Animal Models In Ts

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Animal models are core to furthering our understanding in that they

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a)develop new treatments and b) to uncover pathgenesis

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Paragraphs

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1. Motor tics induced by GABA

2. McCairn et al (2009)

3. DA model of TS

4. Despite indistinct role of DA, has been shown to be useful in modelling PU

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Bronfield et al (2011)

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microinjection of GABA into the striatum ofrats and monkeys causes the expression of repetitive behaviours in animals thatresembles tic’s. Theese tic’s are associated with strong activation of striatalprojection neurons (MSN’s) indicating reduced specificity. The increasedactivation of MSN’s in response to GABA antagonism leads to disinhibition ofthe cortex, and hence the expression of tic like behaviours. This modelstrongly links GABA dysfunction in the BG to the cause of tics.- In both rats and monkeys thetic like behaviour appeared after a couple of minutes and disappeared after 2hours. The tic like behaviour was highly localised to distinct muscle groups.

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McCairn et al (2009)

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injected bisculline into the putamen ofmonkeys and found that sudden, rapid, brief flexion of the contralateral limb,and orofacial contractions appeared. These behaviours bear a phenomenologicalresemblance to tics as in humans primary site are arms and face. è Furthermore, it was found that administration of antipsychotic drugsblocked these effects, just as we see in humans. è This increases predictive validity of the model and extends theusefulness in understanding human TS.

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Grabli et al (2004)

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Although microinjection into the motor partof the striatum presents motor tics, it was found that if the injection sitevaried slightly, for example entered the limbic or associative loop segments ofthe striatum, then different behaviours that resembled comorbidities wouldoccur.è The relationship between the localization of microinjection sitesand the type of behavioural effect was similar for the three monkeysBUT - Not only further evidence for a central role of GABA buthighlights a shared underlying pathophysiology of comorbid disorders, again,this is common in those with TS so being able to model such comorbidities soeasily gives further weight to the model. è Microinjection may damage structures above area its being injectedinto and damage area of injection. Only way to get specific area targeted atmthough, perhaps more advanced methods such as optogenetics may be a promisingroute in the future.

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Bronfield et al (2011)

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much of the work into the DA hypothesisstems from the fact that DA antagonists can cause a 60-80% recuction in tics.They usefulness of these clinically is limited due to side effects but from aresearch point of view this is very interesting.

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Randrup (1963)

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early evidence suggests that systemicadministration of DA agonist (amphetamine) induced stereotypic behaviors suchas sniffing, licking or biting and these could be relieved with a DAantagonist. However, systemic administration does not tell us exactly where thedrug is having the main effect. Although we know many of the brains D2receptors are in the striatum, cannot rule out the possibility that it ishaving effects elsewhere, so do not knw precise locations or amount going toregions of interest.z

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Bronfield et al (2011)

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Animal studies on DA show that there is aspecific involvement of the limbic circuit. When amphetamine microinjectionsare given to the limbic part of the striatum can see oral stereotypies whichcannot be seen when given to the other parts of the stritim. This suggests thatperhaps dopamine’s main role is linked to the non-motor symptoms of TS?Whilst DA models fail to elicit tic likemovement they do induce stereotypic behaviour and hyperactivity. Both of theserelated to comorbidities so it is deffo linked. BUT no directly linked to TSspecifically.

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PU’s are thought to arise from dysfunctionin

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sensiomotor gating (SMG).

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Oneway we can measure sensiomotor gating in animals is through

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. A failure of the weak pre-stimulus toreduce the magnitude of the startle response to the ensuing strong stimulus isregarded as a deficient PPI response indicating a sensorimotor deficit

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Swerdlow et al (2001)

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indicate that D2 agonists regulateresponses to PPI in rats. Too much dopamine for example in the case ofschizophrenia causes PPI deficits. Dopamine agonists have also been shown toinduce PPI deficits in humans however this is extremely dose dependant.HOWEVER;- PPI deficits can be induced bya number of neuromodulators and therefore it is unclear which neural pathway isassociated with PPI deficits observed in TS patients.- Furthermore it is not unique toTS and therefore makes it impossible to rely on this symptoms as a validatingfactor.

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Conclusion

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TS lies between two large domains ofneuropsychiatric and hyperkinetic disorder. Primary symptoms of motor ticswould lead to the classification as a movement disorder and the premonitoryurges and comorbidities would place it in psychiatric spectrum. Animal modelsmirror this dichotomy – different models focus on different parts of thedisorder.