Exploring the effects of adolescent social isolation stress on the serotonin system and ethanol-motivated behaviors

Rationale: Alcohol is one of the most frequently used drugs of abuse and
has a major impact on human health worldwide. People assigned female at
birth and those with adverse childhood experiences are stress-vulnerable
and more likely to report drinking as a means of “self-medication.” Prior
studies in our laboratory showed that adolescent social isolation stress
(SIS) increases vulnerability to ethanol (EtOH) intake and consumption
despite negative consequences in female rats. Objectives: Here, we
explored modulation of the dorsal raphe nucleus (DRN)-serotonin (5-HT)
system, a sexually dimorphic neurotransmitter system involved in
stress-reward interactions, to determine its contribution to
EtOH-motivated behaviors in rats that have undergone SIS. Results: We
employed electrophysiological and functional neuroanatomy strategies to
show that both SIS and EtOH exposure induce persistent hypofunction of the
DRN 5-HT system, particularly in females. Chemogenetic activation of DRN
5-HT neurons attenuated reward value for both EtOH and sucrose and
elevated punished responding for EtOH in a stress-dependent manner.
Conclusions: Our results highlight an inverse relationship between EtOH
consumption and the 5-HT system, the sex- and stress-dependent nature of
this relationship, and a connection between DRN 5-HT signaling and acute
responding to rewards and punishment. These data support the DRN 5-HT
system as a potential target to treat aberrant alcohol consumption and
drinking despite negative consequences in stress-vulnerable populations.