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Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

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Abstract

Rationale

Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is upregulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI), reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression.

Objectives

We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BDNF by testing for region-specific changes in areas CA1, CA3, and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP.

Methods

Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and Western blotting.

Results

LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected.

Conclusions

LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium influx.

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Acknowledgments

This work was supported by NIH grants P20RR016477 and P20GM103434 to the West Virginia INBRE. All animal procedures were approved by the Marshall University Institutional Animal Care and Use Committee and comply with the US Public Health Service policy on humane care and use of laboratory animals.

Conflict of interest

None of the authors declare a conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Robert C. Byrd Biotechnology Science Center, One John Marshall Drive, Huntington, WV, 25755, USA

    Jennifer D. Cooke, Hannah M. Cavender, Hope K. Lima & Lawrence M. Grover

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  1. Jennifer D. Cooke
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  2. Hannah M. Cavender
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  3. Hope K. Lima
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  4. Lawrence M. Grover
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Correspondence to Lawrence M. Grover.

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Cooke, J.D., Cavender, H.M., Lima, H.K. et al. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus. Psychopharmacology 231, 4429–4441 (2014). https://doi.org/10.1007/s00213-014-3587-1

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