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Tandem regulation of phosphoinositide signaling and acute behavioral effects induced by antidepressant agents in rats

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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 5HT2 receptors, implicated in depression or the actions of some antidepressants, signal through phosphoinositide hydrolysis. Thus, cross talk between antidepressant-induced CDP-diacylglycerol and 5HT2 signaling could contribute to the antidepressant mechanism.

Objective

The objective of the study was to test the hypotheses that antidepressants enhance net signaling via 5HT2 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 [3H]inositol in the presence of various antidepressant concentrations were washed and incubated with the 5HT2 agonist, α-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 α-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 5HT2 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.

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Acknowledgments

This work was supported by Grant no. DA017614 from the US National Institutes of Health.

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  1. Laboratory of Integrative Neuropharmacology, Programs in Neuroscience and Molecular Medicine, Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD, 21201-1075, USA

    Kimberly R. Tyeryar & Ashiwel S. Undie

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Tyeryar, K.R., Undie, A.S. Tandem regulation of phosphoinositide signaling and acute behavioral effects induced by antidepressant agents in rats. Psychopharmacology 193, 271–282 (2007). https://doi.org/10.1007/s00213-007-0784-1

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