Inhibitory Circuit From Rostral Ventral Tegmental To Dorsal Raphe Nucleus Affects Morphine-induced Reward Memory

Dorsal raphe nucleus and the ventral tegmental area are small nuclei that exert an important influence on brain function through widespread release of serotonin and dopamine.Numerous studies have shown that serotonin and dopamine neurons are required for motivated behavior and are involved in many common neuropsychiatric disorders including depression and drug addiction.Both areas also contain GABAergic neurons which are involved in regulating behavior through local inhibition and their own projections,respectively.The potential diversity of these neurons has not been fully studied.The dorsal raphe and ventral tegmental area have been known to be tightly interconnected,but the characteristics and functions of the circuits between the dorsal raphe and ventral tegmental area remain unclear.Opioid receptors are broadly expressed through the central nervous system,especially in inhibitory neurons and their nerve terminals,and μ-opioid receptors on ventral tegmental area GABAergic neurons are thought to be critically involved in opioid reward.How μ-opioid receptor modulate the ventral tegmental area neurons activities at the circuit level is still unkown.In this study,by combining rabies virus tracing,immunohistochemistry,chemogenetic manipulation,optogenetics manipulation and behavioral tests,we showed that1.Dorsal raphe serotoninergic and GABAergic neurons received dense differential projections from caudal and rostral ventral tegmental area neurons,respectively.2.Ventral tegmental area sent strong GABAergic projections to bothserotoninergic and GABAergic neurons in the dorsal raphe.3.μ-opioid receptors were located on rostral ventral tegmental area GABAergicterminals,but not caudal ventral tegmental area GABAergic terminals,andinhibited rostral ventral tegmental area GABAergic transmission in the dorsalraphe.4.The projections from rostral ventral tegmental area to dorsal raphe specificallycontributes to morphine reward without affecting the analgesic effects ofmorphine.Overall,we investigated the precise connections between the ventral tegmental area to dorsal raphe.Our studies provide a new framework for understangding the circuitry that regulates reward behavior.We found that the rostral ventral tegmental area to dorsal raphe circuit is involved in behaviors and reward memory induced by repeated morphine administration suggesting that this circuit may be a new targeting candidate for treatment of opioid addiction.