Karl Y. Bosque-Cordero ¹ , Rafael Vazquez-Torres¹ , Cristhian Calo-Guadalupe ¹,

Daisy Consuegra-Garcia ² , Giulia R. Fois ³,⁴ , François Georges³,⁴, and Carlos A. Jimenez-Rivera ²

1 Biology Department, UPR Rio Piedras Campus, San Juan, PR.

2 Physiology Department, UPR Medical Sciences Campus, San Juan, PR.

3 Neurodegeneratives Diseases Institute, University of Bordeaux, IMN-UMR-CNRS 5293, 146 rue Léo

Saignat, 33076 Bordeaux, France.

4 Neurodegeneratives Diseases Institute,CNRS, IMN-UMR-CNRS 5293, 146 rue Léo Saignat, 33076

Bordeaux, France.

The hyperpolarization-activated cation current (Ih) is a contributing factor of intrinsic neuronal excitability in different cells, including dopaminergic neurons (DA) of the ventral tegmental area (VTA).

In contrast to other cellular conductances, Ih is activated by hyperpolarization and produces a timedependent depolarizing current. Our laboratory demonstrated that cocaine sensitization, a noncontingent cocaine model, significantly reduces Ih amplitude in VTA DA neurons. However, the role of Ih in controlling VTA DA excitability is still poorly understood. It has been shown that VTA DA cell’s spontaneous activity remains unchanged when compared to the saline control groups after cocaine sensitization. Our hypothesis is that Ih reduction could function as a homeostatic regulator compensating for the cocaine-induced alteration in excitability thus, explaining the above-mentioned results. Using in vivo single-unit extracellular electrophysiology in isoflurane-anesthetized rats, we explored the Ih contribution on acute cocaine-induced VTA neuronal spontaneous activity. We locally perfused an Ih blocker (ZD7288, 8.3 μM) and evaluated its effect on VTA DA spontaneous firing patterns. Ih blockade significantly reduced acute cocaine-induced spontaneous firing rate, bursting frequency, and percent of spikes within a burst. Ih local inhibition also significantly increased the mean interspike interval (ISI) in VTA DA neurons. These findings suggest that Ih blockade can significantly reduce cocaine-induced firing activity in VTA DA neurons in part due to an increase in the mean ISI. Furthermore, using whole-cell patch-clamp, we found a significant reduction in Ih after 24 but not 2hours (hrs) of acute cocaine administration (15mg/kg, i.p). Using a current clamp rebound spiking protocol, we determined at different intervals of acute cocaine administration (2hrs, 24hrs and, 24hrs following 7-days cocaine administration) that there was a significant increase in rebound action potentials. This increase was progressively diminished as the sensitization protocol developed. In addition, the Ih blockade significantly reduced rebound action potentials. These results suggest that a progressive Ih reduction could serve as a homeostatic regulator of cocaine-induced spontaneous firing patterns which are correlated to an enhanced VTA DA excitability.

Funding: This research was funded by the National Institute of General Medical Sciences (GM084854), the National Center for Research Resources (5R25GM061838-15, 2G12-RR003051), the National Institute on Minority Health and Health Disparities (8G12-MD007600), the NSF Partnerships in International Research and Education (PIRE) Program Neural Mechanisms of Reward & Decision (OISE-1545803), the Research Initiative for Scientific Enhancement RISE Program (5R25GM061151-18), the Centre National de la Recherche Scientifique (CNRS), the Universite de Bordeaux and by LABEX BRAIN ANR-10-LABX-43.

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