Faculty Collaboration Database

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement. Mol Psychiatry 2023 Sep;28(9):3930-3942

Date

10/17/2023

Pubmed ID

37845497

Pubmed Central ID

PMC10730389

DOI

10.1038/s41380-023-02290-x

Scopus ID

2-s2.0-85174315132 (requires institutional sign-in at Scopus site)

Abstract

Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1-4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (I_h), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of I_h in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced I_h selectively in VTA dopamine neurons. This differential modulation of I_h currents is likely mediated by a D₂ autoreceptor-induced decrease in cAMP as D₂ (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D₁ (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in I_h in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of I_h in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.

Author List

Mu L, Liu X, Yu H, Vickstrom CR, Friedman V, Kelly TJ, Hu Y, Su W, Liu S, Mantsch JR, Liu QS

Author

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Dopaminergic Neurons
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
RNA, Messenger
Rats
Up-Regulation
Ventral Tegmental Area