Abstract
Background: Our previous studies show that withdrawal from prior D2 antagonist treatment interferes with the ability of novel target compounds to reverse the hyperresponsive state of the DA system in the methylazoxymethanol acetate (MAM) model of schizophrenia; therefore we tested whether pomaglumetad methionil, which showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, impacted the hyperdopaminergic state
Methods: MAM and SAL rats were treated with pomaglumetad methionil (1, 3, 10 mg/kg, i.p) or 1 mg/kg saline 30 minutes prior to anesthetized in vivo electrophysiological recordings. The population activity of DA neurons in the VTA was measured by passing an electrode in a preset pattern and counting the number of spontaneously firing DA neurons, and analyzing their firing rate and bursting activity. Normal rats received 3 mg/kg pomaglumetad methionil or 1 ml/kg saline 30 minutes prior to 2 hours restraint in Plexiglas cylinders. Control rats remained in their home cage for an equivalent duration. Electrophysiological recordings of DA neuron in the VTA were preformed immediately following the 2-hour session.
Results: Pomaglumetad methionil dose-dependently reduced the number of spontaneously active DA neurons in the VTA of MAM rats and this effect was not observed in SAL rats. Activating DA neurons via acute restraint stress, which like MAM also caused a hippocampal-dependent increase in spontaneous DA neuron activity in the VTA of normal rats, was also normalized in pomaglumetad-treated rats.
Conclusion: Pomaglumetad methionil reduced hyperdopaminergic activity in MAM rats and blocked a stress-induced increase in DA neuron activity in normal rats, suggesting that it can indirectly regulate DA neuron activity, which may contribute to its potential therapeutic effects.