Abstract
Nicotine addiction is a concern worldwide. Most mechanistic investigations are on nicotine substance dependence properties based on its pharmacological effects. However, no effective therapeutic treatment has been established. Nicotine addiction is reinforced by environments or habits. We demonstrate the neurobiological basis of the behavioural aspect of nicotine addiction. We utilized the conditioned place preference to establish nicotine-associated behavioural preferences (NABP) in rats. Brain-wide neuroimaging analysis revealed that the medial prefrontal cortex (mPFC) was activated and contributed to NABP. Chemogenetic manipulation of µ-opioid receptor positive (MOR(+)) neurons in the mPFC or the excitatory outflow to the nucleus accumbens shell (NAcShell) modulated the NABP. Electrophysiological recording confirmed that the MOR(+) neurons directly regulate the mPFC-NAcShell circuit via GABA(A) receptors. Thus, the MOR(+) neurons in the mPFC modulate the formation of behavioural aspects of nicotine addiction via direct excitatory innervation to the NAcShell, which may provide new insight for the development of effective therapeutic strategies.