Ih blockade reduces cocaine-induced firing patterns of putative dopaminergic neurons of the ventral tegmental area in the anesthetized rat
Introduction
Hyperpolarization-activated cation current (Ih) is a significant modulator of intrinsic excitability on neurons of the mesocorticolimbic system, including dopaminergic cells (DA) from the ventral tegmental area (VTA) (DiFrancesco, 1981; Adams and Halliwell, 1982; Kase and Imoto, 2012). Neuroadaptations in this network are hypothesized to trigger substance abuse disorder. In contrast to other ionic conductances, Ih is a slowly activating cation inward current activated by hyperpolarizing inputs negative to -55 mV. Ih activation depolarizes the membrane to a threshold level for the generation of action potentials (Tsantoulas et al., 2016). Additionally, Ih is involved in various neuronal properties such as the control and modulation of the rhythmic activity of neural circuits (Leresche et al., 1990; McCormick and Pape, 1990), regulation of the resting membrane potential (Doan and Kunze, 1999), firing frequency modulation (Friedman, 2014; Okamoto et al., 2006), regulation of synaptic transmission (Beaumont and Zucker, 2000; Sparks and Chapman, 2014) and dendritic integration of synaptic inputs (Arencibia-Albite et al., 2017; Engel and Seutin, 2015; Magee, 2000). On VTA DA neurons, Ih is classified as an excitatory driving force (Santoro and Shah, 2020; Zhong et al., 2017; Wanat et al., 2008; Neuhoff et al., 2002).
Neuromodulation of intrinsic properties is a decisive determinant of neuron excitability (Desai et al., 1999; Nelson et al., 2003). Intrinsic excitability is a measure of the neuron's inherent electrical properties that can be adjusted by numerous factors (Kemenes et al., 2006; O'Leary, 2010). These adjustments arise through changes in morphological features and the expression level or biophysical properties of ion channels in the membrane (Williams et al., 2013). The activity of a single neuron results from the summation of excitatory and inhibitory synaptic inputs, and the intrinsic membrane properties (Beck and Yaari, 2008). Neuroadaptations can be categorized as either homeostatic, that contribute to stabilizing neuronal excitability, or non-homeostatic, that produce an alteration from basal excitability (Desai et al., 1999; Howard et al., 2007; Wijesinghe and Camp, 2011). Homeostatic changes in neuronal excitability can arise in response to long periods of altered activity (Turrigiano Gina, 1999; Turrigiano and Nelson, 2000; Keck, 2017). For example, 3 h after acute cocaine administration, activity of VTA DA neurons recorded in vivo, is significantly increased (Creed et al., 2016). Our laboratory demonstrated that cocaine sensitization, a chronic cocaine behavioral model, significantly reduces Ih amplitude by ~40% in VTA DA neurons (Arencibia-Albite et al., 2012). This reduction of current occurs concomitantly with the reduction of membrane surface HCN2 protein, the main HCN subunit in VTA DA neurons (Santos-Vera, 2019). An important observation is that after the development of cocaine sensitization, the spontaneous firing of VTA DA cells remains similar to that of control groups (Arencibia-Albite et al., 2012). These findings suggest that Ih reduction could reduce cocaine-induced excitability as a homeostatic adaptation to regulate neuronal excitability of VTA DA neurons.
Ih increases burst firing by enhancing rebound spiking after the disinhibition of VTA DA neurons (Tateno and Robinson, 2011). Additionally, pharmacological blockade of this current on VTA DA neurons can significantly decrease (by 40%) the firing rate in the majority of these neurons; this reduction is suggested to be behaviorally significant (Seutin et al., 2001). While this study indicates that the modulation of Ih can have a role in controlling VTA DA neuronal excitability, the relationship is still poorly understood. Hence, the study of Ih modulation on spontaneous firing activity could lead us to elucidate its contribution to VTA DA neuronal excitability.
To determine if reduction of Ih can alter basal VTA DA neuronal excitability, we evaluated the effect of Ih blockade on spontaneous firing patterns using in vivo single-unit extracellular recordings. VTA DA neurons can be divided by their firing patterns, classified by the average firing rate and the percentage of spike within a burst (%SWB) (Mameli-Engvall et al., 2006). To investigate how Ih modulates cocaine-dependent excitability, we measured Ih using whole-cell patch-clamp electrophysiology, 2 and 24 h after acute cocaine injection. Additionally, we determined the effect of Ih blockade on cocaine-induced spontaneous firing patterns using in vivo single-unit extracellular recordings. We postulate that a progressive Ih reduction serves as a homeostatic regulator to oppose cocaine-induced excitability in VTA DA neurons.
Section snippets
Effect of Ih blockade on in vivo anesthetized single-unit spontaneous VTA DA neuron firing
To evaluate the effect of Ih blockade on in vivo anesthetized spontaneous firing, we used double barrel pipettes (Georges and Aston-Jones, 2002). These pipettes were comprised of a recording electrode and a perfusion pipette that contained ZD 7288 (8.3 μM). We recorded a minimum of 100 s of baseline extracellular firing activity and then locally perfused at the vicinity of the recorded cell, 60 nL of ZD 7288 to see the effect of Ih blockade on neuronal firing patterns as seen on sample traces (
Discussion
We have previously shown that cocaine sensitization reduces Ih in VTA DA neurons (Arencibia-Albite et al., 2012). In the present study we report that Ih blockade reduces spontaneous firing parameters in VTA DA neurons of rats. We elucidated the contribution of Ih to spontaneous activity using in-vivo extracellular recording in anesthetized rats. Through local infusion of ZD 7288 from a micropipette in the vicinity of the recording electrode, we determined that Ih blockade significantly reduces
Animals
Procedures involving experimental animals were performed according to the U.S. Public Health Service Publication Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee at the University of Puerto Rico Medical Sciences Campus. Behavioral and electrophysiological experiments were performed with male Sprague-Dawley rats (35–51 days postnatal). Animals were housed two per cage and were maintained at constant temperature and humidity with a 12:12-h
Author contributions
Conceptualization, K.Y.B.-C., R.V.-T. and C.A.J.-R.; methodology, K.Y.B.-C., R.V.-T. and C.A.J.-R.; validation, K.Y.B.-C., R.V.-T., C.C.-G., D.C.-G., G.R.F., F.G. and C.A.J.-R.; formal analysis, K.Y.B.-C. and F.G.; investigation, K.Y.B.-C., C.C.-G., D.C.-G., G.R.F. and F.G.; resources, F.G. and C.A.J.-R.; data curation, K.Y.B.-C. and F.G.; writing—original draft preparation, K.Y.B.-C.; writing—review and editing, K.Y.B.-C., R.V.-T., C.C.-G., D.C.-G. and C.A.J.-R.; visualization, K.Y.B.-C.;
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
Ethical statement
All procedures involving experimental animals were performed according to the U.S. Public Health Service Publication Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee at the University of Puerto Rico Medical Sciences Campus.
Declaration of Competing Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Acknowledgments
The authors thank Dr. Mark S. Brodie for the excellent proofreading and critiques of the manuscript. This work was in partial fulfillment of Karl Y. Bosque-Cordero doctoral dissertation as a requirement to obtain a Ph.D. degree from the University of Puerto Rico, Rio Piedras Campus.
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