A prelimbic cortex-lateral hypothalamus circuit regulates acquisition of alprazolam-induced conditioned place preference in male mice.

Alprazolam (Alp), a high-potency benzodiazepine, poses a significant risk of abuse and addiction, yet the precise mechanisms underlying Alp-associated reward memory remain poorly defined. Here, we first established that administration of Alp at 10 mg/kg reliably induces conditioned place preference (CPP) in male mice. Our results indicated that prelimbic cortex (PrL) CaMKⅡα neurons were hyperactive in Alp-trained mice. Chemogenetic manipulation of the activity of PrL CaMKⅡα neurons bidirectionally regulated acquisition of Alp-induced CPP. Furthermore, virus tracing indicated a strong PrL CaMKⅡα neuron projection to lateral hypothalamus (LH). Suppression of the PrL-LH circuit significantly decreased acquisition of Alp-induced CPP, while potentiation of this circuit facilitated Alp-induced CPP. Activation of PrLCaMKⅡα-LH circuit failed to produce real-time place preference. In summary, our results indicate that PrL glutamatergic neurons and the PrL-LH circuit regulate Alp-induced reward memory formation, providing a foundation for elucidating the neural mechanisms underlying Alp addiction.