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During reproductive maturation, characteristic changes occur in the morphology of the gonadotropin releasing hormone (GnRH) cell population within the hypothalamus. In the early stages of development, GnRH neurons are bipolar cells; however, just before pubertal onset, the majority of these neurons transform into unipolar cells. Our laboratory has reported that valproic acid (VPA), an antiepileptic medication that has previously been shown to slow the velocity of pubertal development in both humans and seizure-prone mice, is capable of delaying the normal process of GnRH morphological differentiation. As VPA is primarily believed to act via a GABAergic mechanism, the present study investigated potential influences of VPA on GnRH-GABA interactions within the medial preoptic area (mPOA) across pubertal development (experiment 1), as well as in adult animals (experiment 2). The results from experiment 1 revealed the expected drug effects on GnRH cell morphology. For VPA animals, there was a greater percentage of bipolar neurons at every time period except for the 24-day sample. Additionally, VPA animals had greater numbers of bipolar and unipolar GnRH neurons with GABA associations across all ages. However, experiment 2 showed a lack of drug effects on GnRH-GABA interactions in adulthood. These results suggest that VPA may delay GnRH cell morphological maturation by altering the density of GABAergic inputs to GnRH neurons. These inputs may normally play a role in timing the activation of the GnRH pulse generator. However, any neuroendocrine effects of VPA in adulthood are most likely due to the actions of VPA at another level of the hypothalamic-pituitary-gonadal axis.

Sodium valproic acid (VPA) is a widely prescribed anticonvulsant medication that has been shown to interfere with pubertal maturation of the reproductive system, and induce endocrine abnormalities in adults, within a subset of the clinical population. While VPA's mechanism of action is still poorly understood, it may exert its anti-reproductive effects by enhancing GABAergic inhibition of the GnRH neuronal population within the medial preoptic area (mPOA). The purpose of this study was to determine if chronic administration of VPA alters GABA levels within the mPOA region. In Experiment 1, the mPOA, caudate, and arcuate nucleus regions were harvested from VPA-treated and control mice. Analysis of whole tissue content of GABA revealed that levels were lower in the caudate and arcuate nucleus regions of VPA-treated animals, whereas there were no group differences for the mPOA region. Collapsing across drug group, there was also a trend for males having overall higher levels of GABA as compared to females. In Experiments 2 and 3, mice were implanted with microdialysis probes within the mPOA region and sampled for extracellular GABA levels. Females (Exp. 3) were sampled either on diestrous, proestrous, or estrous. Results from males (Exp. 2) revealed that VPA enhanced extracellular GABA levels in the mPOA region compared with controls. However, GABA levels for both groups remained stable across the sampling period. Conversely, in Exp. 3, females showed cyclical release of GABA across the sampling period. For control females, GABA levels increased during the afternoon on all cycle days, but the rise on proestrus was smaller than on other cycle days. VPA-treated animals showed an overall reduction in GABA levels compared with controls. Furthermore, while GABA increased over sampling time on estrus and diestrus days of the cycle, there was not a significant rise in GABA on proestrus. These data indicate: (1) regional specificity in VPA effects upon GABA levels, (2) a sex difference in the effects of VPA on GABA levels within the mPOA, and (3) GABA levels increase on the afternoon of all days of the estrous cycle with VPA attenuating the rise seen on the afternoon of proestrus. These results provide evidence that VPA effects upon the reproductive axis may involve changes in GABA release, and that males and females show different patterns of neurochemical response to the drug.