mCPP modulates compulsive checking behaviour in rats: Neurobiological and behavioural correlates of a potential role for serotonergic stimulation in the quinpirole sensitization model of obsessive-compulsive disorder (OCD)

Abstract

The 5-HT agonist drug mCPP contributed to a 5-HT hypothesis of obsessive-compulsive disorder (OCD), but the effects of the drug in human and animal studies have been inconsistent. The objective of this thesis was to shed light on the behavioural and neurobiological effects of mCPP using the quinpirole sensitization rat model of OCD and in a reciprocal manner, to use the drug to further reveal behavioural and neurobiological components of the animal model. The utility in using the quinpirole model is that the process of analysis by experimentation can be employed to observe effects of the drug on three separate behavioural components identified to underlie the model compulsive behaviour: vigor, focus and satiety. Four original studies were designed to address this objective, and the findings yielded novel contributions to the literature. We suggest that mCPP attenuates compulsive checking by attenuating the exacerbated vigor and satiety characteristic of compulsive behavior, but this effect may not have been captured in previous clinical studies because OCD was measured as a unitary phenomenon across different symptom subtypes. We also reveal that separate systems underlie the development and performance of compulsive behaviour in the animal model, and mCPP reduces its performance but not its development. Hence, the animal model findings suggest that mCPP can attenuate performance of OCD behavior but the drug does not reverse the pathology of OCD or arrest the pathogenesis of OCD. Neurobiologically, we hypothesize that the underlying mechanism mediating the response to mCPP is mediated downstream of the nucleus accumbens core (NAc), at the substantia nigra pars reticulata, based on the finding that the effects of mCPP on vigor and satiety are present in NAc lesioned animals. Finally, although findings of this thesis indicate that 5-HT2A/C receptors do not mediate the response to mCPP, an oppositional role for DA and 5-HT on the model of compulsive behaviour is proposed, consistent with a security motivation theory of OCD. Overall, this thesis shed new light on the effects of mCPP on OCD, and reveals novel neurobiological and behavioural correlates of the quinpirole model.