Overview of ANS week 1 PART 1 Flashcards
Where are the cell bodies located for the sympathetic ANS (SANS)?
Describe the relative length of pre and post ganglionic fibers of the SANS.
What NT(s) are release from pre and post ganglionic fibers of SANS? What receptor(s) do the NT(s) act on?
What NT(s) are released from the adrenal medulla? What cells synthesize and release this NT?
SANS has a thoraco-lumbar distribution with short pre-ganglionic fibers that release acetylcholine (ACh) and long post-ganglionic fibers that primarily release norepinephrine (NE), although there is a notable exception where ACh is released from SANS fibers to cause constriction of sweat glands.
The adrenal medulla, which releases mostly epinephrine (EPI) (80% E, 20% NE), should be viewed as a post-ganglionic effector since preganglionic fibers activate chromaffin cells to release EPI, which circulates hormonally to affect its target sites.
Note: The role of epinephrine is often overlooked in determining the actions of ANS drugs. In contrast to activation of SANS, epinephrine circulates in blood to have global effects.
Describe the structures that the superior cervical ganglion (SCG) innervates and result of its innervation.
Paravertebral ganglia (chain ganglia) allow considerable integration and amplification of signal among preganglionic fibers. There is considerable cross-talk within the chain ganglia.
1) Of note is the superior cervical ganglion (SCG) which is the only ganglion in the sympathetic nervous system that innervates the head and neck. It is the largest and most rostral (superior) of the three cervical ganglia. The SCG innervates many organs, glands and parts of the carotid system in the head.
a) The postganglionic axons of the SCG innervate the pineal gland and are involved in Circadian rhythm.[7] This connection regulates production of the hormone melatonin, which regulates sleep and wake cycles.
b) The postganglionic axons of the SCG innervate the internal carotid artery and form the internal carotid plexus. The internal carotid plexus carries the postganglionic axons of the SCG to the eye, lacrimal gland, mucous membranes of the mouth, nose, and pharynx, and numerous blood-vessels in the head.
c) The postganglionic axons of the SCG innervate the eye and lacrimal gland and cause vasoconstriction of the iris and sclera, pupillary dilation, widening of the palpebral fissure (opening btwn eyes and eyelids), and the reduced production of tears. Dilation of the pupils allows for an increased clarity in vision, and inhibition of the lacrimal gland stops tear production allowing for unimpaired vision and redirection of energy elsewhere.
What is Horner’s syndrome? What are the symptoms? What is the cause?
Horner’s syndrome is a disorder resulting from damage to the sympathetic autonomic nervous pathway in the head. Damage to the SCG, part of this system, often results in Horner’s syndrome. Damage to the T1-T3 regions of the spinal cord is responsible for drooping of the eyelids (ptosis), constriction of the pupil (miosis), and sinking of the eyeball (apparent Enophthalmos; not truly sunken, just appears so because of the drooping eyelid.
PAM is Horny: Ptosis, Anhidrosis (decreased sweat), Miosis (pupil constriction)
Where are the cell bodies located for the parasympathetic ANS (PANS)? What nerves have PANS fibers?
Describe the relative length of pre and post ganglionic fibers of the PANS.
What NT(s) are released from pre and post ganglionic fibers of PANS?
What receptors do the NT(s) work on?
PANS has a cranio-sacral distribution involving the 4 cranial nerves (III [oculomotor]; VII [facial]; IX [glossopharyngeal]; and X [vagus]) and sacral efferents 2, 3 and 4. Distribution is through long preganglionic fibers that release ACh and short post-ganglionic fibers located generally near the target structure that also release ACh. ACh acts on muscarinic receptors.
ganglia located near target structures allow amplification of signal.
Explain control of the enteric nervous system (ENS). Which of the branches of the ANS (SANS or PANS) has more influence on the ENS?
What is the result of how the ENS is controlled as it pertains to the effect of drugs on the ENS?
What NTs affect ENS function? Which are the most important?
What is the effect of opiods on the ENS?
The Enteric Nervous System (ENS) consists of two series of interconnected neuronal plexuses that run longitudinally throughout the entire GI tract. Control of function within the ENS is generally regulated by local network reflexes, but the overall tone of the ENS is modulated by mostly PANS and to a lesser extent, SANS. Because local control is dominant, drugs affecting the ENS produce temporary effects (e.g., constipation) that allows normal local control to return after a period of time.
In addition to NE and ACh, there are numerous other neurotransmitters that affect ENS function. Enkephalin (EN) and serotonin (5HT) are the most important. Opioids acting on ENS receptors produce significant constipation. Several drugs affecting 5HT can alter GI motility.
Where do sensory fibers of the ANS project to?
State what side each of the branches of the ANS project to.
How does this allow for sensation in organs?
The Sensory limb of the ANS utilizes the same pathways as the effector limbs except that sensory fibers from the targets are afferent to the CNS. This is an often overlooked aspect of the system design. These fibers project primarily to the insular cortex which, through its projections to other cortical areas, provides sensation in the organs.
Visceral sensation coming up PANS afferents is generally to the right insular cortex while SANS visceral sensation is left insular cortex. From the insular cortex, fibers project to several other areas to produce coordinated ANS responsiveness.
Name the structures in the body that are innervated by only one branch of the ANS. State which branch it is innervated by.
Islets of Langerhan’s in pancrease (SANS only)
Blood vessels (SANS only) but do have some ACh receptors that when bound cause vasoconstriction
Adrenal medulla (SANS only)
Spleen (SANS only)
Sweat glands (SANS only)
Explain the function of central command centers. Describe examples of the role central command centers play in ANS function.
Central command centers within the brain perform numerous integrative functions and coordinate autonomic responsiveness system wide. Although the ANS effector limb is mostly reflexive, the role of the command centers within the CNS is to integrate those reflexes body-wide to generate the most appropriate patterned response in concert with CNS function (e.g., CNS generated fear increases SANS function while reducing PANS function). From the medulla up, it is a hierarchical organization allowing for different patterned responses based on reflex activity in combination with ongoing cognitive and limbic activity. These command centers also provide sensory perception of the internal activity of the organs. The major point here is that there is no single PANS or SANS central regulatory area, but rather an integration of several areas that coordinates a peripheral response.
- Parasympathetic cranial nerve input is physiotopically organized within the n. Solitary tract (NST-GVA and SSA for VI, IX, X) with further projections to the parabrachial complex (fxns in drive related behavior-hunger, thirst, survival, etc.)
- Areas of the prefrontal cortex and amygdala (esp. central n.) play major roles in generating ANS responses to fear.
- Hypothalamic regions play active roles in regulating vascular tone mediating temperature regulation (reduced SANS to produce vasodilation to reduce body temperature while SANS stimulates sweating to also reduce body temperature; SANS activation causes vasoconstriction to reduce heat loss) and ENS function.
- The insular cortex appears to be the primary seat of visceral sensation with lateralization. Visceral sensation coming up PANS afferents is generally to the right insular cortex while SANS visceral sensation is left insular cortex. From the insular cortex, fibers project to several other areas to produce coordinated ANS responsiveness.
Define vaso-vagal syndrome and vaso-vagal syncope. Explain the cause AND symptoms of each.
In what age group are these syndromes more common?
Vaso-vagal syndrome is a consequence of increased PANS outflow (primarily vagus) and reduced SANS activity initiated from CNS “triggers” that produce lightheadedness, feelings of malaise, being hot or cold, sweating, cognitive “fuzziness,” changes in vision, and even difficulty initiating speech (stuttering). In many cases, this prodrome proceeds to fainting (vaso-vagal syncope). It is more common in young adults. The increased vagal tone reduces heart rate significantly and the precipitous fall in blood pressure occurs through reduced SANS outflow leading to hypoxia in the brain and fainting. The triggers can be as diverse as seeing blood, severe pain (including menstrual cramps), significant arousal, lack of sleep, or severe coughing. This syndrome epitomizes the notion that there is no single PANS or SANS center, but rather a distributed network of CNS sites that produce patterned responses.
Define dysautonomia. What disorders are types of dysautonomia?
What diseases are associated with dysautonmia?
What are causes of dysautonomia?
What are the symptoms of dysautonomia?
Dysautonomia or autonomic dysfunction is a catch-all term that describes a variety of syndromes and symptoms associated with dysfunction of the ANS. This includes postural orthostatic tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST), vaso-
vagal syncope, pure autonomic failure, neurocardiogenic syncope (NCS; i.e., vaso-vagal syndrome), neurally mediated hypotension (NMH), orthostatic hypotension, orthostatic hypertension, and autonomic instability. Dysautonomia is also commonly seen in a number of diseases including diabetes mellitus, multiple system atrophy (Shy-Drager syndrome), and Guillain-Barré syndrome. Dysautonomia associated with diabetes and Guillain-Barre’ results from dysfunction of the peripheral effector limbs of the ANS often due to demyelination. Since the pre-ganglionic fibers are myelinated, they are more subject to demyelination. Thus, diabetes and Guillain-Barre’ are more associated with PANS loss than SANS loss (the symptoms, however, are dependent upon predominant tone to the affected structures (see below) Symptoms of dysautonomia are generally “body-wide” and include excessive fatigue, excessive thirst, panic attacks (excessive anxiety), fast heart rate, slow heart rate, syncope, mydriasis, constipation, diarrhea, acid reflux, visual disturbances, and even seizures. It can be caused by autoimmune attack, Lyme disease, neurodegeneration, genetic, spinal cord injury, or physical trauma.
What is multiple-system atrophy (MSA)? What is it caused by? What are the symptoms?
In what population is MSA more prevalent?
What is Shy-Drager syndrome?
Multiple-system atrophy (MSA) is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance, and autonomic functions of the body such as bladder control or blood-pressure regulation. The cause of MSA is unknown and no specific risk factors have been identified. Around 55% of cases occur in men, with typical age of onset in the late 50s to early 60s. MSA often presents with some of the same symptoms as Parkinson’s disease. However, MSA patients generally show minimal if any response to the dopamine medications used for Parkinson’s. Because of the typical presentation of akinetic rigidity it is often grouped with the Parkinson’s Plus syndromes. MSA is often accompanied by dysautonomia sometimes referred to as Shy-Drager Syndrome. This dysautonomia includes postural or orthostatic hypotension, resulting in dizziness or fainting upon standing up, urinary incontinence or urinary retention, impotence, constipation, dry mouth and skin, and trouble regulating body temperature due to sweating deficiency in all parts of the body. These autonomic dysfunction is due to degeneration within the CNS resulting in poor integration of CNS autonomic efferent regulation.
State the following facts pertaining to small molecule NTs:
Site of synthesis
molecular weight
how biotransformed
what happens after release
types of receptors they act on
Excitation leads to release of NE and ACh, which are responsible for 99% of the small molecule neurotransmission within the ANS. Small molecule neurotransmitters are:
a. synthesized at the site of release
b. have small molecular weights (<500)
c. are biotransformed by specific enzymes
d. are taken back up to aid in termination
e. act through specific transmembrane receptors
State the following facts about large molecule NTs:
Site of synthesis
molecular weight
how biotransformed
what happens after release
types of receptors they act on
Higher levels of excitation are often required to release the co-localized large molecule neurotransmitter, which can augment the function of the small molecule neurotransmitter and in some cases even reverse it. Large molecule neurotransmitters are:
a. synthesized in the nucleus and anterogradely transported to the terminal
b. are large molecular weight proteins (>1,000)
c. are biotransformed by non-specific esterases
d. are not taken back up
e. act through specific transmembrane receptors
Name two examples of gas NTs.
State the following facts about gas NTs:
site of synthesis
mechanism of release
location of receptors
What is the role of NO in long-term potentiation (LTP)?
Gas neurotransmitters (primarily NO, but also CO) are also released and diffuse as a gas to produce their effects. NO, formerly endothelial derived relaxing factor (EDRF) causes vasodilatation. Gas neurotransmitters
a. are synthesized at site of action
b. simply diffuse away for termination of action
c. act through intracellular receptors (e.g., guanylate cyclase) after diffusing into target sites.
d. NO can retrogradely diffuse back across the synapse to the presynaptic side and increase future release of neurotransmitter as occurs in long-term potentiation (LTP)
State what enzymes (and other molecules, if applicable) are responsible for the synthesis, packaging into vesicles, release, and reuptake of acetylcholine.
If applicable, state what drugs are inhibit each process.
What receptors does ACh act on?
How is ACh degrated?
What heteroreceptors may be present on ACh terminals? What is the function?
ACh
- Synthesized by choline acetyl transferase (ChAT) from choline and acetyl Co-A (inhibited by methyl mercury compounds)
- Concentrated in vesicles by H+ counter-transporter vesicular ACh transporter (VAT) along with ATP that also has neurotransmitter function in several structures (e.g., bladder). Inhibited by vesamicol.
- Traditional Ca++ dependent-release mediated through SNAPs (Soluble attachment proteins) and SNAREs (Soluble attachment protein receptors). SNAREs are inhibited by botulinum toxin (BoTox)
- Acts through nicotinic and muscarinic receptors
- Degraded by Acetyl-choline esterase (AChE) to choline and acetyl co-A and by non-specific esterases in plasma (Butyrylcholinesterase). AChE inhibitors (AChEIs) inhibit AChE.
- Choline is taken back up by the choline transporter (CHT) which is inhibited by hemicholinium.
ACh terminals often have alpha receptors that bind NE/E to inhibit ACh release.
Explain the synthesis pathway of NE and E. What is the rate limiting step?
What enzyme is used to convert Levodopa to dopamine (DA)?
See attached figure for synthesis pathway of NE and E
Synthesized as part of the catecholamine pathway involving tyrosine hydroxylase (TH) as the rate-limiting step with tetrahydropterin (BH4) as a co-factor. TH is subject to end-product inhibition and is regulated by a number of pathways. Levodopa, the product of TH, is converted to dopamine (DA) by aromatic amino acid decarboxylase (AAAD) which is present in terminals as well as throughout the body. It is inhibited by carbidopa and uses Vitamin B6 as a co-factor. DA is converted to NE by DA beta hydroxylase (localized in NE terminals) which is further converted to Epi by phenyl-ethanolamine-N-methyl transferase present in the adrenal medulla.
How is NE concentrated into vesicles? What inhibits this process?
What enzymes are responsible for the biotransformation of NE? Where are these enzymes located within the cell? What is the primary breakdown product of NE?
NE is concentrated in vesicles by the vesicular monoamine transporter (VMAT) using H+ counter-transport, which is inhibited by reserpine. ATP is also released.
NE is biotransformed by catechol-O-methyl transferase (COMT) and monoamine oxidase (Types A and B; MAO-A and MAO-B). The primary breakdown product is Vanilla-mandelic acid (VMA). MAOs and COMT are all inhibited by several drug classes (MAO inhibitors [MAOIs] and COMT inhibitors). MAO is located in mitochondria within the presynaptic neuron and astrocytes and other cells (e.g., liver) while COMT is located in the membrane of the target cell as well as glia and other cells (e.g., liver).
What is responsible for the reuptake of NE? Explain how this process occurs.
What drugs inhibit the reuptake of NE? How do they work?
Greater than 85% of released NE is taken back into the terminal via the NE transporter (NET) which is a counter-transporter using Na+ subject to inhibition by a number of substances (e.g., the pressor amine, tyramine, amphetamine, and several drugs, [e.g., antidepressants]) and can be a source of Ca++-independent release by drugs that serve as full ligands for the binding site (e.g., tyramine and amphetamine). NET is also subject to non-competitive inhibition through allosteric regulation (e.g., cocaine or tricyclic antidepressants). Guanethidine, is taken up by NET as well as VMAT where it replaces NE in the vesicles depleting them of NE and thereby reducing NE release and tone.
