Minocycline engages microglia in the midbrain periaqueductal grey to attenuate hypoxia-triggered panic-like behaviour in rats

Abstract

Panic disorder (PD) is a chronic and highly disabling psychiatric disorder characterised by recurrent and unexpected panic attacks, with underlying neurobiological mechanisms poorly understood. Emerging evidence suggests that inflammatory processes may contribute to the triggering of panic attacks, with a subset of PD patients exhibiting alterations in circulating cytokine levels, while animal studies indicate that an immunoresponsive microglial phenotype may contribute to the disorders pathophysiology. Minocycline, a tetracycline-class antibiotic that crosses the blood-brain barrier, exerts anti-inflammatory effects and has demonstrated therapeutic potential in attenuating panic attacks, supporting its potential as an alternative strategy for reducing PD-related symptoms by modulating microglial activity. In this study, we investigated whether exposure of male Sprague-Dawley rats to a panicogenic stimulus, hypoxia (7% O2), is followed by microglial morphological remodelling in the midbrain periaqueductal grey (PAG), a well-known panic-associated structure, at baseline and after minocycline treatment. The effects of hypoxia on the expression of panic-like jumping behaviour were measured during the respiratory challenge, whereas microglial morphology was assessed at 1, 6, or 24h following the aversive stimulus. In a second experiment, the effects of minocycline (30 mg/kg, i.p., administered once daily for 5 days) on the immediate behavioural responses to hypoxia were compared with those produced by an acute administration of alprazolam (2 mg/kg, i.p.), a benzodiazepine widely used in the clinical management of PD. Minocycline effects on microglial morphology in the PAG were also assessed. Our findings show that hypoxia elicited robust jumping behaviour, without affecting overall locomotion. This panicogenic effect was accompanied by marked and time-dependent microglial morphological changes in the dorsomedial (dmPAG) and ventrolateral (vlPAG) columns of the PAG, consistent with a shift towards an immunoresponsive phenotype. Notably, minocycline, similarly to alprazolam, reduced the number of jumps, indicating a panicolytic effect, while also preventing hypoxia-induced microglial remodelling in the dmPAG. Altogether, these findings suggest a role for microglia in regulating hypoxia-induced panic- like behaviour, indicating that microglial inhibition, as achieved here with minocycline, represents a promising therapeutic strategy for preventing panic attacks.