We propose to determine the role of age-related alterations in catecholamine (CA) and endogenous opioid peptide (EOP) neuronal systems in the initiation and maintenance of reproductive senescence in rats. We will also evaluate the role of age-related alterations in hormone secretion in the process of the aging of brain dopaminergic neurons. The proposed experiments will utilize young (3 to 4 months old), sexually mature rats; middle- aged (11-15 months old) rats which are either normally cycling or in the constant estrous (CE) state; and old (24-25 months old) CE rats of the Long Evans strain. We will evaluate LH pulses during the proestrous LH surge in middle-aged rats to determine the components of LH secretory dynamics which are altered just prior to the onset of the CE state. We will conduct similar evaluations of pulsatile LH release during the preovulatory surge of LH induced by clonidine in CE rats or by bromocriptine in repeatedly pseudopregnant rats. These studies will utilize frequent (every 5 min.) blood sampling of rats which are unanesthetized and unstressed. The role of chronic elevations in serum (E2) and prolactin (PRL) in the age-related decline in dopamine (DA) neuronal function will be evaluated. The dose-and time- dependency and the regional specificity of the effects of E2 and PRL on brain DA neurons would be determined. Also, the time- course of the recovery of DA neurons from the E2 on PRL insult will be determined. We have documented recently that chronic stimulation of opiate receptors cause a marked increase in the negative feedback effects of testosterone on LH secretion in males and in the negative and positive feedback effects of E2 in females. We would evaluate the role of EOP neuronal systems in the age-related increase in negative feedback sensitivity in males. These studies will utilize chronic exposure to the narcotic antagonist, naloxone, by a sustained-release pellet. Similar studies will be done using chronic morphine treatment in old CE rats and subsequent determination of the resulting changes in the effects of E2 on LH release. Finally, we have observed that a steroid-induced down-regulation of opioid receptors is involved in the series of neuronal events which generate the proestrous LH surge. Thus, we will evaluate the hypothesis that the age-related extinction of the preovulatory LH surge is a consequence of a deficit in this opioid-neuronal mechanism. Collectively, these studies will advance our knowledge of the neuronal and hormonal mechanism involved in the initiation and persistence of reproductive senescence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG002021-07
Application #
3114297
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1987-09-30
Project End
1991-08-31
Budget Start
1987-09-30
Budget End
1988-08-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Pharmacy
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Simpkins, J W (1994) Effects of aging on morphine withdrawal in the rat. Exp Gerontol 29:67-76
Simpkins, J W (1994) Effects of age and ovarian steroids on responses to opiates in the female rat. Neurobiol Aging 15:545-52
Simpkins, J W; Millard, W J; Berglund, L A (1993) Effects of chronic stimulation or antagonism of opiate receptors on GH secretion in male and female rats. Life Sci 52:1443-50
Simpkins, J W (1992) Effects of haloperidol and prolactin secreting tumors on cerebrospinal fluid concentrations of prolactin in the female rat. Life Sci 51:295-301
Singh, M; Millard, W J; Layden, M P et al. (1992) Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment. Neuroendocrinology 56:195-203
Simpkins, J W (1992) Effects of advancing age on cerebrospinal fluid concentrations of prolactin in the female rat. Brain Res 582:357-8
Singh, M; Simpkins, J W; Layden, M P et al. (1992) Opiate modulation of growth hormone secretion is compromised during the steroid-induced luteinizing hormone surge. Neuroendocrinology 55:214-20
Peris, J; Decambre, N; Coleman-Hardee, M L et al. (1991) Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release. Brain Res 566:255-64
Ganesan, R; Romano, T; Simpkins, J W (1991) Comparison of morphine tolerance in body temperature and luteinizing hormone secretion. Physiol Behav 50:505-9
Simpkins, J W; Swager, D; Millard, W J (1991) Evaluation of the sites of opioid influence on anterior pituitary hormone secretion using a quaternary opiate antagonist. Neuroendocrinology 54:384-90

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