500. Restoring excitatory/inhibitory balance in OCD; the mGluR2 receptor approach

Abstract

Abstract Background Converging evidence shows overactivity in cortical regions such as the anterior cingulate cortex (ACC) in obsessive-compulsive disorder (OCD), including evidence of increased BOLD activity in cortical structures such as the ACC, orbitofrontal cortex and supplementary motor area (SMA), enhanced error-related negativity, and therapeutic effects of cingulotomy in patients with severe symptoms. Such overactivity may depend on an exaggerated cortical excitatory:inhibitory balance reflected in glutamatergic/GABA ratios, and consistent with recent genetic evidence. We recently showed using 7-Tesla proton magnetic resonance spectroscopy that OCD patients exhibited elevated levels of glutamate and reduced levels of GABA in the ACC of adult patients with OCD, which correlated with a disposition towards greater habitual control over responding1. Related evidence in the same study also indicated relationships of glutamate levels in the SMA with OCD symptom severity and scores on the Obsessive-Compulsive Inventory. Aims & Objectives Consequently, we have pursued a therapeutic strategy based on mGluR2 PAM agonists which pre-synaptically reduce glutamate release in active neurons. We report here some preliminary evidence in two novel translational animal models in support of this strategy, both based on behavioural tests used to show deficits in OCD. Method (i) Rats were trained on a decision-making task measuring the tendency to check future outcomes in a subgroup exhibiting excessive checking behaviour. Rats received systemic administration of different doses of the mGluR2 positive allosteric modulator AZ-D8529 and the mGluR2/3 agonist LY-404039 and their vehicles in Latin square designs2. (ii) Marmoset monkeys performed a contingency degradation test that measures the balance between habitual and goal-directed behaviour by degrading the coupling between actions and their outcomes. Performance on this test has been shown to depend on the dorsal ACC in this species and in OCD patients. They received chemogenetic activation of the orbitofrontal cortex (area A11) using excitatory DREADDs, to excite ACC and striatal outflow, and then in combination with systemic AZ-D8529, to reverse this over-activation. Results (i) In the rat checking paradigm, both AZ-D8529 and LY-404039 produced dose-dependent reductions in excessive checking behaviour, including at doses that did not impair generalised measures of task performance. (ii) In the marmoset contingency degradation test, activation of the A11 DREADDs by the designer drug deschloroclozapine produced persistent instrumental responding under contingency degradation, indicating habitual control. This persistent responding was dose-dependently reduced by AZD-8529, confirming the involvement of glutamate receptors. Discussion & Conclusions These preliminary results show that compulsive-like behaviours indicating excessive responding in an habitual mode are selectively reduced by mGluR2 agonists in two animal models based on neural and psychological features of OCD. They provide promise for more effective treatment of this often severe and disabling disorder that represents a major clinical need. 1. Biria M et al (2023) Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls. Nat Commun. 14:3324. 2. McKenzie C. et al (2025) Agonism at mGluR2 receptors reduces dysfunctional checking on a rodent analogue of compulsive-like checking in obsessive compulsive disorder. Psychopharmacology 242:1893-1907.