Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state.

Abstract

Brain-derived neurotrophic factor (BDNF) has been implicated in the transition from a non-dependent motivational state to a drug-dependent and drug-withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine-non-dependent to a nicotine-dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non-dependent male mice find aversive is found rewarding in chronic nicotine-treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin-receptor-kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine-dependent and nicotine-withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.