Pharmacology Biochemistry andBehavior, Vol.46, pp. 897-904, 1993 0091-3057/93$6.00 + .00 Printedin the U.S.A.All rightsreserved. Copyright© 1993 Pergamon PressLtd. Progesterone Withdrawal Decreases Latency to and Increases Duration of Electrified Prod Burial: A Possible Rat Model of PMS Anxiety MARY ANN GALLO AND SHERYL S. SMITH l Department of Anatomy, Institute of Neuroscience, Hahnemann University, Broad and Vine, Philadelphia, PA 19102-1192 Received 26 January 1993 GALLO, M. A. AND S. S. SMITH. Progesterone withdrawal decreases latency to and increases duration of electrOTed prod burial: A possible rat model of PMS anxiety. PHARMACOL BIOCHEM BEHAV 46(4) 897-904, 1993.-The pur- pose of this study was to determine whether withdrawal from chronic exposure to the female sex steroid progesterone (P) alters response of female rats to an electrified prod using the defensive burying paradigm, considered a rat model of anxiety. Withdrawal from chronic exposure to 500/tg P (daily, SC, for four days) resulted in a significant decrease in the latency (77e/e, P < 0.05) to prod burial and an increase in duration (75e/e, P < 0.05) of this reflexive response, compared with the behavior of oil-injected controls. These results are consistent with the idea that withdrawal from chronic exposure to P increases behaviors that accompany anxiety. At a lower dose (50/~g), withdrawal from chronically administered P produced significant changes in response to this paradigm only when the steroid was given concomitantly with estradiol (2 pg, SC, for two days). Prior exposure to indomethacin, which blocks the conversion of P to its metabolite 3~,5c~-tetrahydroprogesterone (3-c~-hydroxy-5-c~-pregnan-20-one), prevented P withdrawal from altering response in the defensive burying paradigm. This finding suggests that it may be withdrawal from this metabolite, rather than P, which increases behaviors associated with increased anxiety. Progesterone Pregnanolone 3~x,5cr-tetrahydroprogesterone GABA^ Defensive burying paradigm Defensive withdrawal paradigm Anxiety Premenstrual syndrome Hormone Withdrawal Rat WITHDRAWAL from sustained exposure to the female sex steroid P may play a role in triggering anxiety (11) related to the premenstrual syndrome (PMS). Dennerstein et al. (7) have described a correlation between decreasing and lower than normal levels of circulating P and increases in anxiety, pre- menses. Conversely, their studies demonstrated that adminis- tration of P reversed this symptomatology (7). Other studies have demonstrated that P may have tranquilizing effects in humans (5,16) and in rats (2,32). The anxiolytic actions of P are most likely due to local formation of the 3-ot-hydroxy-5-a-reduced metabolite 3ot,5ot- tetrahydroprogesterone (3¢x,5a-THP). Local intraventricular administration of this metabolite has been shown to decrease anxiety in rats, using performance in the elevated plus maze as a test of anxiety (l). In addition, the anxiolytic actions of systemically injected P have been shown to be associated with increased levels of 3%5ot-THP in the cortex (2). This metabo- lite binds to a novel site (19,23,24,30,41) on the the GABA^ receptor (25). It can then amplify GABA-mediated Cl- con- ductance in cultured hippocampal neurons (12,21), much in the same manner as the anxiolytic barbiturates (20,26). These actions may be physiologically relevant, as the parent com- pound, P, markedly potentiates GABA-mediated inhibition of cerebellar Purkinje cells at circulating levels similar to those seen endogenously (34,37,38). This neuromodulatory action of the steroid also appears to be mediated by the GABA-active metabolite 3%5ot-THP (35,36). Withdrawal from chronic exposure to other psychoactive GABA-active agents, such as ethanol, benzodiazepines, and barbiturates, can result in anxiogenic and, in extreme cases, convulsant effects (3,14,22). The purpose of the present study was to determine whether withdrawal from chronic exposure to P is also anxiogenic. P was tested for withdrawal properties rather than 3ot,5o~-THP because P more readily crosses the blood-brain barrier, where it can then be rapidly converted to the GABA-active metabolite (17). In addition, levels of P are i To whom requests for reprints should be addressed. 897