Preferential Potentiation of the Effects of Serotonin Uptake Inhibitors by 5‐HT 1A Receptor Antagonists in the Dorsal Raphe Pathway: Role of Somatodendritic Autoreceptors

5‐HT 1A 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‐HT ext ) induced by the 5‐HT uptake inhibitor paroxetine in forebrain were potentiated by the 5‐HT 1A 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‐HT ext 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‐HT ext in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5‐HT ext 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‐HT 1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5‐HT 1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.