U n i v e r s i d a d d e B a r c e l o n a |
Departamento de Personalidad, Evaluación y Tratamientos Psicológicos |
Cursos asistidos por ordenador a través de i n t e r n
e t |
Modelos animales
de la depresión. Tetrabenazine
Tetrabenazine: An animal model of depression?Tetrabenazine (TBZ) depletes catecholamines (NA & DA) and was used to test the Catecholamine Theory of Mood. The picture below illustrates the effects of tetrabenazine on the avoidance behaviour of a rat trained to avoid electric shock on a Sidman avoidance schedule. Compare control (A-1,A-2) performance (steady response rate) with the effects of
2.0 mg/kg TBZ (B1-B3).
These results were reported by G.A. Heise and E. Boff (1960) J.pharmacol. exper.
Therap., 129, 155-161, and are described by David Warburton in his book Brain
Behaviour and Drugs, Wiley, 1975. We can now use some of our knowledge about CA
synthesis and the drugs that affect it, to test the hypothesis that CAs are responsible
for the short period of behavioural excitation following TBZ injection in rats pretreated
with a MAOI.
Tetrabenazine and imipramineAt this point in the story you might think we have succeeded in producing a pretty good
animal model of human depression that could be used to test novel drugs for antidepressant
potential. The logic would be that if a new drug reversed the disruption of conditioned
avoidance behaviour produced by 2.0 mg/kg TBZ then it would be a potential candidate for
clinical trials in humans. But there is a sting in the tail of this story. The first thing
we need to do is ask whether other antidepressant drugs reverse TBZ-induced behavioural
disruption in our rat model. We already know that tricyclic drugs such as imipramine are
effective antidepressants. Unfortunately imipramine does not antagonise the effects of 2.0
mg/kg TBZ. But imipramine does interact with TBZ in an interesting way. A very low dose of
TBZ (0.2 mg/kg) on its own does not interfere with conditioned avoidance behaviour. When
this low dose of TBZ is given in comination with imipramine, a period of behavioural
excitation is seen - but not until 2.25 hours after the TBZ injection.
Summary of TBZ antagonism studiesHere is a summary of the current state of our slightly battered animal model of human depression.
That's as far as we can take this story this year of the 'ups and downs' encountered when trying to construct simple models of complex human emotional states. One obvious problem with this model is the issue of theraputic-lag. It been known for some time that the antidepressant effects of drugs like imipramine take some time to develop - typically 21 days or more. This is clearly at variance with the rapid changes of behaviour seen in the animal model we examined. But don't get too depressed. Bear in mind that I am not aiming to give you 'cut and dried' answers to the biology of depression. Instead, I am trying to introduce you to a way of exploring possibilities in a scientific manner. At the end of the day there are no clear-cut answers. We have some good clues to what is going on, but the truth - whatever that is - eludes us. This is what makes it an exciting research area! The research I have described was carried out some time ago and there have been significant changes in our theoretical understanding of depression at a biological level.
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