Protein kinases in natural versus drug reward

Natural and drug rewards act on the same neural pathway, the mesolimbic dopaminergic system. In brain regions such as the nucleus accumbens and ventral tegmental area, drugs of abuse-induced stimulation of signaling pathways can lead to synaptic reshaping within this system. This is believed to be underlying the maladaptive alterations in behaviors associated with addiction. In this review, we discuss animal studies disclosing the implication of several protein kinases, namely protein kinase A (PKA), extracellular signal regulated kinase (ERK) mitogen-activated protein kinases (MAPK), p38 MAPK, and calcium/calmodulin-dependent kinase II (CaMKII), in reward-related brain regions in drug and natural reward. Furthermore, we refer to studies that helped pave the way toward a better understanding of the neurobiology underlying non-drug and drug reward through genetic deletion or brain region-specific pharmacological inhibition of these kinases. Whereas the role of kinases in drug reward has been extensively studied, their implication in natural reward, such as positive social interaction, is less investigated. Discovering molecular candidates, recruited specifically by drug versus natural rewards, can promote the identification of novel targets for the pharmacological treatment of addiction with less off-target effects and being effective when used combined with behavioral-based therapies.