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Stopping and checking of OCD: How can we translate impulsive and compulsive control from rats to humans?

 

Research Seminar at the University of Reading, 21/03/2013

Speaker: Dawn Eagle, University of Cambridge

This presentation advocated using rodent models to investigate impulsive and compulsive disorders, such as obsessive-compulsive-disorder (OCD) and attention-deficit-hyperactivity disorder (ADHD). The focus was on cognitive modelling, which uses behavioural features of disorders. In this case: stopping and checking behaviours.

Firstly, stopping behaviour is modelled in rats using the stop-signal task (SST), which measures the ability to inhibit a response once a signal to stop has been given. In example, rats will press one of two leavers to gain rewards; on 20% of trials there is a stop-signal telling the rat it has to stop pressing to get its reward. Impaired ability to stop is measured because stop-signal-reaction-time (SSRT) cannot be measured directly; the longer the SSRT the less likely a response will be inhibited.

Human studies show a positive correlation between frontal basal ganglia (FBG) lesions and impaired SSRT. From such studies it is not possible to know if this is a causal relationship. To investigate, focal bilateral brain lesions were induced in rats and SSRT was measured. Results showed that lesions in the cingulated cortex, orbital cortex and FBG produce slowing in SSRT, but lesions in the medial cortex have no effect; indicating regional differentiation of control over stopping.

In the pharmacological model Atomoxetine, a serotonin-norepinephrine-reuptake-inhibitor (SNRI), improves SSRT in humans. To see if this was causal rats were given Atomoxetine and completed SST and go/no-go task. SSRT increased with Atomoxetine-treatment. This experiment was repeated with Atomoxetine directly administered into the: cingulated cortex or orbital frontal cortex (OFC). No effect in the former but in the latter SSRT improved. Suggesting the OFC may have functional equivalence in humans.

Another SRI, serotonin-selective-reuptake-inhibitors (SSRI) treats OCD but serotonin depletion has no effect on SSRT. To understand this, two forms of behavioural inhibition: ability to wait and SSRT were measured in rats performing the SST. Results revealed that serotonin depletion impaired only waiting ability, while SSRT was sensitive to the dopamine precursor norepinephrine.

Secondly, OCD patients often report intolerance of uncertainty indicating that compulsive checking behaviour is a way of gaining information. To investigate further, rats treated with Quinpirole, dopamine-receptor D2 (DRD2) antagonist, were given the task: When a light shone above one of two leavers, if pressed a reward would be given. The light would change either on a predictable or non-predictable time schedule. If given a third leaver, ‘the observing-leaver’, which when pressed shows a light above the reward leaver. Predictions were (1) Quinpirole, should induce checking behaviour in a selective manner (2) Leaver pressing will increase as uncertainty increases (3) Rats will press the observing-leaver for information; not in a non-functional way. All three predictions were met. Only Quinpirole-treated rats checked more when the schedule became unpredictable. Non-functional checking increased until the Quinpirole-treatment wore off. Furthermore, an equivalent task has been designed for people, and preliminary data is showing comparable results.

However, in another study DRD1 antagonist treatment improved SSRT; thus indicating dopamine receptor variation for the control of SSRT. The presentation concluded that rodent models of neuropsychological are useful in human studies.

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