Ionotropic Glutamate Receptor Function in Interpeduncular Nucleus Is Modulated by Nicotine Exposure

The medial habenula (MHb) and its main projection target, the interpeduncular nucleus (IPN), play an important role in mood/affect, anxiety, and the aversive experience associated with nicotine withdrawal. Given that MHb axons release glutamate onto IPN neurons, we investigated the expression and functional responses of ionotropic glutamate receptors (iGluRs) in neurons of the rostral IPN (IPR) in male rats. After confirming mRNA expression of Gria1 and Grin1 iGluR subunits in IPR, we employed glutamate uncaging coupled with two-photon imaging and patch-clamp electrophysiology. IPR dendrites, which often contained spine-like protrusions suggestive of synaptic contacts, featured a variety of response profiles following localized glutamate uncaging. Pharmacology experiments confirmed functional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate iGluR responses in IPR neuronal somata. Rats were trained to self-administer nicotine or saline during 10 fixed ratio 1 sessions and seven intermittent access sessions. In rats with a history of nicotine self-administration, perisomatic IPR iGluR responses are reduced. Acute nicotine application to slices from drug-naive rats recapitulated the effect of nicotine self-administration. These results identify a mechanism, whereby nicotine, even acute nicotine, may reduce IPR neuron sensitivity to glutamate from MHb axons, which could play a role in the aversive response to nicotine withdrawal.