Clinical and preclinical evidence suggests anxiolytic-like efficacy of pregabalin (PGB, Lyrica). However, its mechanism of action remains under investigation. The current study applied [(14)C]-iodoantipyrine cerebral blood flow (CBF) mapping to examine the effect of PGB on neural substrates underlying unconditioned fear in a rat model of footshock-induced fear. Regional CBF (rCBF) was analyzed by statistical parametric mapping. Functional connectivity and graph theoretical analysis were used to investigate how footshock and PGB affect brain activation at the network level. Pregabalin significantly attenuated footshock-induced ultrasonic vocalization, but showed no significant effect on freezing behavior. Footshock compared to no-shock controls elicited significant increases in rCBF in limbic/paralimbic regions implicated in the processing of unconditioned fear and ultrasonic vocalization, including the amygdala, hypothalamus, lateral septum, dorsal periaqueductal gray, the anterior insular (aINS) and medial prefrontal cortex (mPFC). The activation pattern was similar in vehicle- and PGB-treated subjects, with PGB significantly attenuating activation in the amygdala, hypothalamus, and aINS. The vehicle/no-shock group showed strong, positive intra-structural correlations within the cortex, hypothalamus, amygdala, thalamus, and brainstem. The cortex was negatively correlated with the hypothalamus and brainstem. Footshock reduced the total number of significant correlations, but induced greater intra-cortical connectivity of the aINS and mPFC, and new positive correlations between the hypothalamus and amygdala. In no-shock controls, PGB significantly reduced the positive intra-structural correlations within the cortex and amygdala, as well as the negative cortico-subcortical correlations. Following footshocks, PGB disrupted both the network recruitment of aINS and mPFC, and the positive hypothalamic-amygdaloid correlations. Our findings suggest that PGB may exert anxiolytic effect by attenuating cortico-cortical and cortico-subcortical communication and inhibiting network recruitment of the aINS, mPFC, amygdala, and hypothalamus following a fear-inducing stimulus. Functional brain mapping in rodents may provide new endpoints for preclinical evaluation of anxiolytic drug candidates with potentially improved translational power compared to behavioral measurements alone.
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