Fluoxetine Modulates Spontaneous and Conditioned Behaviors to Carbon Dioxide (CO2) Inhalation and Alters Forebrain–Midbrain Neuronal Activation

•Acute and conditioned behaviors to CO2, a pathological marker of panic disorder were assessed following SSRI treatment.•Passive (freezing) behavior was observed during inhalation versus active (rearing) upon context re-exposure.•Altered neuronal activation in forebrain-midbrain circuits regulating defensive behaviors was observed.•Chronic fluoxetine normalized CO2-associated acute and conditioned responses and forebrain–midbrain neuronal activity.•Data validate CO2-context conditioning PD model and provide insights on regional contributions and treatment response. Panic disorder (PD), a prevalent anxiety disorder, is characterized by unexpected panic attacks, persistent anxiety and avoidance of panic contexts. Selective serotonin reuptake inhibitors (SSRIs) are effective in treating PD; however, the mechanisms underlying SSRI efficacy are poorly understood. Using CO2-inhalation, a PD-relevant translational paradigm, we examined the effect of chronic SSRI (fluoxetine) treatment on unconditioned and context-conditioned defensive behaviors, as well as respiratory responses, in mice. In addition, cFos expression was evaluated as a measure of the functional activity and interregional correlation matrices were used to explore the neurocircuitry recruited in CO2-conditioned behavior and SSRI treatment response. Chronic fluoxetine attenuated CO2-induced passive (freezing) behavior during inhalation and active (rearing) behavior on re-exposure to context, in addition to reducing CO2-evoked respiratory responses. Brain mapping in CO2-context-conditioned mice revealed altered regional neuronal activation within and correlations across midbrain regions subserving defensive behaviors (periaqueductal gray (PAG) and raphe nuclei) and forebrain emotional and contextual processing loci (medial prefrontal cortex, insular cortex and hippocampus). Importantly, fluoxetine treatment normalized these alterations. Collectively, our results provide novel information on fluoxetine modulation of panic-relevant defensive behaviors and neurocircuitry, facilitating increased understanding of panic neurobiology in the context of treatment response.