH
• GnRH
• GHRH
• Somatostatin
• Dopamine

• Deepest medulla layer produces epinephrine
• Deepest cortical layer produces adrenal androgens
• Middle cortical layer produces glucocorticoids
• Superficial cortical layer produces mineralocorticoids

They bind to the CRF1 receptor. They can increase alertness, but too much can cause depression.

CRF1 antagonists may be effective antidepressants or anxiolytics

Hypothalamic neurons make TRH go to the anterior pituitary, which creates THS. THS goes to the thyroid gland to cause a response

T3 and T4 are thyroid hormones that negatively modulate this loop (come from thyroid gland)

1. They work as negative feedback modulators (hypothyroid is not enough TSH while hyperthyroid is making too much TSH)
2. TRH is pulsatile and follows circadian rhythms, it is highest at night when sleeping.

• Leuprolide: it desensitizes GnRH so it does not detect the pulse as much, so triggers less gonadotroph release. It can be used to treat early puberty and excessive testosterone in prostate cancer
• Downstream sex hormones work as negative feedback modulators

Estrogen production. LH acts on the ovary to induce ovulation to produces estrogen precursors and progesterone.

FSH acts on the ovary to stimulate actual estrogen synthesis.

They increase muscle mass

ROID RAGE

• Ghrelin
• NPY
• Orexin

• Leptin
• Insulin

1. It stimulates other profeeding peptides like POMC and CART
2. It inhibits peptides the decrease feeding like NPY and ARP

1. Projection neurson: they cross middle of the spinal cord and project inot the brain/amygdala
2. Interneurons: they will synapse onto other neurons and cause a reflex response

• GCPRs
• Ligand gated ion channels
• TRP channel: pressure, heat sensitive potassium channels, acid sensing ion channels

Transient receptor potential channels.

They transduce stimuli such as temperature and chemicals

They all have CB1 receptors along with opioid u, delta, and k receptors.

These are all Gi/Go receptors!

SUPER COLLLLDDDDDDDDDD below 18C

Mustard, wasabi, garlic, and bradykinin

• They are larger, myelinated, and conduct faster
• They have a higher threshold for mechano and mechanotermal reception (takes a high degree of stress to activate them)
• They are better at defining the location of the pain
• The can inhibit c fiber activation

• They are smaller, unmyelinated, and conduct slower
• They are activated by many different things (temp, punctures, chemicals, etc.)
• They can detect dull pain because they have a low threshold
• Less accurate and locating pain

The decrease in the threshold required to activate nociceptors, so previously innocuous stimuli become noxious.

Induced by prostaglandins, leukotrienes, interleukins, chemokines, and growth factors. Involves the phosphorylation of TRP channels

1. Ibuprofen
2. Indomethacin
3. Naproxen

1. Celecoxib
2. Rofecoxib

They are expressed in platelets and they make prostacyclin, which inhibits platelet aggregation.

Inhibiting COX2 causes prostacyclin to be replaced by thromboxane, which promotes tablet aggregation (BAD, thrombotic trombone events)

They are released retrograde and act on blood vessels to dilate them to release substances such as bradykinin.

They can also act on mast cells to release histamin, which causes itching on pain receptors.

Calcitonin gene-related peptide. Functions similarly to substanct P.

Migraine meds target it.

When you feel pain somewhere different from where it actually is. 

It occurs when c fibers from the skin are synpasing in the dorsal horn at the same time c fibers from the heart are firing. The brain gets confused.

Second order neurons go to the amygdala to activate this.

The amygdala in response sends signals through the periaqueductal gray, rostroventral medulla, and dorsal horn, to release opioids and inhibit pain.

Enkephalinergic neurons (interneurons).

They release endoenous opioids in the dorsal horn that act presynaptically at the level of dorsal root ganglion or postsynaptically on dendrites in second order neurons to shut off bain signals (they depolarize these to block the signals)

SP binds to SK1

BDNF binds to TrbB; it is the primary growth factor for second order neurons

• Codeine
• Morphine
• Fentanyl
• Methadone
• Oxycodone

Buprenorphine.

It is not addictive but gives similar levels of analgesia

• Butorphanol
• Nalbphine
• Pentazocine

They are also antagonists for u receptors, but still produce analgesic response. They are not as addictive

• Duloxetine
• Cymbalta

• Desipramine

It is chronic pain caused by damage to peripheral or central nociceptive neurons.

Gabapentin (neurontin) is an anticonvulsant used to treat neuropathic pain, MOA unknown.