PS275 Lecture Notes - Fluoxetine, Action Potential, Monoamine Neurotransmitter

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Published on 1 Feb 2013
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THE GENETIC DATA:
bipolar disorder is one of the mot heritable of disorders. Genes account for possibly 85% of
variance in whether a person becomes manic.
Evidence favouring the hypothesis that bipolar disorder results from a dominant gene on the 11th
chromosome.
Within bipolar disorder, variation in the brain-derived neurotrophic factor (BDNF) gene appears to
predict risk for developing rapid cycling. Some people seem to be genetically predisposed to the
onset of MDD when confronted with a series of adverse life-events.
Serotonin transporter gene-linked promoter region (5-HTTLPR), which is involved in modulating
serotonin levels, is a significant predictor of first major depression onset following multiple adverse
events.
NEUROCHEMISTRY, NEUROIMAGING AND MOOD DISORDERS:
The original theory posited that low levels of norepinephrine and dopamine lead to depression
and high levels to mania. The serotonin theory suggests that serotonin, a neurotransmitter
presumed to play a role in the regulation of norepinephrine, also produces depression and mania.
However, the weight of the evidence does not completely support the notion that levels of
neurotransmitters are critical in the mood disorders.
Tricylclic drugs : i.e. imipramine, or Tofranil are group of antidepressant medications so named
because their molecular structure is characterized by three fused rings. They prevent some of the
reuptake of norepinephrine, serotonin and or dopamine by the presynaptic neuron after it has fired,
leaving more of the neurotransmitter in the synapse so that transmission of the next nerve impulse
is made easier.
Monoamine oxidase (MAO) inhibitors: I.e. Tranylcypromine or Parnate are antidepressant
drugs that keep the enzyme MAO from deactivating neurotransmitters, thus increasing the levels of
serotonin, norepinephrine and or dopamine in the synapse. This action produces the same
facilitating effect decried for tricylics, compensating for the abnormally low levels of these
neurotransmitters in depressed people.
Newer antidepressants, called selective serotonin reuptake inhibitors, i.e fluoxetine or Prozac, act
more selectivel, specifically inhibiting the reuptake of serotonin.
It now appears that the explanation of why these drugs work is not as straightforward as it
seemed at first.
Both tricyclics and MAO inhibitors take from seven to 14 days to relieve depression, but by that
time, the neurotransmitter level has already returned to its previous state.
Another approach to further evaluate the theories involved measuring metabolites of these NT,
the by-products of the breakdown of serotonin, norepinephrine, and or dopamine found in urine,
blood serum, and the cerebrospinal fluid.
The problem with such measurements is that they are not direct reflections of levels of NT in the
brain; metabolites measured in this way could reflect NT anywhere in the body.
Further, the expected high or low metabolites were not found consistently, thus, many people
with depression or mania did not have disturbances in absolute levels of NT.
It would seem, then, that a simple change in the level of norepinephrine or serotonin or
dopamine is not a sufficient explanation for why people become depressed and/or manic.
One line of research examined whether antidepressants alter the chemical messengers that a
postsynaptic receptor sends into the postsynaptic neuron. If receptors are overly sensitive they
should respond to very small amounts of a neurotransmitter in the synaptic cleft.
Drugs that increase dopamine levels have triggered manic behaviour in people with bipolar
disorder, suggesting the possibility that dopamine receptors are overly sensitive.
Research on Bipolar disorder is also moving away from the older norepinephrine theory. One
major reason is that lithium, the most widely used and effective treatment for bipolar disorder is
useful in treating both the manic and depressive episodes of the disorder, suggesting that it acts
by affecting some neurochemical that can either increase or decrease neural activity.
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