Abstract
Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.
Highlights
Drug abuse causes serious health and social problems.The United Nations World Drug Report estimates that a quarter of a billion world population uses at least one illegal drug in a year[1]
Heroin activates both dopamine neurons and serotonin neurons We combined an intravenous infusion system with fiber photometry to monitor real-time changes in neuronal activity from freely behaving mice challenged with drugs of abuse (Fig. 1a)
We targeted GCaMP6m to VTA dopamine neurons and dorsal raphe nucleus (DRN) serotonin neurons by stereotaxically injecting Cre-dependent AAVs into the VTA of dopamine transporter (DAT)-Cre mice (DAT-VTA-GCaMP6 mice for simplicity) or into the DRN of Sert-Cre (SERT-DRNGCaMP6) mice (Supplementary Fig. S1a)
Summary
Drug abuse causes serious health and social problems. The United Nations World Drug Report estimates that a quarter of a billion world population uses at least one illegal drug in a year[1]. Opiates and cocaine represent two of the most addictive and devastating drugs of abuse[2]. MDMA is a popular recreational drug that often causes hallucination, cognitive defects, and post-drug depression[3]. Intensive research has revealed many insights into the neurobiological mechanisms underlying the effects of the role of the serotonin pathway in drug addiction is often ignored, the dysfunction of serotonin signaling pathways is implicated in increased vulnerability to cocaine abuse[11,12,13] and potentiated seeking for opiate[14]
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