What Can Genetic Models Tell Us About Attention-Deficit Hyperactivity Disorder (ADHD)?

Re: 0341: relating in vitro studies to functional effects

Vivienne Russell
russell@physio.uct.ac.za

On Mon Dec 14, Henry Szechtman wrote
------------------------------------
>Hi Vivienne, the question I have is one that often comes to mind when one tries to relate in vitro studies to behavioural effects - how can one show that the DA changes observed in the slice reflect the postulated behavioural dysfunction, here, ADHD? Why is it "dysfunction" rather than normal function of a compensated system? And why is it related to ADHD and not, for instance, to psychosis, depression, OCD or other DA-implicated disorders?
>henry

Hi Henry
Thank you for your interest. Your question is a good one. There are very serious limitations to extrapolation of results obtained with rat brains to the human situation. The problem is further compounded when one tries to interpret in vitro results. We have compared our in vitro findings in an animal model for ADHD, the spontaneously hypertensive rat (SHR),to its normotensive control rat (WKY). Any differences that we pick up between SHR and WKY are suggested to reflect in vivo differences. The simplest interpretation is to assume that a similar difference exists in vivo e.g. decreased evoked release of dopamine from mesocortical, mesolimbic and nigrostriatal terminals. We then speculate that these neurochemical differences between SHR and WKY might be related to behavioural differences between the two strains i.e. SHR's hyperactivity, impulsivity and inability to sustain attention as demonstrated by Terje Sagvolden in numerous experiments, (as well as their hypertension), relative to controls (WKY).

I agree with the second point that you raised. We are probably looking at normal function of a compensated system but the compensated system might not function normally in all situations and might have limitations which are only highlighted when appropriately challenged.

There is no simple answer to your third question. We tend to focus on the hypothesis being tested and interpret our results within a prescribed framework. We try to relate neurochemical differences between SHR and WKY to their behavioural differences and extrapolate these findings to ADHD because the behavioural differences between SHR and WKY resemble the core symptoms of ADHD - hyperactivity, impulsivity and inattention.

I am not sure that one can determine psychosis in a rat. One would have to establish a model for depression or OCD etc and then look at neurotransmitter differences between the test and control rats.

Thank you very much for your thought-provoking questions
- and thank you especially for organising this Web conference. I have benefited tremendously and also enjoyed it very much.

Wishing you all the best
Viv

Tue Dec 15