VTA µ-opioidergic neurons facilitate low sociability in protracted opioid abstinence

Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted abstinence is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTA MOR neurons in mediating protracted abstinence-induced negative affect is not fully understood. In our study, we elucidate the role of VTA MOR neurons in mediating negative affect and altered brain-wide neuronal activities following forced opioid exposure and abstinence in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted forced abstinence. VTA MOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted abstinence is facilitated by this neural population, without affecting other protracted abstinence behaviors. Lastly, VTA MORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTA MOR neurons as critical modulators of low sociability during protracted abstinence and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid abstinence. Significance statement The compelling urge for relief from negative affective states during long-term opioid abstinence presents a crucial challenge for maintaining abstinence. The ventral tegmental area (VTA) and its mu-opioid receptor-expressing (VTA MOR ) neurons represent a critical target of opioidergic action that underlie dependence and abstinence. Chronic activation of VTA MOR neurons during opioid exposure induces maladaptations within these neurons and their structurally connected circuitries, which alter reward processing and contribute to negative affect. Using an oral morphine drinking paradigm to induce dependence, we demonstrate that withdrawal engages VTA MOR neurons and identify this neuronal population as key mediators of opioid abstinence-induced social deficits. These findings hold promise to inform development of targeted therapies aimed at alleviating negative affective states associated with protracted opioid abstinence.