The Role of d-Aspartic Acid and N-Methyl-d-Aspartic Acid in the Regulation of Prolactin Release*

Abstract

In this study, using an enzymatic HPLC method in combination with D-aspartate oxidase, we show that N-methyl-D-aspartate (NMDA) is present at nanomolar levels in rat nervous system and endocrine glands as a natural compound, and it is biosynthesized in vivo and in vitro. D-aspartate (D-Asp) is its natural precursor and also occurs as an endogenous compound. Among the endocrine glands, the highest quantities of D-Asp (78 +/- 12 nmol/g) and NMDA (8.4 +/- 1.2 nmol/g) occur in the adenohypophysis, whereas the hypothalamus represents the area of the nervous system where these amino acids are most abundant (55 +/- 9 and 5.6 +/- 1.1 nmol/g for D-Asp and NMDA, respectively). When D-Asp is administered to rats by ip injection, there is a significant uptake of D-Asp into the adenohypophysis and a significant increase in the concentration of NMDA in the adenohypophysis, hypothalamus and hippocampus, suggesting that D-Asp is an endogenous precursor for NMDA biosynthesis. Experiments conducted on tissue homogenates confirm that D-Asp is the precursor of the NMDA and that the enzyme catalyzing this reaction is a methyltransferase. S-adenosyl-L-methionine (SAM) is the methyl group donor. In vivo experiments consisting of ip injections of sodium D-aspartate show that this amino acid induced a significant serum PRL elevation and this effect is dose and time dependent. In vitro experiments conducted on isolated adenohypophysis or adenohypophysis coincubated with the hypothalamus, showed that the release of PRL is caused by a direct action of D-Asp on the pituitary gland and also mediated by the indirect action of NMDA on the hypothalamus. Then, the latter induces the release of a putative factor that in turn stimulates the adenohypophysis reinforcing the PRL release. In conclusion, our data suggest that D-Asp and NMDA are present endogenously in the rat and are involved in the modulation of PRL release.

D‐Aspartate Oxidase: The Sole Catabolic Enzyme Acting on Free D‐Aspartate in Mammals

“…Supporting this, the addition of d-Asp to GH 3 cells, which are a prolactin-producing clonal strain of a rat pituitary tumor cell line, enhances their thyrotropin-releasing hormone-induced secretion of prolactin in a dose-dependent manner [12]. The secretion of prolactin from isolated pituitary glands or dispersed anterior pituitary cells of adult rat is also enhanced by incubation with d-Asp [13]. Interestingly, GH 3 cells contain d-Asp, and the cellular levels of d-Asp increase with the duration of culture, even if d-Asp is not added to the culture medium [12].…”

Analysis of Small Amounts of d-Amino Acids and the Study of Their Physiological Functions in Mammals

“…[8][9][10] D-Asp is widely present in the endocrine tissues (higher than 100 nmol/g tissue) 18,20,21 and its physiological function in regulating hormonal synthesis and secretion has gradually been clarified. 5,6,[22][23][24][25][26][27][28] However, the determination of small amounts of D-amino acids in mammalian tissues and physiological fluids has always been interfered with Reviews by thousands or more peptides, amino acids and other amino compounds. Therefore, a highly selective analytical method is essential.…”

“…40 Large amounts of D-Asp are also found in the testis, pituitary gland and adrenal gland, and the material is reported to regulate the synthesis and/or secretion of hormones such as testosterone and prolactin in the tissues. 5,6,[22][23][24][25][26][27][28]40 D-Ala is one of the D-amino acids present in small amounts in mammalian tissues; its physiological function has not yet been clarified. To obtain fundamental knowledge of its function, we have investigated the tissue distribution of D-Ala in the brain and periphery of rodents.…”

Natural Occurrence and Industrial Applications of d‐Amino Acids: An Overview

“…Excitatory amino acids are known to mediate synaptic excitation and, therefore, nerve signal transmission in the mammalian central nervous system by binding to several receptors [67]. In this sense, d-aspartic acid and NMDA are widely known for being agonists of the l-glutamate receptor of NMDA type in vertebrates and invertebrates, and they are involved in hormone synthesis and release [68]. Recently, d-serine has also been shown to be an agonist of NMDA receptors, mediating several important physiological and pathological processes [9] [69] [70].…”