Hormones and Neuropeptide Receptor Heteromers in the Ventral Tegmental Area. Targets for the Treatment of Loss of Control of Food Intake and Substance Use Disorders.

Hormones and neuropeptides represent biological correlates of internal homeostatic signals detected and integrated in the hypothalamus, which establishes a robust functional connection with the ventral tegmental area (VTA). The hypothalamus-VTA connection determines the ability of these signals to influence central dopaminergic neurotransmission and, therefore, their ability to increase responsiveness to their reward-associated stimuli and to establish appropriate associative learning. The hypothalamus also provides the main source of the multiple neuropeptides that are released in the VTA. With volume transmission of neuropeptides and hormones, extrasynaptic receptors within the VTA provide a fine-tune mechanism, which depends on the ability of molecularly different G protein-coupled receptors (GPCRs) to form heteromers. GPCR heteromer is defined as a macromolecular complex composed of at least two different receptor units (protomers) with biochemical properties that are demonstrably different from those of its individual components. GPCR heteromers can provide unique allosteric properties to specific ligands, which provides new avenues for drug development. We have identified specific GPCR heteromers in the VTA that integrate orexin and CRF neurotransmission and opioid and galanin neurotransmission, which play a very significant role in the modulation of dopaminergic neuronal activity and which can constitute targets for the treatment of loss of control of food intake and substance use disorders.