Figure 2. A novel role for TH⁺/VGLUT2⁺ neurons in drug reinforcement.

Drugs of abuse including cocaine, opioids and alcohol preferentially increase vesicular DA loading and release in a distinct subpopulation of DA neurons that co-transmit both DA and glutamate and express both TH and VGLUT2 (TH⁺/VGLUT2⁺). The cell bodies of these DA/glutamate co-transmitting neurons predominantly localize to the medial VTA and project to the medial nucleus accumbens shell (mNAcSh). In response to drug-induced increases in cell firing, these medial VTA TH⁺/VGLUT2⁺ DA neurons that project to the mNAcSh have functional features unique from other midbrain DA neurons including the DA-only neurons that project to the nucleus accumbens (NAc) core, including: distinct modulatory afferent inputs and high-frequency firing (>20 Hz). Moreover, DA/glutamate co-transmission by this distinct TH⁺/VGLUT2⁺ subpopulation of DA neurons may be a critical mechanism for regulating reward-related behaviors and associated with vulnerability to substance use disorders.