The neural and neurochemical basis of compulsivity in humans and other animals. (360G-Wellcome-089589_Z_09_Z)

The proposed Programme will investigate the neural and neurochemical substrates of compulsive behaviour in animals and in patients with obsessive-compulsive disorder (OCD). We argue that this cross-species approach will enable an analysis of the nature of the compulsivity (the tendency to perseverate in responding in the face of adverse consequences) and how it is mediated by fronto-striatal circuitry, modulated by monoaminergic systems. We hypothesise that compulsivity arises from core c ontributions from specific forms of executive dyscontrol, aberrant habit learning and anxiety, leading to such typical OCD symptoms as checking, illusory control, failure to complete , and harm avoidance. We will assess the particular role of two major fronto-striatal circuits in compulsive behaviour, and their modulation by 5-hydroxytryptamine (5-HT), dopamine and noradrenaline neurotransmitter systems, with implications for understanding current and future drug therapies. These circuits are o rbitofrontal cortex-medial striatum, and also a lateral prefrontal cortex-associative striatal circuit. This translational approach will allow us to gain further insight into the therapeutic effects of selective 5-HT agents in OCD. We maintain that OCD and its comparison with other disorders, such as adult Attention Deficit Hyperactivity Disorder, will also afford us an enhanced understanding of the executive functions of the frontal lobes.