The amygdala to periaqueductal gray pathway: Plastic changes induced by audiogenic kindling and reversal by gabapentin

Abstract Repeated, periodic induction of AGS (AGS kindling) in GEPR-9s increases seizure duration and induces an additional generalized clonus phase [post-tonic clonus (PTC)], which involves expansion of the localized brainstem AGS network to the amygdala. The pathway between central amygdala (CeA) and ventrolateral periaqueductal gray (vlPAG) is implicated in several disorders, including pain and anxiety. This pathway is also implicated in the network of audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR-9s). We examined AGS kindling-induced changes in vlPAG extracellular action potentials evoked by electrical stimuli in CeA in awake, behaving GEPR-9s, using chronically-implanted stimulation electrodes in CeA and microwire recording electrodes in vlPAG. The effect of gabapentin, an anticonvulsant drug that is also effective in pain and anxiety disorders, on the CeA to vlPAG pathway in AGS-kindled GEPR-9s was also evaluated. Electrical stimulation in CeA evoked consistent, short latency and intensity-dependent vlPAG neuronal firing increases. However, in AGS-kindled GEPR-9s these responses showed a precipitous firing increase with increasing stimulus intensity, as compared to non-kindled GEPR-9s. Gabapentin (50 mg/kg, i.p.) significantly reduced vlPAG neuronal responses to CeA stimulation to pre-AGS-kindled levels and reversibly blocked PTC in AGS-kindled GEPR-9s. These data suggest that the amygdala to vlPAG pathway may be critical in mediating the emergence of PTC during AGS kindling. The ability of gabapentin to suppress this pathway may be important for its anticonvulsant effects in AGS-kindled GEPR-9s, and this effect may contribute to gabapentin′s effectiveness in anxiety and pain in which the amygdala to PAG pathway is also implicated.