Preferential Potentiation of the Effects of Serotonin Uptake Inhibitors by 5-HT1A Receptor Antagonists in the Dorsal Raphe Pathway: Role of Somatodendritic Autoreceptors

Authors

  • Luz Romero,

    1. Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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  • Francesc Artigas

    Corresponding author
    1. Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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Address correspondence and reprint requests to Dr. F. Artigas at Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona 18-26, E-08034 Barcelona, Spain.

Abstract

Abstract: 5-HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HText) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HText during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 µmol/L citalopram in the dorsal or median raphe nucleus reduced 5-HText in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HText induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.

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