Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus.
In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA.
Department of Psychiatry, University of Washington, USA.
J F
JF
Neumaier
D C
DC
Root
M W
MW
Hamblin
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D011903:Raphe Nuclei / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D002352:Carrier Proteins; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat