PDE4 inhibitor rolipram dynamically regulates the balance between D1-MSNs and D2-MSNs in the DMS to modulate abnormal “Go” behavior associated with alcohol addiction

Addiction is a chronic relapsing disorder characterized by compulsive seeking and consumption of drugs, with this abnormal “Go” behavior resulting in significant negative consequences. Research has shown that the dorsal medial striatum (DMS) is associated with the pathophysiological mechanisms of addiction; however, drugs targeting the DMS to achieve therapeutic effects for addiction remain unavailable. Intracellular cAMP signaling, regulated by G protein–coupled receptors (GPCRs), critically modulates the excitability, plasticity and neurotransmission of GABAergic medium spiny neurons (MSNs). In this study we investigated how inhibition of PDE4 modulated cAMP levels with a specific focus on how these changes influenced the dopamine D1 receptor MSNs (D1-MSNs) and D2 receptor MSNs (D2-MSNs) in the DMS, thereby influencing abnormal “Go” behavior. We established alcohol-induced conditioned place preference (CPP) model and two-bottle choice drinking model in mice. PDE4 inhibitor rolipram (0.5 μg) were bilaterally microinjected into the DMS of mice 2 h prior to the combination of alcohol. The activation of D1-MSNs and D2-MSNs in the DMS was assayed using c-Fos immunofluorescence staining. We showed that rolipram microinjection significantly increased cAMP levels in MSNs of the DMS and restored the activation balance between D1-MSNs and D2-MSNs. This rebalancing of MSN activity attenuated abnormal “Go” behaviors including high-drinking behavior. We further identified the ERK signaling downstream of cAMP in D2-MSNs of the DMS, together with the PDE4 subtype PDE4B, as key mediators of the inhibitory effects of PDE4 inhibitors on high-drinking behavior. These results highlight a new strategy emphasizing the pivotal role of PDE4 as a key regulator of cAMP signaling in MSNs, maintaining the dynamic balance between D1-MSNs and D2-MSNs, and further identify D2-MSNs specific PDE4B/cAMP/ERK modulation as a promising target for addiction treatment.