Luteinizing Hormone Secretion during Continuous or Pulsatile Infusion of Norepinephrine: Central Nervous System Desensitization to Constant Norepinephrine Input

Abstract

The luteinizing hormone (LH) secretory response to continuous or pulsatile infusion of norepinephrine (NE) into the third ventricle was compared in ovariectomized, steroid-primed rats. Unanesthetized rats were bled continuously through external jugular cannulae at rates of 40 or 75 μl whole blood every 5 or 6 min, respectively, for up to 30 min prior to infusion, and for 3 h during continuous or pulsatile infusion of NE. Animals not infused, and those receiving continuous infusion with artificial cerebrospinal fluid or 11 μg NE/h showed no change in LH release. Continuous infusion with 18 or 22 μg NE/h increased LH secretion, blood LH levels being elevated for the initial 40–60 min of infusion. By 60–80 min, however, blood LH levels had returned to preinfusion values and remained there for 2 h despite continuous NE infusion. This rapid desensitization of the LH secretory system to continuous NE input was not pituitary-mediated, since comparable LH secretion occurred when a single injection of 3 ng luteinizing hormone-releasing hormone (LHRH) was given intravenously 2 h after the onset of a 3-hour continuous infusion of either 18 μg NE/h (i.e. during the desensitization period) or cerebrospinal fluid. In contrast, pulses of NE (6 μg/2 min) given once per hour for 3 h produced increases in LH secretion with each hourly pulse. To further test the importance of the pattern of NE administration, infusion of NE at the rate of 18 μg/h was repeated except that the infusion was either turned on for 20 min, off for 120 min, and then on for 40 min, or turned on for 40 min, off for 80 min, and then on for 60 min. In both experiments LH secretion increased during the first stimulation period, declined to control levels when the infusion was turned off, but now increased in response to the second NE infusion period. These studies demonstrate that the desensitization of the LH secretory system to continuous NE input is not caused by a refractoriness of the pituitary gland to LHRH,but is instead centrally mediated. LHRHneurons (or in-terneurons mediating the NE signal) respond best to pulsatile NE stimulation, and rapidly become desensitized to continuous NE input.