The atypical antidepressants mianserin and mirtazapine induce ERK1/2 signaling and antiapoptotic effects through activation of the lysophosphatidic acid LPA1 receptor in mouse hippocampal HT22 cells

A large body of evidence indicate that the bioactive phospholipid lysophosphatidic acid (LPA) affects neurogenesis, synaptic plasticity and anxietyrelated behaviour by activating specific Gprotein coupled receptors, termed LPA16, which are expressed in the developing and adult brain. However, relatively little is known on whether the LPA receptor system can be targeted by drugs used to treat neuropsychiatric diseases. We have previously reported that different antidepressants promote growth factor receptor transactivation and cell proliferation in CHOk1 fibroblasts and glia cells. In the present study, we show that in immortalized mouse hippocampal HT22 cells the atypical antidepressants mianserin and mirtazapine trigger ERK1/2 phosphorylation and protect against apoptosis through LPA1 receptors. ERK1/ 2 phosphorylation induced by acute exposure to either mianserin, mirtazapine or LPA was inhibited by cell pretreatment with pertussis toxin, indicating the involvement of G proteins of the Gi/o family. LPA, mianserin and mirtazapine also promoted the phosphorylation of the transcription factor CREB, a downstream effector of ERK1/2 signaling. Cell treatment with either AM966, a selective LPA1 receptor antagonist, or Ki16425, which preferentially blocks LPA1 and LPA3, significantly inhibited ERK1/2 and CREB phosphorylation elicited by mianserin and mirtazapine. Serum withdrawalinduced apoptosis of HT22 cells was markedly attenuated by either LPA, mianserin or mirtazapine, as indicated by the decreased cell death, decreased percentage of annexin Vpositive cells, inhibition of procaspase activation and poly( ADP ribose) polymerase cleavage. AM966 reduced the protective effects of mianserin, mirtazapine and LPA against HT22 cell apoptosis. Moreover, cell treatment with the MEK inhibitor PD98059 prevented the antiapoptotic effect of LPA and mianserin. These data provide further evidence for the involvement of the LPA1 receptor in the pharmacological action of antidepressants.