Georgia A. Cottrell

Mossy fiber sprouting induced by repeated electroconvulsive shock seizures

The elicitation of repeated focal seizures (kindling) induces mossy fiber sprouting in the hippocampus of the rat. The present study investigated whether repeated generalized seizures also induce mossy fiber sprouting. Human psychiatric patients receive repeated generalized seizures during electroconvulsive therapy (ECT). Male Long-Evans rats received a course of eight electroconvulsive shock (ECS) seizures administered on a 48-h schedule over a course of 2 1/2 weeks. Control subjects received matched handling, but no stimulation. Fourteen days after the last ECS trial, all subjects were sacrificed and their brains subjected to Timm staining. Cell counts and area measures were also taken in the hilus. Significant sprouting, but not significant cell loss, was seen in the fascia dentata of the subjects that had received ECS.

Rapid visualization of NMDA receptors in the brain: characterization of (+)-3-[12I]-iodo-MK-801 binding to thin sections of rat brain

We have developed and characterized a method for the rapid autoradiographic determination of receptor sites for the non-competitive NMDA receptor antagonist, MK-801, using an iodinated form of the compound, (+)-3-[125I]-iodo-MK-801. The binding site was shown to exhibit those criteria necessary for its definition as a receptor site, i.e., the binding was saturable, of high affinity, easily reversible, and stereospecific. Saturation analysis of binding to thin brain sections revealed a Bmax of 108.1 +/- 10.5 fmol/mg protein and a Kd of 383 +/- 67 pM. The pharmacology of the interaction of the ligand with the binding site yielded good correlation between the potency of various substances to complete for the binding site and their ability to act as antagonists of NMDA. Autoradiographs of thin coronal brain sections using (+)-3-[125I]-iodo-MK-801 yielded high quality images in 24-48 h with a distribution of binding sites paralleling that reported for the tritiated form of the ligand, i.e., with high densities in the hippocampus, cerebral cortex and lateral septum. Other areas with significant binding included parts of the thalamus, the amygdala and the olfactory tubercules. Furthermore, due to its high specific activity, this ligand lends itself to the study of regions not rich in MK-801 binding sites, such as the diencephalon.

Long-term changes in entorhinal-dentate evoked potentials induced by electroconvulsive shock seizures in rats

Entorhinal-dentate evoked potentials were measured in rats before and after: (1) eight electroconvulsive shock (ECS) seizures, or (2) matched handling. In animals that received ECS, evoked potentials were significantly enhanced, as evidenced by a long-lasting increase in the amplitude of the population spike. This increase in population-spike amplitude lasted for at least 3 months after the last ECS trial. No evoked-potential changes were observed in the subjects that received matched handling. These data suggest that ECS seizures produce long-lasting, perhaps permanent, changes in the brain.

The GABA Hypothesis of Kindling

The GABA hypothesis, as recently revised (6), may be stated as follows: “The kindling procedure causes a permanent change in some part of the GABA-A inhibitory system. This leads to a chronic tendency toward GABAergic hypofunction, and to all (or part) of the physiological abnormalities which characterize the ‘kindled state’.”

Amygdala-kindled and electroconvulsive seizures alter hippocampal expression of the m1 and m3 muscarinic cholinergic receptor genes

Expression of m1 and m3 muscarinic cholinergic receptors mRNAs was examined in rat hippocampus following either: (1) kindling to five Stage 5 amygdala-kindled seizures; or (2) eight electroconvulsive shock (ECS) seizures. Twenty-four hours after the last seizure of either type, there was a significant decrease in both m1 and m3 mRNAs in CA1, CA3 and the dentate gyrus subfields of the hippocampus. Twenty-eight days after the last seizure of either type, there was a significant increase in m1 mRNAs in CA1, CA3, and the dentate gyrus; for m3 mRNAs, there was a significant increase in CA3 28 days after the last ECS seizure, and in CA1 and CA3 28 days after the last kindled seizure. These results suggest that seizures alter the cholinergic system in the hippocampus, and that some of the alterations are very long-lasting.

Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat m1 and m3 muscarinic acetylcholine receptor genes

We investigated the gene expression responses using in situ hybridization with radiolabelled riboprobes for the m1 and m3 subtypes of muscarinic cholinergic receptors in the rat hippocampus following a brief (5-min) kainic acid-induced behavioral seizure. The kainic acid was intraperitoneally administered, and the ensuing generalized convulsive seizure terminated with diazepam. Our results demonstrate that the expression of the m1 subtype was significantly reduced in the CA1, CA3 and the dentate granule cells by 3 h after the administration of kainic acid while no significant change was observed in any hippocampal subfield for the m3 subtype. By 6 h post challenge, the m1 subtype was still decreased in all hippocampal subfields examined, while the m3 subtype remained unchanged from vehicle injected control. At 24 h post challenge, both the m1 and m3 subtypes were significantly reduced in the CA1 and CA3 subfields; the expression of the m1 subtype in the dentate granule cells, however, had recovered to levels indistinguishable from vehicle-injected control. These results demonstrate that epileptiform activity induced by kainic acid administration promotes alterations in the expression levels for both the m1 and m3 muscarinic receptor genes, and suggest that the activity of this neuromodulatory system in the hippocampus may be altered through activity-dependent mechanisms at early times following seizures.

Decreased voluntary ethanol selection in amygdala-kindled rats

Kindled and control rats were exposed to either ethanol or dextrose solutions in the limited access paradigm, a paradigm that allows access to the test solution for only 1 h each day. Limited access trials were initiated either 24 h or 30 days after the fifth stage 5 seizure had been elicited in the kindled subjects. As previously reported, increased voluntary ethanol selection was observed in the limited access paradigm. Kindled subjects, however, ingested significantly less ethanol than controls. This difference was found both when limited access trials were started 24 h after the last seizure and when they were started 30 days after the last seizure. Kindled and control subjects did not differ in their intake of dextrose solutions.

Kindling-Like Effects of Electroconvulsive Shock Seizures

Electroconvulsive therapy (ECT) was introduced into clinical practice in 19381. From 1940 to 1950 it was a mainstay of psychiatric inpatient therapy1,30,32. Its use declined in the 1950s due to the introduction of psychotropic drugs and to allegations of risk and abuse33. Since the 1980s, however, there has been a rebirth of interest in ECT, partly due to economic considerations, and partly to disenchantment with the tricyclic antidepressants1,33. In Canada, ECT is administered to about 11% of the hospitalized psychiatric population22.