Chemical communication

PSY 511

Fun

Neural communication

What triggers the action potential?

• Soma receives input from dendrites (and on soma directly)
• Axon hillock sums/integrates
• If sum > threshold, action potential “fires”
• Action potential propagates along the axon

Source: https://commons.wikimedia.org/wiki/File%3A1224_Post_Synaptic_Potential_Summation.jpg

• Action potential’s rapid change in voltage triggers neurotransmitter (NT) release

Synaptic transmission

Synapse permits neuron to pass electrical or chemical messages to another neuron or target cell (muscle, gland, etc.)

Synapse Types

• Electrical
  • Gap junctions
  • Cytosol (and ionic current) flows through adjacent neurons
• Chemical

Source: Blausen.com staff https://commons.wikimedia.org/wiki/File%3ABlausen_0843_SynapseTypes.png

Steps in chemical transmission

• Voltage-gated calcium Ca++ channels open
• Ca++ influx causes synaptic vesicles to bind with presynaptic membrane, fuse with membrane, spill contents via exocytosis
• NTs diffuse across synaptic cleft
• NTs bind with receptors on postsynaptic membrane
  • Cause some post-synaptic effect
• NTs unbind from receptor
• NTs inactivated

Source: https://commons.wikimedia.org/wiki/File%3ASynapseSchematic_en.svg

Exocytosis

Source: http://dx.doi.org/doi:10.1038/nrn2948

Receptor/channel types

Leak/passive

• Vary in selectivity, permeability

Transporters/exchangers

• Ionic
  • \(Na^+\)/\(K^+\) ATP-ase/pump
• Chemical
  • e.g., Dopamine transporter (DAT)

Ionotropic receptors (receptor + ion channel)

• Ligand-gated
• Open/close channel

Metabotropic receptors (receptor only)

• Triggers 2nd messengers
• G-proteins
• Open/close adjacent channels, change metabolism

Receptors generate postsynaptic potentials (PSPs)

• Small voltage changes
• Amplitude scales with # of receptors activated
• Excitatory PSPs (EPSPs)
  • Depolarize neuron (make more +)
• Inhibitory (IPSPs)
  • Hyperpolarize neuron (make more -)

NTs inactivated

• Buffering
  • e.g., glutamate into astrocytes
• Reuptake into presynaptic cell via transporters
  • e.g., serotonin via serotonin transporter (SERT)
• Enzymatic degradation
  • e.g., acetylcholine esterase (AChE) degrades acetylcholine (ACh)

Questions to ponder

• Why do NTs diffuse from pre- to post-synaptic membrane?
• Why must NTs be inactivated?
• What sort of PSP would opening a Na+ channel produce?
• What sort of PSP would opening a Cl- channel produce?
• What sort of PSP would closing a K+ produce?

Synapse location and function

• dendrites
  • usually excitatory
• cell bodies
  • usually inhibitory
• axons
  • usually modulatory (change p(fire))

Neurotransmitters

Family	Neurotansmitter
Amino acids	Glutamate
	\(\gamma\) aminobutyric acid (GABA)
	Glycine
	Aspartate

Glutamate

• Primary excitatory NT in CNS
• Role in learning (via NMDA)
• Receptors on neurons and glia (astrocytes and oligodendrocytes)
• Linked to umami (savory) taste sensation (think monosodium glutamate or MSG)
• Dysregulation in schizophrenia? (Javitt, 2010)

Type	Receptor	Esp Permeable to
Ionotropic	AMPA	Na+, K+
	Kainate
	NMDA	Ca+
Metabotropic	mGlu

\(\gamma\) aminobutyric acid (GABA)

• Primary inhibitory NT in CNS
• Excitatory in developing CNS, [Cl-] in >> [Cl-] out
• Binding sites for benzodiazepines (BZD; e.g., Valium), barbiturates, ethanol, etc.
  • BZD affect subset of GABA-A receptors
  • Increase total Cl- influx

Type	Receptor	Esp Permeable to
Ionotropic	GABA-A	Cl-
Metabotropic	GABA-B	K+

Source: https://commons.wikimedia.org/wiki/File:GABAA-receptor-protein-example.png#/media/File:GABAA-receptor-protein-example.pn

Other amino acid NTs

• Aspartate
  • Like Glu, stimulates NMDA receptor
• Glycine
  • Spinal cord interneurons

Acetylcholine (ACh)

• Primary excitatory NT of CNS output
• Somatic nervous system (motor neuron -> neuromuscular junction)
• Autonomic nervous system (ANS)
  • Sympathetic branch: preganglionic neuron
  • Parasympathetic branch: pre/postganglionic

Source: http://myzone.hrvfitltd.netdna-cdn.com/wp-content/uploads/2014/09/Image-1.jpg

Type	Receptor	Esp Permeable to	Blocked by
Ionotropic	Nicotinic (nAChR)	Na+, K+	e.g., Curare
Metabotropic	Muscarinic (mAChR)	K+	e.g., Atropine

Curare

Atropine

• aka, nightshade or belladonna
• inhibits (acts as an antagonist for) muscarinic ACh receptor

https://cdn.britannica.com/92/183192-050-1741C2F9/Belladonna-nightshade-leaves-berries-alkaloids-humans.jpg

Source: https://commons.wikimedia.org/wiki/File:Eye_treated_with_dilating_eye_drops.jpg

Monoamine NTs

Family	Neurotransmitter
Monoamines	Dopamine (DA)
	Norepinephrine (NE)/Noradrenaline (NAd)
	Epinephrine (Epi)/Adrenaline (Ad)
	Serotonin (5-HT)
	Melatonin
	Histamine

Information processing

• Point-to-point
  • One sender, small number of recipients
  • Glu, GABA
• Broadcast
  • One sender, widespread recipients
  • DA, NE, 5-HT, melatonin, histamine
• Need to know
  • NT, where projecting, type of receptor to predict function

Dopamine

• Released by
  • Substantia nigra -> striatum, meso-striatal projection
  • Ventral tegmental area (VTA) -> nucleus accumbens, ventral striatum, hippocampus, amygdala, cortex; meso-limbo-cortical projection

Source: http://thebrain.mcgill.ca/flash/a/a_03/a_03_cl/a_03_cl_que/a_03_cl_que_1a.gif

Clinical relevance for

• Parkinson’s Disease (mesostriatal)
  • DA agonists treat (agonists facilitate/increase transmission)
• ADHD (mesolimbocortical)
• Schizophrenia (mesolimbocortical)
  • DA antagonists treat
• Addiction (mesolimbocortical)

Inactivated via

• Chemical breakdown (e.g., via monoamine oxidase), http://www.scholarpedia.org/article/Dopamine_anatomy#Dopamine_receptors
• Dopamine transporter (DAT)
  • Psychostimulants (e.g., cocaine, methylphenidate) act upon. (“Dopamine transporter,” n.d.)
  • DAT also transports norepinephrine (NE)

https://ars.els-cdn.com/content/image/3-s2.0-B9780123741059002379-gr1.jpg?_

Type	Receptor	Comments
Metabotropic	D1-like (D1 and D5)	more prevalent
	D2-like (D2, D3, D4)	target of many antipsychotics

Norepinephrine

• Released by
  • locus coeruleus in pons/caudal tegmentum
  • postganglionic sympathetic neurons onto target tissues
  

  https://upload.wikimedia.org/wikipedia/commons/thumb/c/cd/Locus_coeruleus_highlighted.jpg/300px-Locus_coeruleus_highlighted.jpg

https://www.researchgate.net/publication/338194613/figure/fig1/AS:842586742857728@1577899742543/Locus-coeruleus-LC-efferent-pathways-and-relevant-functions-LC-projects-throughout-the.png

Source: http://myzone.hrvfitltd.netdna-cdn.com/wp-content/uploads/2014/09/Image-1.jpg

• Role in arousal, mood, eating, sexual behavior
• Clinical relevance for ADHD, Alzheimer’s, Parkinson’s, depression
• Inactivated by norepinephrine transporter (NET), aka noradrenaline transporter (NAT)
  • Contributes to DA uptake, too.
• Also monoamine oxidase inhibitors (MAOIs)
  • inactivate monoamines in neurons, astrocytes
  • MAOIs increase NE, DA
  • Treatment for depression

Source: https://www.dartmouth.edu/~rswenson/NeuroSci/figures/Figure_9_files/image002.jpg

Type	Receptor	Comments
Metabotropic	\(\alpha\) (1,2)	antagonists treat anxiety, panic
	\(\beta\) (1,2,3)	‘beta blockers’ in cardiac disease

Adrenaline/Epinephrine

• Synthesized from norepinephrine
• As NT: Released in small amounts by medulla oblongata
• As hormone: Released by adrenal medulla
• Binds to (\(\alpha_{1,2}\), \(\beta_{1,2,3}\) receptors in blood vessels, cardiac muscle, lungs, eye muscles controlling pupil dilation, liver, pancreas, etc.
• Release enhanced by cortisol from adrenal cortex
• Unusual in NOT being part of negative feedback system controlling its own release

Serotonin (5-HT)

• Released by raphe nuclei in brainstem
• Role in mood, sleep, eating, pain, nausea, cognition, memory
• Modulates release of other NTs
• Most of body’s 5-HT regulates digestion

Source: https://www.dartmouth.edu/~rswenson/NeuroSci/figures/Figure_9_files/image002.jpg

• Separate cortical, subcortical 5-HT projection pathways?

(Ren et al., 2018)

• Seven receptor families (5-HT 1-7) with 14 types
• All but one metabotropic

Clinically significant because

• Ecstasy (MDMA) disturbs serotonin
• So does LSD
• Fluoxetine (Prozac)
  • Selective Serotonin Reuptake Inhibitor (SSRI)
  • Treats depression, panic, eating disorders, others
• 5-HT3 receptor antagonists are anti-mimetics used in treating nausea

Melatonin

• Released by pineal gland (pine cone-like appearance)

http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/pinealgland.jpg

Histamine

• Released by hypothalamus, projects to whole brain
• \(H_1\)-\(H_4\) Metabotropic receptors, one ionotropic type in thal/hypothal
• Role in arousal/sleep regulation
• In body, part of immune/inflammatory response

Targets of psychotropic drugs

Source: https://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter2_summary.htm&name=Chapter%202&title=Summary

Other NTs

• Gases
  • Nitric Oxide (NO), carbon monoxide (CO)
• Neuropeptides
  • Substance P and endorphins (endogenous morphine-like compounds) have role in pain
  • Orexin/hypocretin, project from lateral hypothalamus across brain, regulates appetite, arousal
  • Cholecystokinin (CCK) stimulates digestion
• Purines
  • Adenosine (inhibited by caffeine)
• Others
  • Anandamide (activates endogenous cannabinoid receptors)

Hormonal communication

• Chemicals secreted into blood
• Act on specific target tissues via receptors
• Produce specific effects

Examples of substances that are both hormones and NTs

• Melatonin
• Epinephrine/adrenaline
• Oxytocin
• Vasopressin

Behaviors under hormonal influence

Ingestive (eating/ drinking)

• Fluid levels
• Na, K, Ca levels
• Digestion
• Blood glucose levels

Reproduction-related

• Sexual Maturation
• Mating
• Birth
• Care giving

To threat/challenge

• Metabolism
• Heart rate, blood pressure
• Digestion
• Arousal

Common factors

• Biological imperatives
• Proscribed in space and time
• Foraging/hunting
  • Find targets distributed in space, evaluate, act upon
• Often involve others

Principles of hormonal action

• Gradual action
• Change intensity or probability of behavior
• Behavior influences/influenced by hormones
  • +/- Feedback
• Multiple effects on different tissues
• Produced in small amounts; released in bursts
• Levels vary daily, seasonally
  • or are triggered by specific external/internal events
• Effect cellular metabolism
• Influence only cells with receptors
• Point to point vs.“broadcast”
  • Wider broadcast than neuromodulators
• Fast vs. slow-acting
• Short-acting vs. long-acting
• Digital (yes-no) vs. analog (graded)
• Voluntary control vs. involuntary

Similarities between neural and hormonal communication

• Chemical messengers stored for later release
• Release follows stimulation
• Action depends on specific receptors
• 2nd messenger systems common

Hormonal release sites

• CNS
  • Hypothalamus
  • Pituitary
    • Anterior
    • Posterior
  • Pineal gland
• Rest of body
  • Thyroid
  • Adrenal (ad=adjacent, renal=kidney) gland
    • Adrenal cortex
    • Adrenal medulla
  • Gonads (testes/ovaries)

Two release systems from hypothalamus

Direct release

• Hypothalamus (paraventricular, supraoptic nucleus) to
• Posterior pituitary
  • Oxytocin
  • Arginine Vasopressin (AVP, vasopressin)

Source: https://upload.wikimedia.org/wikipedia/commons/thumb/7/70/1807_The_Posterior_Pituitary_Complex.jpg/594px-1807_The_Posterior_Pituitary_Complex.jpg

Indirect release

• Hypothalamus -> releasing hormones
• Anterior pituitary -> tropic hormones
• End organs

Case studies

Responses to threat or challenge

• Neural response
  • Sympathetic Adrenal Medulla (SAM) response
  • Sympathetic NS activation of adrenal medulla, other organs
  • Releases NE and Epi into bloodstream

(Ulrich-Lai & Herman, 2009)

• Endocrine response
  • Hypothalamic Pituitary Adrenal (HPA) axis
  • Adrenal hormones released
• Hypothalamus
  • Corticotropin Releasing Hormone (CRH)
• Anterior pituitary
  • Adrenocorticotropic hormone (ACTH)
• Adrenal cortex
  • Glucocorticoids (e.g., cortisol)
  • Mineralocorticoids (e.g. aldosterone)

(Ulrich-Lai & Herman, 2009)

Adrenal hormones

• Steroids
  • Derived from cholesterol
• Cortisol
  • increases blood glucose, anti-inflammatory effects
  • negative consequences of prolonged exposure
• Aldosterone
  • Regulates Na (and water)

Reproductive behavior – the milk letdown reflex

• Supraoptic & Paraventricular nucleus (PVN) of hypothalamus releases oxytocin
  • Into bloodstream via posterior pituitary (endocrine)
  • Onto neurons in nucleus accumbens (neurocrine), amygdala, brainstem
• Oxytocin stimulates milk ducts to secrete

https://64.media.tumblr.com/29ad3be13cc42500c5c0eb496b465745/tumblr_nr55r27dOB1tqg84mo1_640.png

Oxytocin’s role…

• Sexual arousal
• Released in bursts during orgasm
• Stimulates uterine, vaginal contraction during labor
  • But mouse OXY knock-out model still engages in reproductive behavior and gives birth without incident.
• Oxytocin cells in ovarian corpus luteum, testicles, retina, adrenal medulla, pancreas
• Links to social interaction, bonding (Weisman & Feldman, 2013)
• Alters face processing in autism (Domes et al., 2013)
• May inhibit fear/anxiety-related behaviors by gating amygdala (Viviani et al., 2011)

Circadian rhythms

Melatonin

• Diurnal rhythm
• Night time peak, early morning low
• Secretion suppressed by short wavelength or “blue” light (< 460-480 nm)
• Rhythm irregular until ~3 mos post-natal (Ardura, Gutierrez, Andres, & Agapito, 2003)
• Peak weakens, broadens with age

• Suprachiasmatic nucleus (SCN) of the hypothalamus
• Paraventricular nucleus of the hypothalamus
• Spinal cord
• Superior cervical ganglion
• Pineal gland

Thinking about neurochemical influences

• Measure hormones in blood, saliva; can’t effectively measure NTs
• Multivariate, nonlinear, mutually interacting
• Varied time scales
  • Phasic (e.g., cortisol in response to challenge)
  • Periodic (e.g., melatonin; diurnal cortisol)
• Peripheral effects + neural feedback
• State variables and behavior
  • Are your participants sleepy, hungry, horny, distressed…
  • Endogenous & exogenous influences
  • Systems interact; need better, broader, and denser measurement

Gut/brain connection

(Sarkar et al., 2016)

References

Ardura, J., Gutierrez, R., Andres, J., & Agapito, T. (2003). Emergence and evolution of the circadian rhythm of melatonin in children. Horm. Res., 59(2), 66–72. https://doi.org/68571

Domes, G., Heinrichs, M., Kumbier, E., Grossmann, A., Hauenstein, K., & Herpertz, S. C. (2013). Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biological Psychiatry, 74(3), 164–171. https://doi.org/http://dx.doi.org/10.1016/j.biopsych.2013.02.007

Dopamine transporter. (n.d.). https://www.sciencedirect.com/topics/neuroscience/dopamine-transporter. Retrieved from https://www.sciencedirect.com/topics/neuroscience/dopamine-transporter

Javitt, D. C. (2010). Glutamatergic theories of schizophrenia. Israel Journal of Psychiatry and Related Sciences, 47(1), 4.

Ren, J., Friedmann, D., Xiong, J., Liu, C. D., Ferguson, B. R., Weerakkody, T., … Luo, L. (2018). Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems. Cell. https://doi.org/10.1016/j.cell.2018.07.043

Sarkar, A., Lehto, S. M., Harty, S., Dinan, T. G., Cryan, J. F., & Burnet, P. W. J. (2016). Psychobiotics and the manipulation of Bacteria–Gut–Brain signals. Trends in Neurosciences, 39(11), 763–781. https://doi.org/10.1016/j.tins.2016.09.002

Ulrich-Lai, Y. M., & Herman, J. P. (2009). Neural regulation of endocrine and autonomic stress responses. Nature Reviews Neuroscience, 10(6), 397–409. https://doi.org/10.1038/nrn2647

Viviani, D., Charlet, A., Burg, E. van den, Robinet, C., Hurni, N., Abatis, M., … Stoop, R. (2011). Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science, 333(6038), 104–107. https://doi.org/10.1126/science.1201043

Weisman, O., & Feldman, R. (2013). Oxytocin effects on the human brain: Findings, questions, and future directions. Biological Psychiatry, 74(3), 158–159. https://doi.org/http://dx.doi.org/10.1016/j.biopsych.2013.05.026