Nicotine tunes dopaminergic and non-dopaminergic connectivity in ventral tegmental area local circuits

The ventral tegmental area (VTA) is a heterogeneous midbrain nucleus and the main source of dopamine in the mesocorticolimbic pathways. These circuits are involved in reward prediction, aversion, learning, salience, novelty, and valence determination. In normal brain function, cholinergic excitation of VTA dopamine and non-dopamine neurons enhances presynaptic dopamine release in projection targets and modulates local inhibitory circuits within the VTA that, in turn, shape dopamine output. The current study elucidates a potential continuum of events driven by systemic nicotine in VTA local circuits toward attaining net dopamine (DA) excitation. After subcutaneous nicotine administration, we analyzed the response time and connectivity profiles of VTA DA and non-DA cells in anesthetized mice. Our results showed phasic co-activation patterns of both DA and non-DA putative units activated in two perievent firing rate peaks that span minutes. DA cells had a rapid onset, and longer peak periods compared with non-DA cells during the first peak response. The activation time was comparable for both DA and non-DA cells during the second perievent peak. Although more non-DA cells were responsive during the second response phase, the crosscorrelogram of putative pairs indicates a subtle decrease in inhibitory tone and increased excitatory tone for DA to non-DA connections. The results showed that the two mechanisms for nicotinic reinforcement of DA activity likely occur in a time-dependent sequence of events from co-activation of DA and non-DA units until attenuation of non-DA inhibitory tone. In addition, transsynaptic connectivity was enhanced among DA-DA pairs following nicotine administration.