MODULATION OF CEREBELLAR ACTIVITY AND PLASTICITY IN COCAINE SELF-ADMINISTRATION AND DRUG-SEEKING BEHAVIOR

In alignment with two results of our laboratory (1) the modulation of the activity of the cerebellar posterior vermis (lobule VIII, LVIII) can modulate the preference toward the stimuli associated with cocaine, (2) neuroplasticity markers of synaptic stabilization (Perineuronal Nets, PNNs) are up regulated in this region after a long period of abstinence in a voluntary cocaine consumption model; the present research aimed to investigate the role of LVIII in a cocaine self-administration model using chemogenetic tools (designer receptors exclusively activated by designer drugs, DREADDs), and to assess its associated plasticity markers. Male Sprague–Dawley rats underwent catheterization followed by stereotaxic surgery to express the inhibitory DREADD AAV5-hSyn-hM4D(Gi)-mCherry in LVIII, which was activated by intraperitoneal CNO administration during the final five days of cocaine self-administration. Twenty-four hours after the last cocaine administration, rats underwent a drug seeking test under extinction. The results demonstrated that AAV5-hSynhM4D(Gi)-mCherry selectively inhibited inhibitory interneurons of the granular and molecular layer of LVIII resulting in a dramatic reduction of cocaine intake and decreased drug-seeking behavior. This data suggests that this inhibition increases the inhibitory tone of Purkinje cells over the deep cerebellar nuclei, the main output of the cerebellum to the rest of the reward circuit. By manipulating the activity of this region, PNN expressions associated with cocaine consumption were modulated in order to reduce vulnerability to relapse. Therefore, these results demonstrate that the cerebellum is a key component in drug-seeking behavior, positioning it as a promising therapeutic target for more effective treatments.
R&D&I-projectPID2021-128852NB-I00"ERDFA-way-to-do-Europe”from:MCIN/AEI/GACAHPEPC https://doi.org/10.13039/501100011033/