D1 receptor antagonist-induced long-term depression in the medial prefrontal cortex of rat,in vivo: an animal model of psychiatric hypofrontality

Abstract

The objective of the following experiment was to induce a pathogenic hypofrontal condition by administering a dopamine-1 receptor (D₁R) antagonist to rats. The pathophysiological effect of this manipulation upon glutamate-based long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) was examined in vivo. Subjects were surgically implanted with stimulating electrodes into the corpus callosum and recording electrodes into the mPFC. High-frequency stimulation (HFS) was combined with the administration of the selective D₁R family agonist A68930 hydrochloride (0.4 mg/kg/mL) and the selective D₁R family antagonist SKF 83566 (0.15 mg/kg/mL). The administration of SKF 83566 hydrobromide prevented mPFC LTP, and resulted in HFS-induced long-term depression. This indicates that D₁R activation is necessary for the induction of mPFC glutamate-based LTP. This is supported by our finding that the administration of A68930 hydrochloride combined with HFS induced LTP comparable with saline control levels, suggesting that D₁R activation is necessary for the induction of baseline levels of mPFC LTP. Given that the mPFC governs executive behaviours that are subserved by LTP, such as working memory, these findings are relevant for the study of psychopathological conditions in which hypodopaminergic conditions exist in the mPFC and are correlated with psychiatric symptomotology, such as drug addiction and schizophrenia.