Alcohol Dependence and the Ventral Hippocampal Influence on Alcohol Drinking in Male Mice

Examining neural circuits underlying persistent, heavy drinking provides insight into the neurobiological mechanisms driving alcohol use disorder. Facilitated by its connectivity with other parts of the brain such as the nucleus accumbens (NAc), the ventral hippocampus (vHC) supports many behaviors, including those related to reward seeking and addiction. These studies used a well-established mouse model of alcohol (ethanol) dependence. After surgery to infuse DREADD-expressing viruses (hM4Di, hM3Dq, or mCherry-only) into the vHC and position guide cannula above the NAc, male C57BL/6J mice were treated in the CIE drinking model that involved repeated cycles of chronic intermittent alcohol (CIE) vapor or air (CTL) exposure alternating with weekly test drinking cycles in which mice were offered alcohol (15% v/v) 2 h/day. Additionally, smaller groups of mice were evaluated for either cFos expression or glutamate release using microdialysis procedures. In CIE mice expressing inhibitory (hM4Di) DREADDs in the vHC, drinking increased as expected, but CNO (3 mg/kg intraperitoneally [i.p.]) given 30 min before testing did not alter alcohol intake. However, in CTL mice expressing hM4Di, CNO significantly increased alcohol drinking (∼30%; p < 0.05) to levels similar to the CIE mice. The vHC-NAc pathway was targeted by infusing CNO into the NAc (3 or 10 μM/side) 30 min before testing. CNO activation of the pathway in mice expressing excitatory (hM3Dq) DREADDs selectively reduced consumption in CIE mice back to CTL levels (∼35-45%; p < 0.05) without affecting CTL alcohol intake. Lastly, activating the vHC-NAc pathway increased cFos expression and evoked significant glutamate release from the vHC terminals in the NAc. These data indicate that reduced activity of the vHC increases alcohol consumption and that targeted, increased activity of the vHC-NAc pathway attenuates excessive drinking associated with alcohol dependence. Thus, these findings indicate that the vHC and its glutamatergic projections to the NAc are involved in excessive alcohol drinking.