LY-404039

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.

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).

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.

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

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.

We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR₂) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR_2/3) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR_2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR₂ positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR₂ positive allosteric modulation and combined mGluR_2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.