Agonism at mGluR2 receptors reduces dysfunctional checking on a rodent analogue of compulsive-like checking in obsessive compulsive disorder.

Abstract

Rationale: Obsessive-compulsive disorder (OCD) affects 1-3% of the population. Current therapies, including selective serotonin reuptake inhibitors, are not universally effective in managing OCD. Recent discoveries indicating hyperactivation of key regions within the corticostriatal thalamic circuitry that supports OCD, and alterations in the ratio of glutamate: GABA in regions such as the anterior cingulate cortex, suggest that drugs targeting glutamatergic signalling may be effective in reducing OCD symptoms.

Objectives: This study sought to determine whether two drugs targeting metabotropic glutamate receptors could reduce excessive checking behaviour in a rodent analogue of compulsive-like checking in OCD, the Observing Response Task (ORT).

Methods: Rats were trained on the ORT and separately classified on a pavlovian autoshaping task to identify the subpopulation of sign-trackers, which show higher levels of excessive checking. Once responding had stabilised, rats received systemic administration of different doses of the mGluR2 positive allosteric modulator AZD-8529 and its vehicle in a Latin square design, and the effects on ORT performance were assessed. Following completion of AZD-8529 dosing, a subset of rats received administration of different doses of the mGluR2/3 agonist LY404039 and its vehicle in a Latin square design, and ORT performance assessed.

Results: Both AZD-8529 and LY404039 produced dose-dependent reductions in checking behaviour, including at doses that did not impair generalised measures of task performance.

Conclusions: The similarity in effect of AZD-8529 and LY404039 suggests that the capacity of these drugs to reduce checking is mediated by mGluR2s, which may provide a promising target for future treatment development for OCD.