Understanding compulsive behaviour in psychiatric disorders with a touchscreen rodent model of reversal learning

Behaviour is considered to be compulsive when it is performed automatically regardless of whether it results in deleterious consequences. Although most prominently associated with obsessive-compulsive disorder, compulsivity is also present in a host of other psychiatric disorders and likely represents a trans-diagnostic trait with shared dysfunctional circuitry (Gillan et al., 2016a). Despite this, no single treatment shows anticompulsive efficacy across disorders, and disorder-specific treatments are not particularly efficacious either (Grant et al., 2016). This may be because different circuitry parameters are disrupted in different disorders, but result in similar behavioural outcomes, therefore a treatment targeting one parameter will not alleviate dysfunction caused by alterations in a different parameter. This thesis investigates the circuitry of compulsivity by administering drugs that differentially target these parameters to rats undergoing associative learning tasks shown to be dependent on this neural circuitry. We found that the acute administration of phencyclidine – a drug which models the psychotic state (by blocking NMDA receptors; Rafter et al., 2016) – promoted compulsive approach towards a formerly rewarded stimulus but not compulsive avoidance to a formerly unrewarded stimulus. We also found that administration of this drug to neonatal pups in combination with adolescent social isolation led to the opposite effect, that is, reduced compulsive approach towards a formerly rewarded stimulus once it became unrewarded. Administration of a serotonin 5-HT2C receptor antagonist (a putative anti-compulsive agent) had no effect on choices but accelerated the speed of responding. Meanwhile intra-orbitofrontal cortex infusion of the dopamine neurotoxin 6-hydroxydopamine or the serotonin neurotoxin 5,7-dihydroxytryptamine failed to reliably induce neurotransmitter depletion, and subsequently had no effect on any behavioural measure. These findings suggest that targeting glutamate systems upstream of dopamine and serotonin systems may result in better treatment outcomes for compulsivity driven by formerly reinforced associations, e.g. in delusions, behavioural addictions, and drug addiction