Kimberly R Tyeryar1, Ashiwel S Undie. 1. Laboratory of Integrative Neuropharmacology, Programs in Neuroscience and Molecular Medicine, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201-1075, USA.
Abstract
RATIONALE: Antidepressants increase synaptic monoamine concentrations, but the subsequent signaling events that produce the beneficial clinical effects remain unclear. Diverse antidepressants increase CDP-diacylglycerol, a crucial step in phosphoinositide signaling. Serotonin 5HT(2) receptors, implicated in depression or the actions of some antidepressants, signal through phosphoinositide hydrolysis. Thus, cross talk between antidepressant-induced CDP-diacylglycerol and 5HT(2) signaling could contribute to the antidepressant mechanism. OBJECTIVE: The objective of the study was to test the hypotheses that antidepressants enhance net signaling via 5HT(2) receptors by augmenting the supply of phosphoinositide substrates and that this action contributes to the behavioral effects of the drugs. MATERIALS AND METHODS: Brain slices pre-labeled with [(3)H]inositol in the presence of various antidepressant concentrations were washed and incubated with the 5HT(2) agonist, alpha-methylserotonin, followed by measuring phosphoinositide synthesis and inositol phosphate accumulation. Further, rats administered antidepressants after pretreatment with neomycin to inhibit metabolic utilization of phosphoinositides were behaviorally evaluated in the forced swim test. RESULTS: Diverse antidepressants significantly enhanced phosphoinositide synthesis. While alpha-methylserotonin increased inositol phosphate accumulation, this effect was significantly accentuated in hippocampal or cortical tissues pre-incubated in the presence of imipramine, desipramine, fluoxetine, paroxetine, or maprotiline. Drug-induced behavioral antidepressant effects were reversed by neomycin pretreatment, whereas neomycin alone did not alter basal immobility times. CONCLUSIONS: Antidepressants probably exert tandem neurochemical effects by increasing synaptic monoamine concentrations and by producing phosphoinositides used in 5HT(2) receptor signaling. This combination of actions may constitute the mechanism of at least the acute behavioral effects of the drugs and could implicate aberrant neurolipid signaling in the pathophysiology of depression.
RATIONALE: Antidepressants increase synaptic monoamine concentrations, but the subsequent signaling events that produce the beneficial clinical effects remain unclear. Diverse antidepressants increase CDP-diacylglycerol, a crucial step in phosphoinositide signaling. Serotonin 5HT(2) receptors, implicated in depression or the actions of some antidepressants, signal through phosphoinositide hydrolysis. Thus, cross talk between antidepressant-induced CDP-diacylglycerol and 5HT(2) signaling could contribute to the antidepressant mechanism. OBJECTIVE: The objective of the study was to test the hypotheses that antidepressants enhance net signaling via 5HT(2) receptors by augmenting the supply of phosphoinositide substrates and that this action contributes to the behavioral effects of the drugs. MATERIALS AND METHODS: Brain slices pre-labeled with [(3)H]inositol in the presence of various antidepressant concentrations were washed and incubated with the 5HT(2) agonist, alpha-methylserotonin, followed by measuring phosphoinositide synthesis and inositol phosphate accumulation. Further, rats administered antidepressants after pretreatment with neomycin to inhibit metabolic utilization of phosphoinositides were behaviorally evaluated in the forced swim test. RESULTS: Diverse antidepressants significantly enhanced phosphoinositide synthesis. While alpha-methylserotonin increased inositol phosphate accumulation, this effect was significantly accentuated in hippocampal or cortical tissues pre-incubated in the presence of imipramine, desipramine, fluoxetine, paroxetine, or maprotiline. Drug-induced behavioral antidepressant effects were reversed by neomycin pretreatment, whereas neomycin alone did not alter basal immobility times. CONCLUSIONS: Antidepressants probably exert tandem neurochemical effects by increasing synaptic monoamine concentrations and by producing phosphoinositides used in 5HT(2) receptor signaling. This combination of actions may constitute the mechanism of at least the acute behavioral effects of the drugs and could implicate aberrant neurolipid signaling in the pathophysiology of depression.