Insulin and fluoxetine produce opposite actions on lateral septal nucleus-infralimbic region connection responsivity

Some diabetes patients develop depression, the main treatment for which is antidepressants. Pharmacological interactions between insulin and antidepressants (e.g., fluoxetine) are controversial in the literature. Some authors reported hypoglycemic actions of fluoxetine, whereas others reported antidepressant-like actions. In healthy rats, insulin produces an antidespair-like action in rats through an increase in locomotor and exploratory activity, but differences in actions of insulin and fluoxetine on neuronal activity are unknown. The present study evaluated Wistar healthy rats that were treated with saline, insulin, fluoxetine, or fluoxetine + insulin for 3 days (short-term) or 21 days (long-term). The model consisted of electrical stimulation of the lateral septal nucleus (LSN) while we performed single-unit extracellular response recordings in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Stimulation of the LSN produced an initial brief excitatory paucisynaptic response and then a long-lasting inhibitory afterdischarge in the PL and IL. Treatment with saline and fluoxetine, but not insulin, minimally affected the paucisynaptic response. Differences were found in LSN-IL responsivity. The inhibitory afterdischarge was clearly enhanced in the long-term fluoxetine group but not by insulin alone or fluoxetine + insulin. These findings suggest that insulin produces some actions that are opposite to fluoxetine on LSN-mPFC connection responsivity, with no synergistic actions between the actions of insulin and fluoxetine.