All transmission is not through synapses. Other modes are discussed here.

1. Volume Neurotransmission
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Devashish Konar MD Consultant Psychiatrist
Mental Health Care Centre, Kolkata, India
Mob: +91 9434009113 +91 9732221712
Presented at ANCIPS 2015, Hyderabad

2. SOME NEUROTRANSMISSION DO NOT NEED A SYNAPSE AT ALL
• Neurotransmission without a synapse is called volume
neurotransmission.
• Chemical messengers sent by one neuron to another can
spill over to sites distant to the synapse by diffusion.
• Thus ,neurotransmission can occur at any compatible
receptor within the diffusion radius of the
neurotransmitter, like transmission radius of cellular
telephones.
• Here neurotransmission occurs in chemical “puffs”.
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3. HISTORY
• The concept of volume transmission as an important mode
of chemical communication in the brain was introduced in
the 1980s.
• New techniques like receptor autoradiography and
immunohistochemistry allow detailed mapping of the
locations of neurotransmitters.
• Findings indicate that active substances must be getting to
receptors in some manner other than release from an
adjacent terminal.
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4. NONSYNAPTIC RELEASE OF NTs
• Mapping studies have identified axon terminals without
postsynaptic specializations.
• Also, varicosities containing granules filled with monoamine
NTs have been localized, not only in axon terminals, but
also in other portions of neurons e.g., dendrites, soma,
non-terminal axon segments.
• These findings support the possibility of non synaptic
release of NTs into the ECS.
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5. SLOWER TONIC CHANGES
• Volume transmission is an important mode of action for
other Neurotransmitters e.g., glycine, glutamate, GABA.
• Many neuroactive substances e.g., glial transmitters,
peptides, nitric oxide, neurosteroids are also released into
the ECS.
• The location of a receptor, compared with the source of
the neuroactive substance, is likely to be very important in
determining activation.
• Thus, they are more likely to signal slower (tonic) changes
that are occurring over a larger area.
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6. 6
RADII OF NEUROTRANSMISSION
QUANTAL RELESE
AT SINGLE SYNAPSE
LOW AFFINITY RECEPTORS
FOR VOLUME TRANSMISSION
HIGH AFFINITY RECEPTORS
FOR VOLUME TRANSMISSION

7. MEDICINES DON’T ACT ONLY THROUGH SYNAPSE
• Chemically addressed nervous system is particularly
important in mediating the actions of drugs that act at
various neurotransmitter receptors.
• Drugs will act wherever there are relevant receptors, and
not just where such receptors are innervated with
synapse by the anatomically addressed nervous system.
• Modifying volume neurotransmission may indeed be a
major way in which several psychotropic drugs work in
the brain.
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8. LOCAL VOLUME TRANSMISSION
• At the local level, volume transmission occurs via movement of
neuroactive substances through the interstitial fluid that fills the ECS.
• The ECS, which occupies about 20% of the tissue volume, has a very
complex, three-dimensional structure.
• Most signaling by volume transmission via the ECS is short-distance,
particularly within gray matter.
• It has been suggested that the highly linear nature of white-matter tracts
may provide a faster route for interstitial fluid movement than occurs in
gray-matter areas.
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9. DISTANCE VOLUME TRANSMISSION
• It was demonstrated in the 1980s that a tracer introduced into the
cerebrospinal fluid (CSF) quickly distributed into the brain parenchyma,
outlining the microvasculature.
• Transport within the CSF potentially allows neuroactive substances rapid
access to areas of the brain distant from their point of entry into the CSF.
• The PVS may provide a mechanism for coordinated changes in activity across
multiple areas.
• It has been proposed that distribution by this route of CSF containing
neuroactive substances is important for onset and maintenance of specific
behavioral or motivational states (e.g., fear, appetite, mood, circadian
rhythms).
• Overall, this system provides a path by which substances can be both
circulated throughout and removed from the brain parenchyma.
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10. 10
A TRACER INTRODUCED INTO THE CEREBROSPINAL FLUID

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MICROVASCULAR SYSTEM

12. CLEARANCE OF TOXINS DURING SLEEP
• A recent animal study reported that the rate of flow was most rapid
during sleep, slowing abruptly when animals were awakened.
• This was a result of a reduction in the volume fraction of the ECS,
which decreased from about 22%−24% (asleep or anesthetized) to
about 13%−15% (awake).
• As would be predicted, clearance of substances was much faster
during sleep, when the ECS was largest.
• These results suggest that one important function of sleep is
efficient clearance of toxins and wastes from the brain by this
pathway.
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13. IMPAIRED CLEARANCE LEADING TO PATHOLOGY
• Any diminution in this flow through the ECS could impair clearance of
solutes (e.g., amyloid beta), and this has been proposed as an
important pathophysiological mechanism for several
neurodegenerative diseases.
• It may also contribute to sequelae of low-level brain injury
(microinfarction, mild traumatic brain injury).
• These conditions may trigger a prolonged widespread reactive gliosis
and/or focal disruption of vascular perfusion.
• Overall, this system provides a path by which substances can be both
circulated throughout and removed from the brain parenchyma.
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14. VOLUME TRANSMISSION IN UNDERSTANDING THE PATHOLOY
• Volume transmission also provides a route for toxic
substances in the blood or CSF to reach the brain
parenchyma.
• This route has been implicated in both multiple sclerosis and
viral encephalitis.
• It may also be the origin of the neuropsychiatric symptoms
that can occur after some systemic infections.
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15. CONCLUSIONS
• Recent scientific evidence is leading to a greater understanding of
the complexities and intricacies of chemical communication in the
brain.
• The importance and relevance of both fast/precise and
slow/summative types of communication have yet to be fully
appreciated.
• Advancing knowledge is gradually elucidating the roles that volume
transmission plays in supporting normal function.
• Also, this mode of chemical communication provides new avenues
with great potential for intervening in neurodegenerative
conditions, after acute trauma, and in the development of novel
therapeutics for chronic psychiatric conditions that, to date , do not
have satisfactory treatments.
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16. BRAIN: THE ULTIMATE WONDERLAND
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