cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement

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 (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih 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 Ih 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 Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

“…We found some overlap in the differentially expressed genes within the two dopamine neuron populations, including concordant up‐regulation potassium channel Hcn1 , and cAMP binding protein Creb5 . These targets are of particular interest as chronic opioids are known to disrupt expression of potassium channels, 11 and cAMP‐mediated upregulation of HCNs in dopamine neurons was recently shown to promote cocaine self‐administration 44 . We also found enrichment for Pi3k‐Akt signalling pathway genes in the combinatorial neurons and our selected GABA neurons cluster.…”

“…These targets are of particular interest as chronic opioids are known to disrupt expression of potassium channels, 11 and cAMP‐mediated upregulation of HCNs in dopamine neurons was recently shown to promote cocaine self‐administration. 44 We also found enrichment for Pi3k‐Akt signalling pathway genes in the combinatorial neurons and our selected GABA neurons cluster. This included upregulation of neurotrophic factors Ngf and Gdnf .…”

HCN channels in the lateral habenula regulate pain and comorbid depressive‐like behaviors in mice

“… 68 Interestingly, recent studies have demonstrated contrasting modulatory effects of chronically altered cAMP on HCN channels activity in pyramidal neurons from dorsal hippocampal and dopamine neurons from VTA. 64 , 69 Therefore, investigating whether cAMP or TRIP8b participates in the HCN channelopathy of the LHb under the comorbidity of SNI‐induced chronic pain and major depression and elucidating their interactions with HCN channels are important areas for future research aimed at elucidating the central mechanisms underlying the pathogenesis of CADS in chronic pain.…”

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

“…We found some overlap in the differentially expressed genes within the two dopamine neuron populations, including concordant up-regulation potassium channel Hcn1 , and cAMP binding protein Creb5. These targets are of particular interest as chronic opioids are known to disrupt expression of potassium channels 12 , and cAMP-mediated upregulation of HCNs in dopamine neurons was recently shown to promote cocaine self-administration 44 . We also found enrichment for Pi3k-Akt signaling pathway genes in the combinatorial neurons and our selected GABA neurons cluster.…”

“…These targets are of particular interest as chronic opioids are known to disrupt expression of potassium channels 12 , and cAMP-mediated upregulation of HCNs in dopamine neurons was recently shown to promote cocaine selfadministration 44 . We also found enrichment for Pi3k-Akt signaling pathway genes in the combinatorial neurons and our selected GABA neurons cluster.…”