Adolescent Chronic Sleep Restriction Induces a Mesolimbic Hypodopaminergic State Associated with Addiction Vulnerability.
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Adolescent sleep insufficiency is increasingly prevalent, but whether repeated insufficient sleep during this developmental period promotes addiction vulnerability remains unclear. Here, we investigated the effects of chronic sleep restriction (CSR) imposed during adolescence, from 4 to 7 weeks of age, on the mesocorticolimbic dopamine (DA) system and addiction-related behaviors in mice. Behavioral and neuronal responses in the mesolimbic pathway to the psychostimulant Amphetamine (Amph) were examined. Also, DA-related molecular and structural components, including DA receptors, DA turnover, and developmental regulators such as Netrin-1/deleted in colorectal cancer (DCC), were assessed. Our results identified that adolescent CSR induces a hypodopaminergic profile characterized by reduced neuronal activity in the core regions of the mesolimbic DA circuit at baseline and upon acute Amph stimulation, downregulated striatal DA receptors, and reduced DA axon innervation in the ventral striatum. Altered Netrin-1/DCC signaling and mesocortical DA synthesis further suggest that sleep loss during adolescence disrupts ongoing maturation of DA circuitry. Furthermore, these neurobiological profiles were accompanied by enhanced Amph-induced conditioned place preference (CPP). Together, these findings indicate that chronic adolescent sleep insufficiency induces a constellation of behavioral and neurobiological adaptations relevant to addiction susceptibility. In contrast to prior acute sleep-loss paradigms that mainly capture transient DA activation, our data support a model in which repeated sleep restriction imposes cumulative allostatic load and promotes longer-term maladaptive remodeling of reward circuitry. These results identify insufficient sleep during adolescence as a potential risk factor for addiction vulnerability.