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
jgutierrez@psi.ub.es


 

Modelos animales de la depresión. Tetrabenazine
Fuente: Biological Bases of Behavior (http://salmon.psy.plym.ac.uk/year1/bbb97.htm)


 

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).
Response rate declines dramatically about 25 min after injection of the drug.

 the effects of 2.0 mg/kg TBZ


The next set of cumulative records shows the protective effects of iproniazid - a monoamine oxidase inhibitor (MAOI) - against tetrabenazine. Note how response rate is actually increased following pretreatment with iproniazid and tetrabenazine. This effect is outlined in red on the diagram.

 pretreatment with iproniazid before tetrabenazine

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.
The next slide shows the effect of injection the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) on responding in MAOI+TBZ treated animals.
Note how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the AMPT injection.

 the effect of alpha-methyl-para-tyrosine (AMPT) on responding in MAOI+TBZ treated animals
This result tells us that one of the CAs - dopamine or noradrenalin - is involved in this effect. But which catecholamine: DA or NA?
The next slide shows the effect of injection the dopamine-beta- hydroxylase inhibitor, disulphiram on responding in MAOI+TBZ treated animals.


the effect of disulphiram on responding in MAOI+TBZ treated animals


Note once again how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the disulphiram injection. This result suggests that NA is responsible for the behavioural excitation following MAOI treatment.

Tetrabenazine and imipramine

At 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.
This effect is illustrated in the next diagram. The late period of excitation is outlined in red.


Tetrabenazine and imipramine


Point to ponder: From what you know about the mode of action of tricyclics and MAOIs, can you think of an explanation of these drugs' interactions with TBZ?

Summary of TBZ antagonism studies

Here is a summary of the current state of our slightly battered animal model of human depression.

 

  Antagonism of tetrabenazine at
Antidepressant group 0.2 mg/kg 2.0 mg/kg
Tricyclics Yes No
MAOIs No Yes

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.