Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

Abstract

The vagus nerve is an important source of afferent information about visceral states and it provides input to the locus coeruleus (LC), the major source of norepinephrine (NE) in the brain. It has been suggested that the effects of electrical stimulation of the vagus nerve on learning and memory, mood, seizure suppression, and recovery of function following brain damage are mediated, in part, by the release of brain NE. The hypothesis that left vagus nerve stimulation (VNS) at the cervical level results in increased extracellular NE concentrations in the cortex and hippocampus was tested at four stimulus intensities: 0.0, 0.25, 0.5, and 1.0 mA. Stimulation at 0.0 and 0.25 mA had no effect on NE concentrations, while the 0.5 mA stimulation increased NE concentrations significantly in the hippocampus (23%), but not the cortex. However, 1.0 mA stimulation significantly increased NE concentrations in both the cortex (39%) and hippocampus (28%) bilaterally. The increases in NE were transient and confined to the stimulation periods. VNS did not alter NE concentrations in either structure during the inter-stimulation baseline periods. No differences were observed between NE levels in the initial baseline and the post-stimulation baselines. These findings support the hypothesis that VNS increases extracellular NE concentrations in both the hippocampus and cortex.

Figure 1

Effect of various intensities of VNS on extracellular NE in the hippocampus of freely moving rats, shown as percent change from baseline levels. The 0.5 and 1.0mA differed significantly from basal levels (* p<0.05, N= 12). Baseline NE concentration in dialysate from hippocampus averaged 0.096 ± 0.007pg/μL.

Figure 2

Effect of various intensities of VNS on extracellular NE in the cortex of freely moving rats, shown as percent change from baseline levels. The 1.0mA differed significantly from basal levels (* p<0.001, N= 8). Baseline NE concentration in dialysate from cerebral cortex averaged 0.102 ± 0.012 pg/μL.

Figure 3

Increased extracellular NE concentrations in ipsilateral and contralateral cerebral cortex following left vagus nerve stimulation. These increases in extracellular NE did not differ significantly on the basis of hemisphere (p=0.49, N=6). Average baseline NE concentration in ipsilateral dialysate was 0.135 ± 0.012 pg/μL and in the contralateral dialysate was 0.095 ± 0.017 pg/μL.

Figure 4

Panel A.: Changes in extracellular NE concentration in the hippocampus of one rat during alternating 1h periods of dialysate collection for baseline (stimulus off) and stimulation (VNS at 0.5 mA). Panel B: Change in extracellular NE concentration in the cortex of a rat during 1h periods of dialysate collection for baseline (stimulus off) and stimulation (VNS at 1.0 mA). Depicts actual concentration of NE (pg/μL) measured in each sample rather than percent change. Note that the NE concentration returns to baseline when vagus nerve is not being stimulated.

Figure 5

Representative histological sections showing location of microdialysis probes in: (A) cortex and (B) hippocampus. Arrows indicate location of dialysis membrane.