Sidak’s multiple comparisons test shows significant differences in locomotion between the different concentrations. Locomotor activity increased with the concentration of vaporized fentanyl. ( B) Locomotor activity in meters was measured at baseline and after passive exposure to different concentrations of vaporized fentanyl (five vapor deliveries over 10 min) versus vehicle vapor (0 mg/ml). “NV” indicates mice that were not exposed to fentanyl or vehicle vapor. Sidak’s multiple comparisons test shows that the 1, 3, 10, and 30 mg/ml groups were significantly different from vehicle. ( A) Passive administration of vaporized fentanyl (four vapor deliveries over 8 min) increased the latency to nociception in the hot-plate test in a concentration-dependent manner. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.

Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABA B receptor–dependent currents during protracted abstinence from fentanyl vapor self-administration. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. However, its use in mice is limited by frequent complications of intravenous catheterization. Intravenous drug self-administration is considered the “gold standard” model to investigate the neurobiology of drug addiction in rodents.

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