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Peripubertal mGluR2/3 Agonist Treatment Prevents Hippocampal Dysfunction and Dopamine System Hyperactivity in
Susan F Sonnenschein1, Anthony A Grace2
1Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
Abstract:
Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31-40. In either late adolescence (PD 47-56) or adulthood (PD 83-96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats.
Insights
Pomaglumetad methionil (POM) may prevent dopamine system dysfunction in a schizophrenia model. Early POM treatment normalized brain activity and improved recognition memory in adult rats, suggesting potential for early intervention.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists like pomaglumetad methionil (POM) show preclinical antipsychotic promise.
- Clinical trials of POM yielded mixed results, but efficacy in early-stage disease is hypothesized.
Purpose of the Study:
- To investigate POM's potential to prevent dopamine (DA) system dysfunction in the methyazoxymethanol acetate (MAM) rat model of schizophrenia.
- To assess POM's effects on cognitive function and neural activity in a model of psychosis.
Main Methods:
- MAM and control (SAL) rats received POM, vehicle, or no injection during postnatal days 31-40.
- Novel object recognition (NOR) testing was conducted in late adolescence and adulthood.
- In vivo electrophysiological recordings assessed ventral tegmental area (VTA) DA neuron and ventral hippocampal (vHPC) pyramidal neuron activity.
Main Results:
- POM-treated MAM rats showed improved NOR in adulthood compared to untreated MAM rats.
- POM administration normalized VTA DA neuron and vHPC pyramidal neuron activity in MAM rats.
- No significant effects were observed in SAL rats across treatment groups.
Conclusions:
- Peripubertal administration of mGluR2/3 agonist POM can prevent the development of hyperactivity in vHPC pyramidal neurons and increased DA neuron activity in adult MAM rats.
- These findings suggest POM's potential as an early intervention to normalize neurobiological abnormalities in schizophrenia models.
