AGE-RELATED DECREASE IN PROOPIOMELANOCORTIN GENE-EXPRESSION IN THE ARCUATE NUCLEUS OF THE MALE-RAT BRAIN

The decline in reproductive function with aging is due in part to decreased gonadotropin-releasing hormone (GnRH) secretion. Beta-Endorphin (beta-E), an endogenous opioid peptide derived from proopiomelanocortin (POMC), is thought to exert a tonic inhibitory effect upon hypothalamic GnRH secretion. We tested the hypothesis that the age-related decrease in GnRH secretion in male rats is due to increased beta-E synthesis, by comparing POMC mRNA levels in the arcuate nucleus (ARC) of intact young, middle-aged and old male rats. In an initial study (Study 1), sixteen 20-mu-m coronal sections each from the ARC of 3- (n = 5) and 23-month-old (n = 4) male Fischer 344 rats were anatomically matched and analyzed. In a second study (Study 2), four anatomically matched sections of caudal arcuate nucleus from 3- (n = 4), 11- (n = 7) and 23-month-old (n = 5) male rats were compared. POMC mRNA levels were quantitated by in situ hybridization histochemistry, using a S-35-labeled oligodeoxynucleotide probe complementary to a portion of rat POMC cDNA and computerized image analysis. The number of grains per cell and cells per section were used as indices of cellular POMC mRNA content and the number of neurons expressing the POMC gene, respectively. Cellular POMC mRNA content was significantly lower in old compared to young animals (Study 1: 54 +/- 3 vs. 74 +/- 2 grains/cell, p < 0.01; Study 2: 59 +/- 2 vs. 71 +/- 2 grains/cell, p < 0.05). The number of labeled POMC neurons per section was also decreased in old compared to young rats (Study 1: 40 +/- 6 vs. 55 +/- 5 cells/section, p < 0.05; Study 2: 54 +/- 4 vs. 76 +/- 7 cells/section, p < 0.05). These findings were not localized to a specific rostro-caudal region of the ARC. Cellular POMC mRNA content of middle-aged rats was similar to young animals but significantly higher than in old rats (p < 0.05), while the number of neurons expressing the POMC gene demonstrated a significant and progressive decline with age from young to middle-aged to old animals. We conclude that beta-E synthetic capacity is decreased with age in the male rat, and that the decline in GnRH secretion in old animals is not a result of increased beta-E synthesis.