Figure 1:

Schematic diagram of the mesolimbic and nigrostriatal reward pathways, illustrating the action sites (targets) of psychostimulants (cocaine, methamphetamine) and opioids in the brain. The mesolimbic DA circuit (RMTg → VTA → NAc) originates in the midbrain ventral tegmental area (VTA) and projects predominantly to the nucleus accumbens (NAc) and other forebrain regions (not shown). VTA DA neurons receive GABAergic inputs from local VTA GABA neurons and other brain regions including the NAc, ventral pallidum (VP), and rostromedial tegmental nucleus (RMTg), particularly from the RMTg. Psychostimulants elevate extracellular NAc DA by blocking DA transporters (DAT) (by cocaine) and/or reversing VMAT2 (by methamphetamine) on DA axon terminals in the NAc and dorsal striatum (DST). Both pathways receive GABA inputs from the RMTg. The nigrostriatal DA circuit (SNr → SNc → DST) originates from DA neurons in the substantia nigra pars compacta (SNc) and projects to the DST. SNc DA neurons receive dense GABAergic inputs from multiple brain regions including the SNr and RMTg, but mainly from SNr. Mu opioid receptors (MOR) are highly expressed in GABA neurons, particularly in the RMTg and SNr. Opioids bind to MORs and inhibit GABA neuron activity and GABA release, which subsequently disinhibits DA neurons in the VTA and SNc.