Overexpression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels into the Ventral Tegmental Area Increases the Rewarding Effects of Ethanol in UChB Drinking Rats

Authors

  • Mario Rivera-Meza,

    Corresponding author
    1. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
    • Reprint requests: Mario Rivera-Meza, PhD, Laboratory of Pharmacogenetics of Alcoholism, Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Av. Independencia 1027, Independencia, Santiago, RM, Chile; Tel.: +56 2 29786216; Fax: +56 2 27372783; E-mail: mariorivera@med.uchile.cl

    Search for more papers by this author
  • María Elena Quintanilla,

    1. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
    Search for more papers by this author
  • Diego Bustamante,

    1. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
    Search for more papers by this author
  • Ricardo Delgado,

    1. Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile
    Search for more papers by this author
  • Marianne Buscaglia,

    1. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
    Search for more papers by this author
  • Mario Herrera-Marschitz

    1. Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
    2. Millenium Institute Initiative BNI-Chile, University of Chile, Santiago, Chile
    Search for more papers by this author

Abstract

Background

A number of studies have shown that ethanol (EtOH) activates dopamine neurocircuitries and is self-administered into the ventral tegmental area (VTA) of the rat brain. In vitro and in silico studies have showed that hyperpolarization-activated cyclic nucleotide-gated (HCN) ionic channels on VTA dopamine neurons may constitute a molecular target of EtOH; however, there is no in vivo evidence supporting this assumption.

Methods

Wistar-derived University of Chile Drinking (UChB) rats were microinjected into the VTA with a lentiviral vector coding for rat HCN-2 ionic channel or a control vector. Four days after vector administration, daily voluntary EtOH intake was assessed for 30 days under a free-access paradigm to 5% EtOH and water. After EtOH consumption studies, the effect of HCN-2 overexpression was also assessed on EtOH-induced conditioned place preference (CPP); EtOH-induced locomotion, and EtOH-induced dopamine release in the nucleus accumbens (NAcc).

Results

Rats microinjected with the HCN-2 coding vector into the VTA showed (i) a ~2-fold increase in their voluntary EtOH intake compared to control animals, (ii) lentiviral-HCN-2-treated animals also showed an increased CPP to EtOH (~3-fold), (iii) a significant higher locomotor activity (~2-fold), and (iv) increased dopamine release in NAcc upon systemic administration of EtOH (~2-fold).

Conclusions

Overexpression of HCN-2 ionic channel in the VTA of rats results in an increase in voluntary EtOH intake, EtOH-induced CPP, locomotor activity, and dopamine release in NAcc, suggesting that HCN levels in the VTA are relevant for the rewarding properties of EtOH.

Ancillary