The role of norepinephrine in amygdaloid kindling : effects of DSP-4 induced depletion and intracerebroventricular norepinephrine induced repletion

The role of norepinephrine in the development of amygdaloid kindling in rats was investigated. In the first experiment, pretreatment with the noradrenergic neurotoxin, DSP-4 (63 mg/kg, ip), whose action is reportedly specific to locus coeruleus neurons, markedly accelerated the rate of kindling. DSP-4 treated animals and saline controls required 3.8 and 7.5 after-discharges (ADs) to kindle respectively. Furthermore, DSP-4 treatment lengthened the latency of the onset to clonus during the first stage 5 seizure. Norepinephrine levels measured in the telencephalon were lowered by 45% with DSP-4 treatment, whereas dopamine and 5-hydroxytryptamine levels were unaffected. -- In an attempt to test the hypothesis that a tonic presence of norepinephrine serves to inhibit kindling development, rats were treated with DSP-4, and chronically infused (icv) with either norepinephrine (5 ug/.5 ul/hr), or the vehicle, via an osmotic minipump. Telencephalic norepinephrine levels were not raised by the infusion of norepinephrine, and consequently there were no significant differences between the two groups on kindling development. Both infusion groups were combined and compared to those groups in experiment 1. The infused groups had lower norepinephrine levels and kindled faster than the saline group, indicating again that DSP-4 treatment accelerates kindling. -- The third experiment represents a second attempt at ascertaining the effects of norepinephrine repletion following DSP-4 treatment on kindling development. Three groups were given DSP-4 treatment and 1 group saline. One DSP-4 group received chronic ventricular infusion of norepinephrine (10 ug/.5 ul/hr -double that in experiment 2) and another the vehicle alone. Once again the infusion of norepinephrine failed to raise norepinephrine levels above the vehicle control; however the infused groups had norepinephrine levels equivalent to the saline (non-infused) control. Despite a marked amount of within group variance, the DSP-4 alone group had a significant reduction of norepinephrine, and all three DSP-4 treated groups kindled significantly faster than the saline group. These results imply that: 1) initial abnormalities induced by DSP-4 were reversed during kindling, 2) the cannulation and/or vehicle infusion procedure itself accelerates kindling, or 3) norepinephrine depletion may not be necessary for kindling acceleration induced by DSP-4 treatment. -- In conclusion, this study demonstrates that administration of the noradrenergic neurotoxin DSP-4 consistently accelerates kindling. The methods employed, however, failed to indicate whether this depletion-induced acceleration could be reversed by norepinephrine repletion