I h blockade reduces cocaine-induced firing patterns of putative dopaminergic neurons of the ventral tegmental area in the anesthetized rat

The hyperpolarization-activated cation current (I ) is a determinant of intrinsic excitability in various cells, including dopaminergic neurons (DA) of the ventral tegmental area (VTA). In contrast to other cellular conductances, I is activated by hyperpolarization negative to -55 mV and activating...

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Published in:Progress in neuro-psychopharmacology & biological psychiatry 2022-01, Vol.112, p.110431
Main Authors: Bosque-Cordero, Karl Y, Vazquez-Torres, Rafael, Calo-Guadalupe, Cristhian, Consuegra-Garcia, Daisy, Fois, Giulia R, Georges, François, Jimenez-Rivera, Carlos A
Format: Article
Language:English
Subjects:
Action Potentials - drug effects
Animals
Cocaine - pharmacology
Dopaminergic Neurons - drug effects
Electrophysiology
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Male
Rats
Ventral Tegmental Area - drug effects
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Summary:The hyperpolarization-activated cation current (I ) is a determinant of intrinsic excitability in various cells, including dopaminergic neurons (DA) of the ventral tegmental area (VTA). In contrast to other cellular conductances, I is activated by hyperpolarization negative to -55 mV and activating I produces a time-dependent depolarizing current. Our laboratory demonstrated that cocaine sensitization, a chronic cocaine behavioral model, significantly reduces I amplitude in VTA DA neurons. Despite this reduction in I , the spontaneous firing of VTA DA cells after cocaine sensitization remained similar to control groups. Although the role of I in controlling VTA DA excitability is still poorly understood, our hypothesis is that I reduction could play a role of a homeostatic controller compensating for cocaine-induced change in excitability. Using in vivo single-unit extracellular electrophysiology in isoflurane anesthetized rats, we explored the contribution of I on spontaneous firing patterns of VTA DA neurons. A key feature of spontaneous excitability is bursting activity; bursting is defined as trains of two or more spikes occurring within a short interval and followed by a prolonged period of inactivity. Burst activity increases the reliability of information transfer. To elucidate the contribution of I to spontaneous firing patterns of VTA DA neurons, we locally infused an I blocker (ZD 7288, 8.3 μM) and evaluated its effect. I blockade significantly reduced firing rate, bursting frequency, and percent of spikes within a burst. In addition, I blockade significantly reduced acute cocaine-induced spontaneous firing rate, bursting frequency, and percent of spikes within a burst. Using whole-cell patch-clamp, we determine the progressive reduction of I after acute and chronic cocaine administration (15 mg/k.g intraperitoneally). Our data show a significant reduction (~25%) in I amplitude after 24 but not 2 h of acute cocaine administration. These results suggest that a progressive reduction of I could serve as a homeostatic regulator of cocaine-induced spontaneous firing patterns related to VTA DA excitability.
ISSN:1878-4216
DOI:10.1016/j.pnpbp.2021.110431