Inhibition of iNOS reduced cerebral vasoconstriction from chronic cocaine and enhanced angiogenesis in the prefrontal cortex

Cocaine is a highly addictive drug associated with neurovascular complications, such as transient ischemic attacks (TIAs) and strokes. Neuroimaging studies have documented marked decreases in cerebral blood flow (CBF) in the brain of cocaine abusers. Recently we showed astrocytes’ involvement in cocaine-induced vasoconstriction and associated cortical ischemia in the mouse brain. We hypothesize that inducible nitric oxide synthase (iNOS) regulation plays an important role. To investigate this, we applied ultra-high resolution optical coherent tomography (µOCT) to capture 3D vascular images of the prefrontal cortex (PFC) in mice before and after chronic cocaine treatment. We compared vascular parameters including vessel diameter and microvascular density. Our results revealed that chronic cocaine exposure led to marked vasoconstriction in wild-type (WT) mice. In contrast, these effects were significantly attenuated in iNOS knockout (iNOS-KO) mice and in WT mice pretreated with the iNOS inhibitor L-NMMA (iNOS-Inh), thus indicating iNOS's involvement in the vascular changes triggered by cocaine. Furthermore, both iNOS-KO and iNOS-Inh mice exhibited increased microvascular density following cocaine exposure. This suggests a compensatory angiogenic response to mitigate for the vasoconstriction. Complementing structural imaging, we utilized a multimodal imaging platform (MIP) to assess hemodynamic responses during cocaine or saline administration. Consistent with our µOCT findings, WT mice displayed significant reductions in CBF and oxyhemoglobin levels following cocaine treatment. These hemodynamic impairments were notably diminished in iNOS-KO mice, supporting the role of iNOS in mediating cocaine-induced cerebrovascular dysfunction. Together, these findings suggest that iNOS contribute significantly to cocaine-induced vasoconstriction and cerebral hypoperfusion. Thus, the inhibition of iNOS could be a potential therapeutic strategy to reduce the risk of cerebral ischemia in individuals with cocaine use disorder.