14: Serotonin

How is MDMA (ecstasy) related to serotonin?

MDMA blocks SERT (but also affects DA transporters)

What enzyme breaks down serotonin (and other neurotransmitters) in the presynaptic neuron?

Monoamine oxidase (A and B)

_____________, such as fluoxetine and Prozac, are the most common treatment for several anxiety disorders.

SSRIs

Describe how serotonin is related to hunger and eating behavior.

Serotonin release in the hypothalamus increases w/ food = satiety signal.

True or False: Frequent high doses of ecstasy are associated with significant neuropsychiatric impairment.

True

True or False: MDMA has recently been used in low doses to treat chronic PTSD.

True!

What is the vesicular monoamine transporter for serotonin?

VMAT2

Tryptophan increase (e.g., tryptophan loading through food or supplementation) at high levels (can/cannot) elevate mood and cognition (e.g., verbal memory).

can

SSRIs in adults reduce some _____________ behaviors.

compulsive

Similar to amphetamine psychostimulants, MDMA can (increase/decrease) release of monoamines, but has a greater effect on the 5-HT system. MDMA also blocks SERT, and (it is/it is not) selective.

increase; it is not

5-HT1a knockout mice show (increased/decreased) anxiety in behavior tests such as the elevated zero-maze.

increased (this translates to less time spent in open part of maze/less distance moved in open part of maze)

What compound is derived from serotonin (hint: sleeping)?

melatonin

Over 80% of forebrain serotonin comes from the dorsal and median ____________________, midline structures. These nuclei make up the rostral serotonin system. The caudal serotonin system projects to the __________________.

raphe nucleus; spinal cord

How do reserpine, fluoxetine, and buspirone (drugs we've touched on in class) affect serotonin levels?

reserpine: depletes 5-HT by inhibiting vesicular uptake (antipsychotic...) fluoxetine: inhibits 5-HT reuptake (an SSRI) buspirone: stimulates 5-HT1A receptors (agonists) (anxiolytic)

Dexfenfluramine, fenfluramine and others were popular and effective drugs used for weight loss, prescribed for obesity (appetite reducing). Many side effects occurred including heart problems, but also mood and cognitive disturbances - likely due to _____________ depletion.

serotonergic

Catecholamines (dopamine, norepinephrine) and ____________________ are examples of monoamines.

serotonin

The dorsal raphe nucleus activity is linked with ______________ cycles. It facilitates motor output (motor neurons are made more excitable/depolarized).

sleep/wake

In part based on studying ASD patients, we think serotonin plays a role in...

social function, repetitive behavior, sensory development

Abnormal dilation of blood vessels in the brain contributes to migraine headaches. ________________ are 5-HT1B/1D agonists that cause constriction of the vessels, which eases pain.

triptans

Altering _____________ levels is used as a tool to alter serotonin levels.

tryptophan

Serotonin is derived from what compound (hint: eating turkey...)

tryptophan a hydroxyl group is added to tryptophan, forming the compound 5-hydroxytryptophan; this compound is then decarboxylated to form serotonin

SSRIs v. MDMA

"SSRIs mainly operate by stepping up the blocking of re-uptake, i.e. they stop the serotonin level from dropping off but don't increase it, hence preventing low mood," he says. "This is analogous to a swimming pool, in which water levels are kept constant by the water-recycling system. "MDMA works on three stages of neurotransmission: it too blocks re-uptake, but it also boosts the release of serotonin from the presynaptic cell - analogous to water pouring into the swimming pool - and enhances reception on the postsynaptic cell. In short, the impact of MDMA use on serotonin in the synapse is a swimming pool in which the pumping of water into the pool is increased while the drains are simultaneously blocked. Result: the pool is flooded with water."

What 2 key enzymes transform tryptophan into serotonin?

1. tryptophan hydroxylase (adds hydroxyl group to tryptophan to form 5-hydroxytryptophan, 5-HTP) 2. aromatic amino acid decarboxylase (decarboxylates 5-hydroxytryptophan to form serotonin, 5-HT)

What is the name of the reuptake proteins for serotonin?

5-HT transporter (5-HTT or SERT)

Activation of what receptors causes hyperphagia, an increase in food intake and eating behavior?

5-HT1A receptor agonists stimulate somatodendritic autoreceptors, reducing 5-HT release, leading to orexigenic effects (appetite stimulant)

Activation of what receptors causes hypophagia, a reduction in food intake and eating behavior?

5-HT1B or 5-HT2C receptor agonists, and 5-HT6 antagonists produce anorectic effects (reduces appetite); may lead to development of antiobesity drugs

The main receptor involved in SSRI activity is _____________.

5-HT1a

Which two SERT receptors are the most studied?

5-HT1a and 5-HT2a

Describe how a drug might target a type of serotonin receptor to treat a patient who is undergoing chemotherapy and is experiencing nausea...

5-HT3 receptors are located on peripheral terminals of the vagus nerve. Cancer chemotherapy drugs and radiation stimulate release of 5-HT in the gut, which stimulates vagal 5-HT3 receptors and induces vomiting. 5-HT3 antagonists such as ondansetron (Zofran) and granisetron (Kytril) are used to treat the nausea.

Cancer chemotherapy drugs and radiation stimulate release of _____________ in the gut, which stimulates vagal _______________ receptors and induces vomiting.

5-HT; 5-HT3

MAO A and MAO B break down serotonin into what main metabolite that is commonly used as a marker of 5-HT levels?

5-hydroxyindolacetic acid (5-HIAA)

There are ___________ types of 5-HT receptors. They are all metabotropic except for one, the ______________ receptor, which is ionotropic.

6; 5-HT3 the receptors have different functions, sometimes opposite functions

True or False: Serotonin is a catecholamine.

False. Serotonin is a monoamine.

Wait, is 5-HT the same thing as SERT (serotonin)?

Yes! 5-HT stands for 5-hydroxytryptamine.

Monoamines are neurotransmitters that contain a(n) ______________ group (hint: organic chem functional group...)

amine (NH2)

The 5-HT2 agonist mCPP is known to be _____________, and facilitates the ________________ response when injected into the BNST.

anxiogenic (anxiety producing); startle

The partial 5-HT1a agonist _______________ is sometimes prescribed.

buspirone

Serotonin releasing agents (increase/decrease) appetite.

decrease

What is the mechanism of the 5-HT1 receptor?

decreases cellular levels of cAMP; 5-HT1a can be a somatodendritic autoreceptor

Tryptophan depletion doesn't typically have major consequences except in individuals prone to __________________, where it can decrease mood and induce a depressive episode in patients in remission.

depression

Maternal SERT function may play a role in...

development of the serotonergic system

The ______________ nucleus has been subdivided into different subregions that may play roles in different types of behavior.

dorsal raphe

What are the two main locations that serotonin travels from/to in a simplified circuit of serotonin? (NOT 100% SURE ABOUT THIS INFO)

dorsal raphe nucleus; bed nucleus of the stria terminalis (BNST) serotonin travels from the dorsal raphe nucleus to the BNST, actually enhancing fear and anxiety and activating a subpopulation of corticotropin-releasing factor (CRF) neurons; silences anxiolytic BNST outputs to the VTA and lateral hypothalamus

(Elevated/Reduced) blood serotonin levels are observed in ~30% of patients with Autism Spectrum Disorder. Symptoms (worsen/improve) with tryptophan deletion.

elevated; worsen

What is the mechanism of the 5-HT2 receptor?

excitatory