Effects of vagus nerve stimulation on cognitive functioning in rats with cerebral ischemia reperfusion.

BACKGROUND: Vagus nerve stimulation (VNS) has become the most common non-pharmacological treatment for intractable drug-resistant epilepsy. However, the contribution of VNS to neurological rehabilitation following stroke has not been thoroughly examined. Therefore, we investigated the specific role of acute VNS in the recovery of cognitive functioning and the possible mechanisms involved using a cerebral ischemia/reperfusion (I/R) injury model in rats. METHODS: The I/R-related injury was modeled using occlusion and reperfusion of the middle cerebral artery (MCAO/R) in Sprague-Dawley rats. VNS was concurrently applied to the vagus nerve using a stimulation intensity of 1 mA at a fixed frequency of 20 Hz with a 0.4-ms bipolar pulse width. The stimulation duration and inter-train interval were both 3 s. Next, Morris water maze and shuttle-box behavioral experiments were conducted to assess the effects of VNS on the recovery of learning, memory, and inhibitory avoidance following I/R injury. Intracerebroventricular injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective neurotoxin for noradrenergic neurons, was used to evaluate the role of norepinephrine (NE) as a mediator of therapeutic effects of VNS on cognitive recovery. RESULTS: Compared with the MCAO/R group, the VNS+MCAO/R group had improved spatial memory as indicated by swimming path lengths and escape latencies in the Morris water maze, and fear memory, as indicated by the avoidance conditioned response rate, mean shock duration, and avoidance time in shuttle-box behavior experiments. Compared with the VNS+MCAO/R group, the DSP-4+VNS+MCAO/R group, which had reduced NE levels in cortical and hippocampal brain regions, showed a reversal of the VNS-induced benefits on spatial and fear memory performance. CONCLUSIONS: VNS improves spatial and fear memory in a rat model of MCAO/R injury. However, a reduction in NE from the administration of DSP-4 blocks these protective effects, suggesting that NE may contribute to the influence exhibited by VNS on memory performance in rats with cerebral I/R-related injury.

Potentiation by WIN 55,212-2 of GABA-activated currents in rat trigeminal ganglion neurones.

BACKGROUND AND PURPOSE: Although both natural and synthetic cannabinoid compounds have been shown to exert an antinociceptive effect on acute and persistent pain, the anatomical locus of the target of cannabinoid-induced analgesia has not been fully elucidated. Here, we investigated the effects of the cannabinoid agonist WIN 55,212-2 on GABA-activated currents (I(GABA)) in rat primary sensory neurones. EXPERIMENTAL APPROACH: In the present study, experiments were performed on neurones freshly isolated from rat trigeminal ganglion (TG) by using whole-cell patch clamp and repatch techniques. KEY RESULTS: GABA-evoked inward currents were potentiated by pretreatment with WIN 55,212-2 in a concentration-dependent manner (10(-10)-10(-8) M). WIN 55,212-2 shifted the GABA concentration-response curve upwards, with an increase of 30.3 +/- 3.7% in the maximal current response but with no significant change in the EC(50) (agonist concentration producing a half-maximal response) value. WIN 55,212-2 potentiated the responses to GABA in a manner independent of holding potential and in the absence of any change in the reversal potential of the current. This potentiation of I(GABA) induced by WIN 55,212-2 was almost completely blocked by AM 251 (3 x 10(-8) M), a CB(1) receptor antagonist, and, using the repatch technique, was found to be abolished after intracellular dialysis with the protein kinase A (PKA) activator cAMP or the PKA inhibitor H89. CONCLUSIONS AND IMPLICATIONS: The potentiation by WIN 55,212-2 of I(GABA) in primary sensory neurones may help to elucidate the mechanism underlying the modulation of analgesia by cannabinoids in the spinal dorsal horn.

Characteristics of ATP-activated current in nodose ganglion neurons of rats.

The characteristics of ATP-activated currents (I(ATP)) in rat nodose ganglion (NG) neurons have not been fully clarified. Especially, the correlation between I(ATP) phenotype and P2X receptor subunit genotype in rat NG neuron is not clear. By whole-cell patch-clamp and single cell immunocytochemical techniques, we explored the characteristics of the I(ATP) phenotype and its correlation with P2X receptor subunits in acutely isolated NG neuron of rats. The results indicated that I(ATP) of NG neurons can be classified into four types: F type (fast type, 8.1%), I type (intermediate type, 14.8%), S type (slowing type, 37.0%) and vS type (very slowing type, 21.5%). The single immunocytochemical studies have demonstrated that F type cells express P2X1 and P2X3 subunits, I type cells P2X1, P2X3 and P2X4 subunits, S type cells P2X1, P2X2 and P2X3 subunits and vS type cells P2X2, P2X3 and P2X4 subunits. The results reveal that there are four types of I(ATP) in NG neurons, differential expression of distinct P2X subunits may underlie the I(ATP) phenotype.