Cotransmission involves neurons releasing multiple transmitters or modulators simultaneously, often stored in distinct vesicles. Important cotransmitters include purines, peptides, nitric oxide, and prostaglandins, which influence synaptic activity and responsiveness to primary transmitters. This mechanism allows for varied and prolonged effects of neurotransmission, with different time-courses and diffusion properties among cotransmitters.

1. COTRANSMISSION
DR. MERLIN.N.J
Professor
Department of Pharmacology
Ezhuthachan College of Pharmaceutical Sciences,
Trivandrum

2. Definition
 Neurons release more than one transmitter or modulator each of which
interacts with specific receptors and produces effects both pre and
postsynaptically .
 Eg. NA and ATP cotransmission in sympathetic nerve endings
 In other words two or more transmitters are contained within individual nerve
terminals and are released simultaneously on nerve stimulation.

3.  The cotransmitter is stored in the prejunctional nerve terminal alongwith the
primary transmitter, but in separate vesicles (in some cases in the same
vesicle itself).
 Nerve impulse releases both the transmitters concurrently.
 Acting on its own receptors, the cotransmitter modifies responsiveness of the
effector to the primary transmitter or substitutes for it.
 Cotransmitter may also act on prejunctional receptors and modulate release
of the transmitter

5. Important cotransmitters
 In the ANS, besides the primary transmitters ACh and NA, the cotransmitters
are
 purines (ATP, adenosine),
 peptides (vasoactive intestinal peptide or VIP, neuropeptide-Y or NPY, substance
P, enkephalins, somatostatin, etc.),
 nitric oxide (NO) and prostaglandins as cotransmitters.

6.  In most autonomic cholinergic neurones VIP is associated with ACh,
 while ATP is associated with both ACh and NA.
 The transmitter at some parasympathetic sites is NO, and these are called
nitrergic nerves.
 Vascular adrenergic nerves contain NPY which causes long lasting
vasoconstriction.
 The cotransmitter is stored in the same neurone but in distinct synaptic
vesicles or locations .
 However, ATP is stored with NA in the same vesicle.

7.  On being released by nerve impulse the cotransmitter may serve to regulate
the presynaptic release of the primary transmitter and/or postsynaptic
sensitivity to it (neuromodulator role).
 The cotransmitter may also serve as an alternative transmitter in its own
right and/or exert a trophic influence on the synaptic structures.

8.  The time-course of action of the primary transmitter and the cotransmitter is
usually different.
 The cotransmitter VIP of parasympathetic neurones produces a slow and long-
lasting response, while another one (NO) has an intermediate time-course of
action between VIP and ACh (fast acting).
 Similarly, in sympathetic neurones, the cotransmitter NPY is slower acting
and ATP faster acting than NA.
 Moreover, cotransmitters like NO, VIP, NPY diffuse to a wider area, and can
affect receptors at some distance from the site of release.

9. Advantages of cotransmission
 One constituent of the cocktail(eg. a peptide) may be removed or inactivated
more slowly than the other( eg. A monoamine) and therefore reach targets
from the site of release and produce longer lasting effects. This appears to be
the case with Acetyl choline and GnRh in sympathetic ganglia
 The balance of the transmitters released may vary under different conditions
 At sympathetic nerve terminals where NA and NPY are stored in separate vesicles,
NPY is released at high stimulation frequencies, so that differential release of one
or more mediator result from varying impulse patterns
 Differntial effect of presynaptic modulators are also possible eg. Activation of beta
adrenoreceptor inhibits ATP release while enhancing NA release from sympathetic
nerve terminals