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Increased hippocampal nitric oxide synthase activity and stress responsiveness after imipramine discontinuation: Role of 5HT 2A/C -receptors

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Abstract

Chronic depressive illness may cause shrinkage of the hippocampus with stress-induced release of glutamate and nitric oxide possibly causally linked to this pathology. Poor antidepressant compliance may contribute to this pathology as well as to long term morbidity. However, antidepressant withdrawal-associated symptoms in depressed patients often reflect hyperserotonergia. The effect of chronic imipramine (IMI; 15 mg/kg/d ip × 3wks) treatment and withdrawal on swim stress responsiveness was studied in Sprague-Dawley rats together with assay of hippocampal NO synthase (NOS) activity. The dependence of any biobehavioral changes following IMI withdrawal on 5HT2A/C receptor-mediated events was studied using the 5HT2A/C receptor antagonist, ritanserin (RIT; 4 mg/kg/day ip × 7 days), administered alone or during IMI withdrawal. IMI significantly inhibited the situational stress response to forced swimming while also significantly decreasing NOS activity. IMI withdrawal was associated with a significant increase in swim immobility together with a significant increase in NOS activity compared to both control and IMI-treated groups. RIT re-established the anti-immobility effects and reversed NOS hyper-function during IMI withdrawal, although alone it increased NOS activity. Antidepressant discontinuation therefore increases stress responsiveness together with disinhibition of hippocampal NOS through a mechanism involving 5HT2A/C receptor activation. The resulting increased nitrergic activity may have significant implications for depressive illness and its treatment.

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Acknowledgments

The South African Medical Research Council and the National Research Foundation (Grant 2053203) for funding. Cor Bester, Antoinette Fick and Dr Douw van der Nest for assistance in the behavioural experiments and the welfare of the animals.

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Authors and Affiliations

  1. School of Pharmacy (Pharmacology), Faculty of Health Sciences, North-West University, Potchefstroom, South Africa

    Brian H. Harvey, Renché Retief & Ané Korff

  2. Center for Basic Psychiatric Research, University of Aarhus, Aarhus, Denmark

    Gregers Wegener

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  1. Brian H. Harvey
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  2. Renché Retief
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  3. Ané Korff
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  4. Gregers Wegener
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Correspondence to Brian H. Harvey.

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Harvey, B.H., Retief, R., Korff, A. et al. Increased hippocampal nitric oxide synthase activity and stress responsiveness after imipramine discontinuation: Role of 5HT 2A/C -receptors. Metab Brain Dis 21, 201–210 (2006). https://doi.org/10.1007/s11011-006-9018-1

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  • DOI: https://doi.org/10.1007/s11011-006-9018-1

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