Summary Theme 4 - Apply your knowledge

Stahl – Chapter 11: Mood disorders

 Neurotransmitters and circuits in mood disorders
o Many of the symptoms of mood disorders involve dysfunction of various
combinations of norepinephrine, dopamine, and serotonin =trimonoaminergic neurotransmitter
system
 Noradrenergic neurons
o it utilizes norepinephrine (noradrenaline) as its neurotransmitter.
o Norepinephrine is synthesized / produced from the precursor amino acid tyrosine,
which is transported into the NS from the blood by means of an active transport pump
o Once inside the neuron, the tyrosine is acted on by 3 enzymes in sequence:
1) tyrosine hydroxylase (TOH) = the rate-limiting + most important enzyme
in the regulation of NE synthesis; converts the amino acid tyrosine into dopa
2) dopa decarboxylase (DDC) = converts dopa into dopamine (DA)
a. DA is a neurotransmitter in dopamine neurons a precursor of NE
3) dopamine beta hydroxylase (DBH) = converts DA into NE
o NE is then stored in synaptic vesicles until it is released by a nerve impulse
o NE action is terminated by 2 principal destructive/catabolic enzymes that turn NE
into inactive metabolites:
a) monoamine oxidase (MAO) A or B = located in mitochondria in the presynaptic neuron and
elsewhere
b) catechol-O-methyl-transferase (COMT) = located largely outside of the presynaptic nerve
terminal
o The action of NE can be terminated not only by enzymes that destroy NE but also by a
transport pump (= NE transporter/NET/NE reuptake pump) for NE that prevents NE from
acting in the synapse without destroying it
o such inactivated NE can be restored for reuse in a later neurotransmitting nerve impulse
o NET is located on the presynaptic noradrenergic nerve terminal as part of the presynaptic
machinery of the neuron, where it acts like a vacuum cleaner, whisking NE out of the synapse,
off the synaptic receptors, and stopping its synaptic actions
o Once inside the presynaptic nerve terminal, NE can either be stored again for subsequent
reuse when another nerve impulse arrives or it can be destroyed by NE-destroying enzymes

, o The noradrenergic neuron is regulated by a multiplicity of receptors for NE
o NET is one type of receptor, as is the vesicular monoamine transporter (VMAT2) - transports
NE in the cytoplasm of the presynaptic neuron into storage vesicles
o NE receptors are classified as alpha 1A, IB, 1C or alpha 2A, 2B, or 2C, or as beta 1, beta 2, or
beta 3
o All can be postsynaptic, but only alpha 2 receptors can act as presynaptic
autoreceptors
 Postsynaptic receptors convert their occupancy by norepinephrine at alpha 1A, B, or C;
alpha 2A, B, or C; or beta 1, 2, or 3 receptors into physiological functions and ultimately into
changes in signal transduction and gene expression in the postsynaptic neuron
 Presynaptic alpha 2 receptors regulate norepinephrine release= "autoreceptors"; located
both on the axon terminal (i.e., terminal alpha 2 receptors; Figures 11-32 and 11-33) + at the
cell body (soma) + nearby dendrites latter alpha 2 presynaptic receptors = somatodendritic alpha 2
receptors
o important because are autoreceptors  when presynaptic alpha 2 receptors recognize NE,
they turn off further release of NE  act as a brake for the NE neuron + cause a negative
feedback regulatory signal
o Stimulating this receptor stops the neuron from firingoccurs physiologically to prevent
overfiring of the NE neuron, as it can shut itself off once the firing rate gets too high + the
autoreceptor becomes stimulated
 drugs can not only mimic the natural functioning of the NE neuron by stimulating the
presynaptic alpha 2 neuron BUT those which antagonize this same receptor will have the
effect of cutting the brake cable, thus enhancing release of NE 😊




 Monoamine interactions: NE regulation of 5HT release
o 5HT also regulates 5HT neurons
o the regulation is that of negative feedback inhibition: both neurotransmitters inhibit their
own release
o NE regulates 5HT neurons and reciprocally, that 5HT also regulates NE neurons

,o In NE regulation of  not only negative feedback inhibition of NE on 5HT release at alpha 2
receptors on axon terminals acting as a brake on 5HT release BUT also positive feedback at
alpha 1 receptors at the somatodendritic area acting as an accelerator of 5HT release
o NE has bidirectional control of 5HT release, depending on whether input to the axon terminal
alpha 2 heteroreceptor or to the somatodendritic alpha 1 receptor predominates 😊

 Monoamine interactions: 5HT regulation of NE and DA release
o 5HT also regulates NE release only as negative feedback at either 5HT2A or 5HT2C
receptors inhibiting NE release
o same serotonergic negative feedback regulation occurs for dopamine release
o simultaneous negative feedback regulation of 5HT on both NE and DA release in the
prefrontal cortex due to the actions of 5HT in the brainstem on 5HT2A receptors or on
5HT2C receptors
o In both cases5HT blocks release of both NE and DA in the prefrontal cortex
o evidence suggests that some 5HT2A receptors in some brain areas under certain circumstances
can facilitate DA release
o A separate circuit regulates 5HT2C inhibition of DA release in the nucleus accumbens5HT
acts upon GABA neurons in the brainstem, one of which inhibits the mesolimbic dopamine
projection when 5HT2C receptors are occupied
o 5HT actions on a 2nd GABA neuron that projects to prefrontal cortex result in inhibition of a
descending excitatory glutamate projection to the dopamine neuron, further inhibiting
dopamine release in the nucleus accumbens

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