The role of parvalbumin interneurons and the matricellular protein Hevin in cocaine-induced locomotor context-specific sensitization in rats

Abstract

Drug addiction is a chronic relapsing disease marked by long-lasting alterations in the brain's reward pathway. One of the main problems for treating addiction is the high rate of relapse. Environmental stimuli previously associated with drug use can cause drug relapse even after prolonged periods of abstinence. Studies revealed that cocaine craving induced by contextual cues increases over the first weeks of abstinence and remains raised for considerable periods, intensifying susceptibility to relapse. This phenomenon is called "incubation of drug craving". Association between contextual cues and drug use is a high-resolution process, and several studies support the idea that those cues are encoded by specific, strongly-connected and sparsely-distributed neurons called neuronal ensembles. Numerous studies have demonstrated correlation between nucleus accumbens neural ensembles and drug-seeking and -taking evoked by contextual cues. Nucleus accumbens (NAc) is ~ 90% composed of GABAergic medium-sized spiny neurons (MSNs), a neuronal type in charge of converting diverse stimuli into executive behavior. The activity of MSNs is regulated, among others, by GABAergic interneurons. Among these, NAc Parvalbumin positive GABAergic interneurons (PV) strongly inhibit the MSNs. PV neurons have been implicated in several psychiatric disorders, such as addiction. However, there is a lack of information about its functional role in controlling drug-seeking behavior. Furthermore, sinaptic plasticty in PV neurons have been linked to some drug related-behaviors. Hevin (high endothelial venule protein), a secreted matricelullar protein has been widely implicated in formation and mintance of mammalian neural circuits. Also, studies suggest that hevin is involved in the neuroplasticity underlying positive affect and motivation. Hevin is mainly secreted by astrocites, but recent investigations demonstrated its secretion by GABAergic interneurons, including PV. Based on these considerations, we propose to combine rodent behavior, molecular biology, viral-mediated gene transfer and calcium phtometry to unravel the role of Hevin and PV interneurons on cocaine-induced locomotor context-specific sensitization. (AU)