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Task-Specific Effects of mGlu2/3 Receptor Agonist LY379268 on MK-801-Induced Behavioral and Neural Dysfunctions in
K Hruza1, D Cernotova, K Maleninska
1Laboratory of the Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic david.levcik@fgu.cas.cz.
Abstract:
NMDA receptor hypofunction can lead to behavioral and cognitive disturbances, including hyperlocomotion, and is considered a core pathophysiological mechanism underlying cognitive and negative symptoms in schizophrenia. This study examined whether treatment with the mGlu2/3 receptor agonist LY379268 (1 and 2 mg/kg) could counteract such disruptions induced by the NMDA antagonist MK-801 (0.1 mg/kg). Rats were tested under two conditions: an aversive learning task (active place avoidance on a rotating arena) and a non-aversive open field test. Additionally, local field potentials were recorded from the medial prefrontal cortex during the open field test and later under urethane anesthesia. Contrary to expectations, LY379268 did not consistently alleviate MK-801-induced impairments. In the aversive learning context, the combination of MK-801 with LY379268 (2 mg/kg) paradoxically led to exacerbated hyperlocomotion and impaired navigational performance. In contrast, the 1 mg/kg dose of LY379268 had a modest beneficial effect in the non-aversive setting, slightly reducing MK-801-induced hyperactivity. Electrophysiological recordings revealed that MK-801, alone or in combination with LY379268 (1 mg/kg), disrupted theta-high gamma phase-amplitude coupling in the open field test, indicating impaired neural processing. Under anesthesia, MK-801 increased low gamma power. LY379268 did not reverse this alteration. These findings highlight the task- and dose-dependent nature of LY379268's effects. While it offered limited improvement in a non-aversive environment, it failed to mitigate and sometimes exacerbated deficits in more challenging, aversive tasks. This complexity underscores the need for further research to refine the therapeutic potential of mGlu2/3 modulation in conditions associated with glutamatergic dysfunction. Key words MK-801 " LY379268 " Electrophysiology " Medial prefrontal cortex " Hyperlocomotion.
Insights
The mGlu2/3 agonist LY379268 did not consistently reverse NMDA receptor antagonist MK-801-induced deficits in rats. Higher doses exacerbated impairments in aversive tasks, while lower doses showed modest benefits in non-aversive settings.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- NMDA receptor hypofunction is linked to schizophrenia symptoms like hyperlocomotion and cognitive deficits.
- Targeting metabotropic glutamate 2/3 (mGlu2/3) receptors is a potential therapeutic strategy for glutamatergic dysfunction.
Purpose of the Study:
- To investigate if the mGlu2/3 agonist LY379268 can counteract behavioral and neural disruptions induced by the NMDA antagonist MK-801.
- To assess the effects of LY379268 on MK-801-induced impairments in both aversive and non-aversive behavioral tasks and medial prefrontal cortex electrophysiology.
Main Methods:
- Rats were administered MK-801 (0.1 mg/kg) alone or in combination with LY379268 (1 and 2 mg/kg).
- Behavioral testing included an active place avoidance task (aversive learning) and an open field test (non-aversive).
- Local field potentials were recorded from the medial prefrontal cortex during behavioral tasks and under anesthesia.
Main Results:
- LY379268 did not consistently alleviate MK-801-induced impairments; higher doses (2 mg/kg) paradoxically worsened hyperlocomotion and navigation in the aversive task.
- The lower dose (1 mg/kg) of LY379268 showed a modest reduction in MK-801-induced hyperactivity in the non-aversive open field test.
- Electrophysiology revealed MK-801 disrupted theta-high gamma phase-amplitude coupling and increased low gamma power, effects not reversed by LY379268.
Conclusions:
- The effects of LY379268 are task- and dose-dependent, failing to mitigate or sometimes exacerbating deficits in challenging aversive tasks.
- These findings suggest limited therapeutic potential for mGlu2/3 modulation with LY379268 in conditions mimicking glutamatergic dysfunction.
- Further research is needed to refine strategies for mGlu2/3 modulation in neuropsychiatric disorders.
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