Dentate gyrus μ-opioid receptor-mediated neurogenic processes are associated with alterations in morphine self-administration

Adult hippocampal dentate gyrus (DG) neural stem cells (NSCs) continuously undergo proliferation and differentiation, producing new functional neurons that remodel existing synaptic circuits. Although proliferation of these adult DG NSCs has been implicated in opiate dependence, whether NSC neuronal differentiation and subsequent dendritogenesis are also involved in such addictive behavior remains unknown. Here, we ask whether opiate exposure alters differentiation and dendritogenesis of DG NSCs and investigate the possibility that these alterations contribute to opiate addiction. We show that rat morphine self-administration (MSA), a paradigm that effectively mimics human opiate addiction, increases NSC neuronal differentiation and promotes neuronal dendrite growth in the adult DG. Further, we demonstrate that the μ-opioid receptor (MOR) is expressed on DG NSCs and that MSA leads to a two-fold elevation of endogenous MOR levels in doublecortin expressing (DCX⁺) NSC progenies in the rat DG. MOR expression is also detected in the cultured rat NSCs and morphine treatment in vitro increases NSC neuronal differentiation and dendritogenesis, suggesting that MOR mediates the effect of morphine on NSC neuronal differentiation and maturation. Finally, we show that conditional overexpression of MOR in DG NSCs under a doxycycline inducible system leads to facilitation of the acquisition of MSA in rats, without affecting the extinction process. We advocate that targeting MOR selectively in the DG NSC population might offer a novel therapeutic intervention for morphine addiction.