Chapter 22 — Quiz

Neuropeptide Y, Substance P, and the Peptides That Regulate Stress, Pain, and Appetite in the Brain

Twenty-two questions. Answer before opening the key. Several questions have a tempting distractor that is true but does not answer the question asked — read the stems carefully.

1. Neuropeptides are typically released under which condition?

A. Any single action potential B. Sustained, higher-frequency firing C. Only in the absence of classical transmitter release D. Only when the postsynaptic cell depolarizes first

2. Neuropeptides act principally on:

A. Ligand-gated ion channels B. Voltage-gated sodium channels C. G-protein-coupled receptors D. Nuclear hormone receptors

3. The best reason neuropeptides are called neuromodulators rather than neurotransmitters is that they:

A. Are larger molecules B. Are released more slowly from the cell body C. Change how a target cell responds to other inputs rather than directly exciting or inhibiting it D. Are broken down into amino acids

4. Which statement about neuropeptide clearance is correct?

A. They are recovered by reuptake transporters and reused B. They are degraded by extracellular peptidases and must be resynthesized in the cell body C. They are recycled locally at the nerve terminal within milliseconds D. They are cleared exclusively by the liver

5. Neuropeptide Y is:

A. A 36-residue peptide and one of the most abundant neuropeptides in the mammalian brain B. A 9-residue peptide made in the posterior pituitary C. A 191-residue protein hormone D. A small molecule structurally related to serotonin

6. In the arcuate nucleus, NPY is co-released with:

A. POMC B. AgRP C. Leptin D. Insulin

7. Injected centrally in animals, NPY produces:

A. Modest appetite suppression B. No reliable effect on feeding C. The most potent stimulation of food intake of any known substance D. Feeding only in previously food-deprived animals

8. Antagonists at feeding-associated Y receptors were tested in human obesity trials. The outcome was:

A. Weight loss comparable to GLP-1 receptor agonists B. No clinically meaningful weight loss, and the programs were abandoned C. The trials were never run D. Approval for obesity in several jurisdictions

9. The human evidence linking NPY to stress resilience is best described as:

A. Multiple randomized controlled trials of NPY administration B. Observational associations between circulating NPY and performance under extreme stress C. Placebo-controlled trials of an oral NPY supplement D. Absent — no human data exists

10. Which of the following would most directly change the ❌ rating for "boosting NPY improves stress resilience"?

A. A new animal study showing amygdala NPY reduces anxiety-like behavior B. A survey finding that people who take NPY supplements report less stress C. A controlled human trial of an intervention demonstrated to raise central NPY signaling, with a prespecified stress outcome D. Identification of a new NPY receptor subtype

11. Substance P is:

A. A 9-residue peptide acting at NK2 B. An 11-residue tachykinin acting principally at NK1 C. A 37-residue vasodilator from trigeminal neurons D. A 33-residue peptide from the lateral hypothalamus

12. The "P" in substance P stands for:

A. Pain B. Peptide C. Powder D. Primary afferent

13. Which of these was NOT part of the preclinical case for NK1 antagonists as analgesics?

A. Substance P localization in small-diameter primary afferents B. NK1 expression on second-order neurons in the superficial dorsal horn C. Human provocation studies in which substance P infusion reproduced a defined pain syndrome D. Reduced responses to intense noxious stimuli in animals lacking NK1 receptors

14. NK1 antagonists failed in human trials of pain and depression. Human PET imaging established that:

A. The compounds never reached the brain B. The compounds reached the brain and occupied NK1 receptors at the doses tested C. NK1 receptors are absent in the human brain D. The compounds bound NK2 rather than NK1

15. The approved indication for NK1 receptor antagonists is:

A. Chronic neuropathic pain B. Major depressive disorder C. Chemotherapy-induced nausea and vomiting D. Migraine prevention

16. §22.5 argues that the ❌ for NK1 antagonists in depression is epistemically stronger than most ❌ ratings in this book because:

A. The compounds were more selective than most B. The evidence is present and negative rather than absent C. Several regulators formally rejected the application D. The preclinical data was later retracted

17. Narcolepsy type 1 is characterized by:

A. Overproduction of orexin B. Loss of orexin-producing neurons, with low or undetectable CSF orexin-A C. A mutation in the gene encoding substance P D. Excess CGRP in the trigeminal ganglion

18. Dual orexin receptor antagonists differ mechanistically from benzodiazepines and Z-drugs because they:

A. Enhance GABA-A signaling more selectively B. Remove a wake-promoting signal rather than broadly increasing inhibition C. Act on melatonin receptors D. Are peptides rather than small molecules

19. Orexin replacement for narcolepsy remains unsolved primarily because:

A. The deficiency is not well characterized B. Orexin's receptors have not been identified C. Orexin is a peptide and does not cross the blood-brain barrier in useful amounts D. There is no commercial interest in narcolepsy

20. Erenumab, fremanezumab, galcanezumab, and eptinezumab are:

A. Peptides B. Monoclonal antibodies C. Small-molecule receptor antagonists D. Peptide-drug conjugates

21. CGRP-targeting therapies for migraine largely avoid the blood-brain barrier problem because:

A. CGRP itself crosses the barrier freely B. The antibodies are small enough to diffuse across C. Much of the relevant trigeminal signaling occurs at sites — the trigeminal ganglion and dura — outside the barrier D. The drugs are given intrathecally

22. According to §22.9, the three things that differed between the CGRP and substance P programs were:

A. Funding, timing, and luck B. Receptor affinity, selectivity, and half-life C. A specific indication with a validated endpoint, direct human evidence of the peptide's causal role, and an accessible target D. Species choice, trial size, and regulatory jurisdiction

Answer key **1 — B.** Dense-core vesicles sit farther from the active zone and require broader calcium accumulation, which generally means sustained or burst firing. A single spike releases the classical transmitter and essentially no peptide. **2 — C.** Every neuropeptide discussed in this chapter signals through a GPCR (Chapter 2). This is why the effects unfold over seconds to minutes rather than milliseconds. **3 — D is wrong for an interesting reason:** peptides *are* broken down into amino acids, but that has nothing to do with the neuromodulator label. **The answer is C.** The label describes function — changing how a cell interprets other inputs — not size, speed, or metabolism. **4 — B.** No reuptake transporter exists for neuropeptides. They diffuse away, are degraded extracellularly, and must be replaced by synthesis in the cell body and axonal transport, which makes peptide stores exhaustible over hours. **5 — A.** 36 residues, with an N-terminal tyrosine and an amidated C-terminal tyrosine — hence "Y." **6 — B.** The NPY/AgRP population of the arcuate nucleus drives feeding and is inhibited by leptin. POMC neurons are the opposing population; leptin and insulin are inputs, not co-transmitters. **7 — C.** And note the detail that makes it striking: the effect appears in animals that have just eaten and should be sated. **8 — B.** This is the first appearance in the chapter of the pattern that dominates §22.5 — correct mechanism, target engaged, drug did not work. **9 — B.** Observational and correlational. The most-cited work involves military personnel in demanding survival training. Note that D is wrong: human data exists; it is just the wrong design to support the claim built on it. **10 — C.** Only an intervention arm can settle a causal claim. A is more animal data; B is uncontrolled self-report on an intervention not shown to change the variable; D is mechanism. **11 — B.** Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. C describes CGRP and D describes orexin-A. **12 — C.** For the dried powder preparation the original investigators worked with in 1931. The name predates knowledge of the sequence by four decades. **13 — C.** No such human provocation study exists for substance P — and §22.9 argues that this absence is precisely what distinguished the substance P program from CGRP's. A, B, and D were all part of the preclinical case. **14 — B.** This is the load-bearing fact of the whole story. It eliminates underdosing and target miss as explanations, which is what makes the negative result so informative. **15 — C.** Aprepitant and relatives, particularly effective against delayed emesis — an indication nobody set out to develop. **16 — B.** Most ❌ ratings in this book mean nobody has run the trial. This one means the trials were run, repeatedly, by well-resourced groups, and failed. That is knowledge, not an open question. **17 — B.** Most likely from autoimmune destruction of the orexin neurons in genetically susceptible people. Low CSF orexin-A is now a diagnostic criterion. **18 — B.** Benzodiazepines and Z-drugs enhance GABA-A signaling broadly. DORAs remove a specific wake-promoting input, allowing sleep to establish rather than suppressing arousal by brute force. Note D is wrong: DORAs are small molecules. **19 — C.** The deficiency is understood better than almost any in neurology; the barrier is what stands in the way. This is why the field is pursuing small-molecule orexin receptor agonists instead of the peptide. **20 — B.** Every one ends in `-mab` (Chapter 1 §1.8). Roughly 150,000 daltons, produced in cell culture. They are not peptides — CGRP is the target, not the drug. **21 — C.** The therapy did not solve the delivery problem; it routed around it by targeting an accessible part of the circuit. A is false, B is false (an antibody cannot diffuse across), and D describes a route these drugs do not use. **22 — C.** And the point of the comparison is that none of the three is "better mechanism." Mechanism did not distinguish the two programs in advance.