Related Experiment Video
Updated: May 16, 2025
Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder
Published on: January 9, 2015
Agonism at mGluR2 receptors reduces dysfunctional checking on a rodent analogue of compulsive-like checking in
Colin McKenzie1, Bart Sloot2, Felippe Espinelli Amorim1
1Department of Psychology, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
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.
Insights
New drugs targeting metabotropic glutamate receptors (mGluR2) significantly reduced compulsive checking behaviors in a rodent model of obsessive-compulsive disorder (OCD). These findings suggest mGluR2s as a promising therapeutic target for OCD treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Obsessive-compulsive disorder (OCD) affects 1-3% of the population, with current treatments like SSRIs showing variable efficacy.
- Hyperactivation in corticostriatal thalamic circuitry and altered glutamate: GABA ratios in OCD suggest glutamatergic signaling as a potential therapeutic target.
Purpose of the Study:
- To investigate the efficacy of two drugs targeting metabotropic glutamate receptors (mGluRs) in reducing compulsive-like checking behavior.
- To assess the effects of an mGluR2 positive allosteric modulator (AZD-8529) and an mGluR2/3 agonist (LY404039) on the Observing Response Task (ORT) in rodents.
Main Methods:
- Rats were trained on the ORT, with a subset identified as sign-trackers exhibiting higher checking behavior.
- Systemic administration of varying doses of AZD-8529 or LY404039 and their respective vehicles were performed using a Latin square design.
- Effects on ORT performance were assessed to determine drug efficacy and specificity.
Main Results:
- Both AZD-8529 and LY404039 demonstrated dose-dependent reductions in checking behavior.
- These reductions were observed at doses that did not impair generalized measures of task performance, indicating specificity.
Conclusions:
- The similar effects of AZD-8529 and LY404039 suggest that mGluR2s mediate the reduction in checking behavior.
- Targeting mGluR2s represents a promising avenue for the development of novel pharmacological treatments for OCD.
