student research day - Case Western Reserve University School of ...

Franklin D. Warren II
Serotonin-Dopamine Interactions in PET Knock-out Mice
Franklin D. Warren II and Elizabeth A. Pehek
Department of Psychiatry and Neurosciences, Case Western Reserve School of Medicine
Louis Stokes Cleveland DVA Medical Center
The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and
reward, as well, as a number of syndromes including drug abuse, schizophrenia, and Parkinson’s disease (1). Studies
have shown that serotonin, by way of several receptors located in various parts of the brain, has the ability to modulate
DA neurons. There are at least fourteen serotonin (5-HT) receptor subtypes, many of which have been shown to play
some role in mediating 5-HT/DA interactions (1). The effects of serotonin on DA have historically been exploited in
efforts to create therapeutic drugs for drug abuse, schizophrenia, Parkinson’s disease, and other disorders of DA action.
We have shown previously that mild handling stress increases DA and 5-HT release in the rat prefrontal cortex (PFC).
The increase in DA is blocked by administration of an antagonist at the serotonin 5-HT2A receptor subtype (Pehek et al.,
2006). These data indicate that 5-HT, released during stress, acts on 5-HT2A receptors to augment stress-induced DA
release. It is important, however, to provide alternative lines of evidence. We propose to test the hypothesis that 5-HT
release is necessary for stress-induced DA release in the PFC through the use of the PET KO mouse. Brain 5-HT is
severely depleted in these mice. Thus, while basal DA levels may be normal, a diminished serotonergic response to
stress may result in a decreased dopaminergic response. We also wish to test the responsivity of these mice to a 5-HT2C
receptor antagonist. A collaborator, Dr. Bryan Roth, formerly with Case and now with the University of North Carolina,
has determined that 5-HT2C (but not 5-HT2A) receptors are upregulated in PET KO mice. Administration of 5-HT2C
antagonists increases cortical DA in normal rats. We predict that, relative to wild-type (WT) controls, PET KO mice will
show a heightened response to 5-HT2C antagonist administration.
References:
[1] Pehek, E.A., Alex, K.D. (2007). Pharmacologic mechanisms of serotonergic regulation of dopamine
neurotransmission. Pharmacology and Therapeutics 113, 296-320)
Supported by Louis Stokes Cleveland DVA Medical Center
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