Glutamatergic neurons in ventral pallidum modulate heroin addiction via epithalamic innervation in rats

Glutamatergic neurons in ventral pallidum (VP^Glu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VP^Glu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VP^Glu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VP^Glu. Chemogenetic manipulation of VP^Glu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VP^Glu, and its neuronal activity was consistent with VP^Glu in different phases of heroin addiction and contributed to the motivation for heroin. VP^Glu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VP^Glu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VP^Glu was involved in the regulation of heroin addiction and identified the VP^Glu-LHb pathway as a potential intervention to reduce heroin seeking motivation.