ABSTRACT
Selective serotonin (5-HT) reuptake inhibitors such as fluoxetine are widely used in the treatment of depression and anxiety; however, the mechanisms underlying their action and particularly the delay in therapeutic onset remain unclear. It is proposed that 5-HT reuptake inhibitors exert their therapeutic activity by increasing serotonergic neurotransmission; therefore, the aim of the present study was to investigate the effects of repeated treatment with fluoxetine (25 mg/kg/day p.o., 14 days) on expression of genes coding for proteins that involved in the synthesis and reuptake of 5-HT. Exposure of animals to plus-maze conditions on the first day of drug administration produced an increase in baseline anxiety on subsequent trial 2 weeks later. Fluoxetine strengthened the anxiogenic effects of maze experience. Two-week fluoxetine treatment also significantly reduced expression of tryptophan hydroxylase-2 (TPH2) and 5-HT transporter mRNAs as determined by RT-PCR in the brainstem. These changes were consistent with the decreased 5-HT levels and 5-HT turnover in the brain, and might contribute to the anxiogenic effects of the drug. The results also suggest that recently found association between treatment responses to fluoxetine and polymorphic variants of human TPH2 gene [Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP. Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004; 9:879-889] may be related to the drug effect on the TPH2 gene expression.
Subject(s)
Brain Stem/drug effects , Fluoxetine/administration & dosage , Gene Expression Regulation, Enzymologic/drug effects , Tryptophan Hydroxylase/genetics , Animals , Base Sequence , Behavior, Animal/drug effects , Brain Stem/enzymology , DNA Primers , Fluoxetine/pharmacology , Hydroxyindoleacetic Acid/metabolism , Male , RNA, Messenger/genetics , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Serotonin/metabolismABSTRACT
The effects of the serotonin reuptake inhibitor fluoxetine (FL) and its complexes with glycyrrhizic acid (GA) in molar ratios of 1:1 (FLG-1) and 4:1 (FLG-4) on the behavior of adult rats were studied in an elevated cross maze, with measurement of brain monoamine and monamine metabolite levels. Agents were given via the intragastric route using a cannula at a dose of 25 mg/kg 1 h before testing. FL increased anxiety in the rats and decreased their movement activity; FLG-1 and FLG-4 had no effect on behavior. None of the agents affected brain serotonin content, though all decreased the levels of its metabolite 5-hydroxyindoleacetic acid in the hypothalamus, FLG-4 also decreasing this in the cortex. Noradrenaline levels in the hypothalamus were increased after FLG-1 and FLG-4. In the striatum, FL increased the levels of dopamine and its metabolite dihydroxyphenylacetic acid but had no effect on the level of transmitter catabolism. Unlike FL, FLG-1 activated dopamine metabolism in the striatum. Overall, use of FL complexed with GA significantly modified its behavioral effects, which appears to be associated with the effects of FL and its complexes on the function of the monoaminergic systems involved in controlling behavior.
