Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

Abstract

The hyperpolarization-activated cyclic nucleotide-gated channel (HCN), which underlies the hyperpolarization-activated cation current (Ih), has diverse roles in regulating neuronal excitability across cell types and brain regions. Recently, HCN channels have been implicated in preclinical models of substance abuse including alcohol. In the prefrontal cortex of rodents, HCN expression and Ih magnitude are developmentally regulated during adolescence and may be vulnerable to alcohol’s effects. In mice, binge alcohol consumption during the adolescent period results in a sustained reduction in Ih that coincides with increased alcohol consumption in adulthood, yet the direct role HCN channels have on alcohol consumption are unknown. Here, we show that the genetic deletion of Hcn1 causes an increase in alcohol preference on intermittent 2-bottle choice task in homozygous null (HCN1−/−) male mice compared to wild-type littermates without affecting saccharine or quinine preference. The targeted viral deletion of HCN1 in pyramidal neurons of the medial prefrontal cortex resulted in a gradual loss of Hcn1 expression and a reduction in Ih magnitude during adolescence, however, this did not significantly affect alcohol consumption or preference. We conclude that while HCN1 regulates alcohol preference, the genetic deletion of Hcn1 in the medial prefrontal cortex does not appear to be the locus for this effect.

HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum

“…Therefore, in the future, it will also be important to investigate the role of HCN1 in MOR-LTD at AIC inputs to D1-or D2-expressing MSNs (direct or indirect pathway respectively). It has recently been reported that HCN1 contributes to alcohol preference (Salling & Harrison, 2020). Given that alcohol disrupts MOR-LTD in DLS, this mechanism of MOR-HCN1…”

HCN1 channels mediate mu opioid receptor long‐term depression at insular cortex inputs to the dorsal striatum

“…Therefore, in the future, it will also be important to investigate the role of HCN1 in MOR‐LTD at AIC inputs to D1‐ or D2‐expressing MSNs (direct or indirect pathway respectively). It has recently been reported that HCN1 contributes to alcohol preference (Salling & Harrison, 2020). Given that alcohol disrupts MOR‐LTD in DLS, this mechanism of MOR‐HCN1 signalling may be a target of alcohol's effects and contribute to alcohol‐related, dorsal striatal‐dependent behaviours such as habitual and compulsive alcohol drinking.…”

HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum

“…Therefore, in the future, it will also be important to investigate the role of HCN1 in MOR-LTD at AIC inputs to D1- or D2-expressing MSNs (direct or indirect pathway respectively). It has recently been reported that HCN1 contributes to alcohol preference(Salling & Harrison, 2020). Given that alcohol disrupts MOR-LTD in DLS, this mechanism of MOR-HCN1 signaling may be a target of alcohol’s effects and contribute to alcohol-related, dorsal striatal-dependent behaviors such as habitual and compulsive alcohol drinking.…”