Neuropharmacology Poster Session

Re^3: Poster 693

James Churchill

On Wed Dec 9, grover wrote
>Dr, Churchill
>  I have to admit that I did not understand this answer.

I will dissect my comments, point by point:

>On Wed Dec 9, James Churchill wrote

>>We view the fact that the rats used in this study were "normal" (at least as normal as an albino, lab rat can be) as incidental.  We are specifically evaluating the effects of these in the absence of such confounds as a seizure.

The first point is that by definition, albino rats are not normal.  Moreover, as is certainly the case with many animal colonies, the breeding patterns are not ideal.  However, that said, the design of the experiment was such that we are investigating the behavioral effects of maintenance on these drugs in isolation of other factors that would certainly influence performance (e.g., seizures).  By using an animal who has experienced seizures, we would be in a compromised position to make any claims about what, exactly, caused the observed deficits.

>>The fact is that antiepileptic compounds are used to treat a number of disorders, not all being seizure-related and that even when epilepsy is the disorder targeted, seizure frequency is not overly prevelant in many cases.

While antiepileptic drugs are the primary treatment route for most seizure-like disorders (epilepsy), these drugs are also used to treat a number of other disorders that in which seizures are not a phenotypical symptom.  Moreover, pharmacologic intervention is often the first treatment strategy utilized when "seizure-like activity" is initially observed.  Often-times, these medications are continued for extended periods of time, without ever observing symptoms that resemble seizure activity again.  Clearly, the control of seizure activity is paramount for both the physician and the patient.  However, our data (this poster and others that have been published) support the contention that these drugs produce differential effects and as such, our goal is to further elucidate the deficits that these compounds produce, relative to one another.

>>Moreover, an abundance of seizure-models exist that don't necessarily mimic the disorder observed in humans and the mere presence of seizures has been shown to be related to cognitive deficits.

There is a wealth of literature that debates which animal model best resembles human seizure activity.  It is not our intention to address those issues as we do not view any one of those models as particularly better than any of the others.  Even so, the use of animals who have expressed a history of seizures makes the interpretation of these data difficult to accomplish.  Consider the following: 1) The loci of many seizure disorders has been vaguely defined as presiding within the medial temporal lobe or frontal cortex.  2) The hippocampal complex, in particular, has been repeatedly implicated in such disorders.  3) Both the duration and severity of seizures can produce pathological alterations in brain structures such as the hippocampus.  Lesions to the hippocampus have been shown to produce deficits in animals performing inthe Morris water maze (the task we used in this study).  Therefore, if we had used a seizure model and treated animals with these compounds to control seizure activity, would the results we observed be due to the drugs or to the pathological changes brought about by the seizures themselves?  We would expect even control animals to express difficulty in mastering this task if pathology exists.

>>Finally, regardless of the seizure model used, it seems reasonable to assume that these drugs would produce comparable effects to those observed in "normal" rats.

We target the blood-plasma levels of these compounds that are frequently used in the treatement of epilepsy in humans.  Therefore, it is not so much a matter of whether the subject has experienced seizures or not, but that the doses we use are comparable to that used in humans.  In fact, the plasma levels observed in these rats frequently are far below that desired in humans as toxicity issues become a problem in administering appropriate doses to these animals.

[ Previous ] [ Next ] [ Index ]           Thu Dec 10