Compensatory changes of in vivo acetylcholine and noradrenaline release in the hippocampus after partial deafferentation, as monitored by microdialysis

Abstract

Lesions of the fimbria-fornix pathways are known to induce a partial cholinergic and noradrenergic denervation of the hippocampal formation, which is followed by a slow and protracted collateral sprouting by the spared afferents. Using the intracerebral microdialysis technique, compensatory changes in extracellular levels of acetylcholine (ACh) and noradrenaline (NA) have been monitored over time in the partially denervated hippocampus of awake unrestrained rats subjected to an unilateral fimbria-fornix (FF) transection. One week after the lesion, baseline ACh output was reduced by 90% and 80% in the dorsal and ventral hippocampus, respectively, and it remained depressed still by 6 months after lesion. KCl-evoked and atropine-stimulated ACh efflux were equally reduced by 1 week after lesion, remained depressed at 3 months, but showed a significant recovery by 6 months post-lesion. Tissue choline acetyltransferase (ChAT) activity levels, initially reduced by 92% and 86%, in the dorsal and ventral hippocampus, respectively, recovered significantly by 3 months and remained unchanged at 6 months. Baseline NA output was significantly reduced (-80%) in the dorsal hippocampus by 1 week after the lesion and showed a partial recovery over time (to 50% of normal), whereas the ventral part was not significantly affected by the FF lesion. The significant FF lesion-induced reduction in KCl- or desipramine (DMI)-stimulated NA release observed in the dorsal hippocampus at 1 week after the lesion remained unchanged during the subsequent months. By contrast, in the ventral hippocampus, the initial 65-70% reduction in KCl- and DMI-stimulated NA release significantly recovered to normal levels within 3 months post-lesion. The NA tissue levels were significantly reduced by 4 weeks after lesion, in the dorsal hippocampus and did not show any significant recovery over time. In the ventral hippocampus, these levels were significantly reduced only at 4 weeks. Transmitter turnover, expressed as the ratio between dialysate levels and tissue ChAT or NA content, showed a 3-fold increase in the dorsal hippocampus at 4 weeks after lesion, but not at later time points. This indicates that the spared noradrenergic and cholinergic afferents respond to the partial denervation by a transient increase in transmitter turnover, evident as early as 4 weeks post-lesion in the region of maximal denervation. This was followed by a long-term increase in evoked transmitter release which may result from a slowly progressing compensatory sprouting of the spared afferents.