This review focuses on transmitter-receptor mismatches in the brain, which is one of the hallmarks of the Volume Transmission (VT) concept, and how this phenomenon may be related to local temperature gradients created by brain uncoupling protein 2 (UCP2), which uncouples oxidative phosphorylation from ATP synthesis, hereby generating heat. Recent studies on transmitter-receptor mismatches have revealed dopamine and opioid peptide receptor mismatches in the intercalated islands of the amygdala, which are GABAergic cell clusters regulating amygdaloid output. Such mismatches have also been found in regions belonging to the extended amygdala and the nucleus accumbens shell. Now substantial UCP2 immunoreactivity has been found within the above transmitter-receptor mismatch regions, suggesting that UCP2 may enhance diffusion and convection of DA and opioid peptides in such regions by generation of local temperature gradients, thereby contributing to a dynamic regulation of VT.