Microglial activation increases cocaine self-administration following adolescent nicotine exposure by a D2 receptor mechanism
With the increasing use of e-cigarettes, teen nicotine exposure is becoming more widespread. This is a growing public health crisis, given findings from both clinical and preclinical studies that show adolescent brain to be uniquely sensitive to nicotine. Animal studies have shown that adolescent nicotine exposure results in increased sensitivity to cocaine and other drugs, although the mechanisms that underlie this are poorly understood. We now show microglia to be critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has age-dependent effects on microglial morphology and immune transcript profiles. Moreover, blocking D2 receptors eliminates both nicotine-induced increases in cocaine self-administration and microglial activation. Finally, we show nicotine causes microglial-dependent synaptic pruning and plasticity. Taken together, we demonstrate that adolescent microglia are uniquely sensitive to perturbations by drugs of abuse, crucial for nicotine-induced increases in cocaine-seeking, and D2 receptors play a mechanistic role in these phenomena.