Complex opioid-driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward, and addiction.

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical, and cellular components which, in concert, perform computations to drive emotion, reward, and addiction behaviors. Although housing one of the most prominent mu-opioid receptor (mOR) expression levels in the brain, remarkably little is known as to how they impact mHb/IPN circuit function at the granular level. In this study, our systematic functional and pharmacogenetic analyses in mice demonstrate that mOR activation attenuates glutamatergic signaling while producing an opposing potentiation of glutamatergic/cholinergic co-transmission mediated by mHb substance P and cholinergic neurons, respectively. Intriguingly, this latter non-canonical augmentation is developmentally regulated only emerging during later postnatal stages. In addition, we reveal that specific potassium channels act as a molecular brake on nicotinic receptor signaling in the IPN with the opioid-mediated potentiation of this arm of neurotransmission being operational only following attenuation of Kv1 function. Thus, mORs play a complex role in shaping the salience of distinct afferent inputs and transmitter modalities that ultimately influence synaptic recruitment of downstream GABAergic IPN neurons. Together, these observations provide a framework for future investigations aimed at identifying the neural underpinnings of maladaptive behaviors that can emerge when opioids, including potent synthetic analogs such as fentanyl, modulate or hijack this circuitry during the vulnerable stages of adolescence and in adulthood.