Sex Differences Distinguish Intracortical Glutamate Receptor-Mediated Regulation of Extracellular Dopamine Levels in the Prefrontal Cortex of Adult Rats

Abstract

Executive functions of the prefrontal cortex (PFC) are sensitive to local dopamine (DA) levels. Although sex differences distinguish these functions and their dysfunction in disease, the basis for this is unknown. We asked whether sex differences might result from dimorphisms in the glutamatergic mechanisms that regulate PFC DA levels. Using antagonists selective for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, we compared drug effects on in vivo microdialysis DA measurements in the PFC of adult male and female rats. We found that baseline DA levels were similar across sex, AMPA antagonism decreased PFC DA in both sexes, and NMDA antagonism increased DA in males but decreased DA in females. We also found that, at subseizure-producing drug levels, γ-aminobutyric acid (GABA)-A antagonism did not affect DA in either sex but that GABA-B antagonism transiently increased PFC DA in both sexes, albeit more so in females. Finally, when NMDA antagonism was coincident with GABA-B antagonism, PFC DA levels in males responded as if to GABA-B antagonism alone, whereas in females, DA effects mirrored those induced by NMDA antagonism. Taken together, these data suggest commonalities and fundamental differences in the intracortical amino acid transmitter mechanisms that regulate DA homeostasis in the male and female rat PFCs.

Keywords: NMDA-R hypofunction; Schizophrenia; hyperdopaminergia; hypodopaminergia.