Topic 9: Serotonergic Systems and Receptors Flashcards
Where are serotonergic receptors located in the brain?
serotonergic neurons project from a number of locations in the brainstem and innervate the entire forebrain
most interesting are located in the raphe nuclei (~165,000 seratonergic cells)
What is the caudal raphe nuclei?
seratonergic projections to the cerebellum and descending projections to the spinal cord
mediate sensory, motor, and autonomic functions
What is the rostral raphe nuclei?
comprises dorsal and medial raphe nuclei
ventral projections to basal ganglia, substantia nigra, VTA, limbic system and cortex
dorsal projections to midbrain (tegmentum and tectum)
cerebellar projections to cerebellar cortex and deep cerebellar nuclei
What are seratonergic lesions?
seratonergic neurotoxins can be used to probe pathway functions
para-chloroamphetamine, MDMA both have neurotoxic effects selectively on seratonergic pathways
MDMA is neurotoxic at high doses or via microinjection
5,7-dihydroxytryptamine (5,7-DHT) is a BBB impermeable selective toxin that can induce robust serotonergic injury
seratonergic lesions produce deficits in food intake, reproductive behavior, pain sensitivity, anxiety, learning, memory, and motor function
How does the dorsal raphe nuclei fire during behavior-dependent activity?
microelectrodes implanted into the dorsal raphe nuclei in free moving cats
while awake a steady firing pattern is observed
frequency increases with motor activity: especially repetitive activities like grooming, walking on a treadmill, chewing
sudden sensory stimulus causes an abrupt cessation of output from the dorsal raphe nuclei
What are the motor effects of seratonergic neurons?
seratonergic firing patterns in the dorsal raphe suggests activity during repetitive movements: facilitation of motor control, proposed to suppress sensory processing and facilitate repetitive tasks
seratonergic firing patterns are stopped during sensory processing
presentation of novel stimuli disrupts tonic firing of the DRN
What are the broad behavioral effects of seratonergic neurons?
diverse effects on behavior make it difficult to ascribe an overall function to seratonergic systems
5-HT is colloquially thought to contribute to happiness: antidepressants target 5-HT reuptake and improve mood
5-HT binding capacity has been suggested to correlate with tendency towards spirituality
What are the different types of 5-HT receptors?
5-HT1: GPCR-Gi (1A, B, D)
5-HT2: GPCR-Gq (2A, B, C)
5-HT3: ligand gated Na+ and K+ channel
What are 5-HT 1A receptors?
agonists: Buspirone (partial agonist), Cannabidiol (partial agonist)
functions as somatodendritic autoreceptors
agonists at 5-HT 1A cause hyperphagia: agonists decrease 5-HT release, prevents attenuation of appetite
concentrated in hippocampus, amygdala, and septim
inhibitory neurotransmitter: signals through Gi to inhibit adenylate cyclase, signals through G beta-gamma to specialized inhibitory K+-channels (GIRK)
What is WAY-100,635?
numbered compound developed by Wyeth-Ayerst
experimental selective 5-HT1A receptor agonist
used as a PET ligand to identify 5-HT1A receptors in the human brain
How is the 5-HT1A receptor connected to spirituality?
2003 study from a Swedish group correlated 5-HT1A binding capacity with components of the Temperament and Character Inventory self-report questionnaire in 15 male volunteers (age 20-45)
found a significant correlation with spiritual acceptance (component of self-transcendence metric)
proposed 5-HT system was the source of individual variation in spiritual zeal
What are 5-HT 1B and 1D?
inhibitory through cAMP and GIRK
1B not expressed in humans, instead there are two 1D variants (1Dalpha and 1Dbeta)
found on intracranial blood vessels
agonists include anti-migraine medication
sumatriptan (Imitrex) agonized 1B and 1D receptors
What is migraine pathogenesis?
cortical spreading depression: expanding pulse of activity followed by hypoactivity, often originates in occipital cortex (causing perception auras)
accompanied by constrictions in blood flow
reactive vasodilation causes pain
no pain fibers in the brain parenchyma but dura mater and meningeal blood vessels are well innervated by pain fibers
sensory fibers release vasodilating peptides
peptides promote a sterile inflammatory response
inflammation cause sensitization of sensory fibers
How does 5-HT modulate neuropeptide release in migraine treatment?
5HT1D receptors are inhibitory
agonists of 5-HT1D inhibit release of vasodilating peptides
promotes vasoconstriction rather than vasodilation
leads to decreased excitation of trigeminal nerve and decreased effect on nausea centers
What is the 5-HT2 receptor family?
Gq alpha to PLC resulting in increased Ca2+ and PKC activation
mostly function as postsynaptic receptors
many agonists affect all three receptors: soem antagonists show specificity
high densities in nucleus accumbens, striatum, cortex (especially frontal)
What is the 5-HT2A receptor?
“classic” 5-HT2 receptor, best characterized
experimental agonists: DOI administration to rodents leads to a characteristic head twitch (brief and periodic)
antagonists: ketanserin: antihypertensive and useful as a PET radioligand for 5-HT2A receptors, atypical antipsychotics clozapine and risperadone
How do psychedelics affect 5-HT2A receptor?
LSD, mescaline, psilocybin are all agonists at 5HT2 receptors (particularly 5HT2A)
5HT2A agonists are consider potent hallucinogens
How do 5-HT2B and 2C receptor affect appetite?
an active metabolite of fenfluramine (norfenfluramine) is an agonist for 5-HT2B and 5-HT2C (and 2A at sufficient dose)
Lorcaserin (Belviq) is a specific agonist for 5-HT2C and anorectic drug in limited use to treat obesity: agonists of 5-HT2C are thought to promote satiety through effects on the hypothalamus
5-HT2C is also expressed in the choroid plexus and regulates CSF composition and volume in response to 5-HT in the CSF
Why are 5-HT2C receptors in the amygdala proposed to be the cause of acute side effects of SSRIs?
5-HT2C in the amygdala is anxiogenic and proposed to be the cause of acute side effects of SSRIs
early period of use of SSRIs often accompanied by anxiety and depression
5-HT2C expression decreases slowly with SSRI use - compensatory downregulation
5-HT2C expression correlates with the onset of clinical effectiveness
What are 5-HT3 receptors?
5-HT3 is the only 5-HT ligand-gated ion channel
structured and functional relationship to nAChR
5-HT3 receptors are expressed in the chemoreceptor trigger zone and in the gut
agonists are emetic (nausea inducing)
antagonists are anti-emetic: ondasetron is a prescription anti-emetic used to treat chemotherapy-related nausea
How does the dorsal raphe nuclei impact anxiety and mood?
subdivisions of the DRN have been implicated in anxiety, panic and mood disorders
anxiety: DRN, dorsal part (DRD) and DRN, caudal part (DRC)
panic: DRN, ventrolateral (DRVL) and ventrolateral periaqueductal gray (VLPAG)
How does the DRN impact anxiety and stress?
serotonergic neurons in the DRN are active in response to anxiogenic stimuli
anxiogenic agents (caffeine) increase activity
social defeat paradigms increase DRN activity
DRD activated in fear-potentiated startle
DRC activated by unpredictable noise stress
How are 5-HT 1A receptors involved in anxiety?
antidepressants targeting serotonergic neurotransmission are effective anxiolytics
MAOI, TCA antidepressants are highly effective but with severe side effects
SSRI and SNRI are effective and well tolerated
5-HT depletion (via tryptophan depletion) increases depressive symptoms
5-HT1A receptors function primarily as autoreceptors: autoreceptors drive negative feedback to inhibit 5HT release
5-HT1A agonists are effective anxiolytics: cannabidiol, buspirone
polymorphisms of the 5-HT1A receptor gene are implicated in risk of depression and anxiety: predicts poor response to SSRI therapy
How are 5-HT receptors involved in anxiety and mood?
in the presence of SSRI antidepressants 5-HT is broadly increased
early phase of AD treatment has mixed effects
may increase anxiety and mood symptoms, increase suicidal thoughts
in the basolateral amygdala 5-HT activates 5-HT2C receptors
5-HT2C activation is anxiogenic
5-HT2C receptors are downregulated slowly with SSRI use
proposed to play a role in the early anxiety and depression in initial SSRI use
