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.

Rewarding Social Interaction in Rats Increases CaMKII in the Nucleus Accumbens.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is known to be involved in the sensitized locomotor responses and drug-seeking behavior to psychostimulants. However, little is known about the contribution of CaMKII signaling in the nucleus accumbens (NAc) in natural rewards such as social interaction. The present experiments explored the implication of CaMKII signaling in drug versus natural reward. In the NAc of rats expressing cocaine or social interaction conditioned place preference (CPP), αCaMKII activation was induced in those expressing social interaction but not cocaine CPP. In order to investigate the role of NAc CaMKII in the expression of reward-related learning of drug versus non-drug stimuli, we inhibited CaMKII through an infusion of KN-93, a CaMKII inhibitor, directly into the NAc shell or core, before the CPP test in a concurrent paradigm in which social interaction was made available in the compartment alternative to the one associated with cocaine during conditioning. Whereas vehicle infusions led to equal preference to both stimuli, inhibition of CaMKII by a KN-93 infusion before the CPP test in the shell but not the core of the NAc shifted the rats' preference toward the cocaine-associated compartment. Altogether, these results suggest that social interaction reward engages CaMKII in the NAc.