By using m-chlorophenylpiperazine (m-CCP, a 5-HT1 agonist) as a challenge agent, we have demonstrated that long-term (21-25 days) lithium (antidepressant/antimanic) treatment accentuated m-CPP's effect on plasma prolactin and corticosterone but not on growth hormone levels. On the other hand, short-term (2-6 days) lithium treatment accentuated m-CPP's effect on plasma corticosterone but not on plasma prolactin or growth hormone levels. In another study, long-term (21 days) treatment with imipramine, clomipramine (tricyclic antidepressants) and clorgyline (monoamine oxidase type A inhibiting antidepressant) produced significant decreases in plasma corticosterone levels in Fawn-Hooded (FH) rats. On the other hand, plasma adrenocorticotropic hormone (ACTH) levels were not altered by chronic imipramine or clorgyline treatment but were significantly higher in chronic clomipramine-treated FH rats. These findings demonstrate a differential effect of chronic antidepressant treatment on plasma ACTH and corticosterone concentrations in FH rats and, furthermore, support our earlier studies suggesting that the FH rat strain may represent a genetic model of depression. In a separate series of experiments, chronic administration of imipramine, clomipramine and fluoxetine (5-HT uptake inhibiting antidepressants) but not clorgyline (monoamine oxidase type A inhibiting antidepressant) or 5-HT receptor agonists (m_CCP, DoI, 8-OHDPAT) decreased 5-HT transport steady-state mRNA concentrations in rat brain. In another study, chronic fluoxetine treatment decreased Galphas mRNA in midbrain, while mRNA expression of the novel G protein alpha subunits, Galphaq, and Galpha12, was increased in neostriatum and frontal cortex. These findings indicate that regulation of G protein function and the 5- HT transporter by antidepressant drugs may occur at the level of gene expression and , furthermore, may contribute to the neuroadaptive mechanisms that likely underlie their therapeutic efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH000332-16
Application #
3759351
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
1994
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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