Heightened Anxiety With Distinct Prefrontal Substrates Is Differentially Sensitive to the Anxiolytics Citalopram and...

Individual variability in pharmacological treatment efficacy remains a persistent obstacle to ameliorating clinical anxiety. This may originate, in part, from the different neural etiologies that underlie pathological anxiety. To provide novel insights into patient heterogeneity in anxiolytic responsiveness, we compared the efficacy of distinct anxiolytic drugs, a selective serotonin reuptake inhibitor (SSRI) and ketamine, on anxiety states with different etiologies, but of known origin, in marmoset monkeys.

Using an uncertain threat paradigm, the human intruder test, we cannulated 2 cohorts of marmosets (Callithrix jacchus) (N = 14) in either area 14 of the ventromedial prefrontal cortex (vmPFC-14) or area 11 of the orbitofrontal cortex (OFC-11). This allowed for induction of heightened threat reactivity by either overactivation of vmPFC-14 by blocking glutamate reuptake or inactivation of OFC-11 by infusion of GABA (gamma-aminobutyric acid) agonists. The efficacy of the SSRI citalopram and ketamine administered both peripherally and centrally to ameliorate the heightened threat reactivity were then compared.

Heightened threat reactivity induced by vmPFC-14 overactivation was responsive to citalopram administered both peripherally and centrally into vmPFC-14. However, it was inconsistently reduced by subacute ketamine pretreatment administered either peripherally or centrally. In contrast, heightened threat reactivity induced by inactivation of OFC-11 was responsive to centrally applied pretreatment of ketamine but not peripheral or central SSRI administration.

These data provide evidence that different faces of anxiety generated by distinct forms of prefrontal dysregulation are differentially responsive to differing classes of anxiolytics, providing novel insight into the relationship between the neuro-etiology of anxiety and its treatment.