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

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.