Heightened anxiety with distinct prefrontal substrates is differentially sensitive to the anxiolytics, citalopram and ketamine

Abstract

BACKGROUND: Individual variability in pharmacological treatment efficacy remains a persistent obstacle to ameliorating clinical anxiety. This may originate, in part, from the different neural aetiologies underlying pathological anxiety. To provide novel insights into patient heterogeneity in anxiolytic responsiveness we compare the efficacy of distinct anxiolytic drugs, a Selective Serotonin Re-uptake Inhibitor (SSRI) and ketamine on anxiety states with different aetiologies, but of known origin, in marmoset monkeys. METHODS: Using an uncertain threat paradigm, the human intruder test, we cannulated two 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 agonists. The efficacy of the SSRI, citalopram, and ketamine administered both peripherally, and centrally, to ameliorate the heightened threat reactivity was then compared. RESULTS: Heightened threat reactivity induced by vmPFC-14 overactivation was responsive to citalopram administered both peripherally and also centrally into vmPFC-14. It was inconsistently reduced, however, by subacute ketamine pretreatment, 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. CONCLUSIONS: 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-aetiology of anxiety and its treatment.