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Cardiac autonomic function in panic disorder: Analysis of 24-hour heart rate time series
622
BIOL PSYCHIATRY 1995;37:593-683
FRIDAY, MAY 19
105. BRAIN BLOOD FLOW IN POST TRAUMATIC STRESS DISORDER: SPECT ACTIVATION I. Liberzon 1,2, L.M. Fig 1,3, & T.D. Jung JPsychiatry and Nuclear Medicine, Veteran Affairs Medical Center, Ann Arbor, MI 48105; 2Department o f Psychiatry, University o f Michigan, A n n Arbor, MI 48104; 3Nuclear Medicine Division Department o f Internal Medicine, University of Michigan, Ann Arbor, MI 48104 The study describes patterns of brain blood flow in post traumatic stress disorder (PTSD), using single photon emission computed tomography (SPECT). PTSD patients exhibit symptoms of abnormal memory, and it was hypothesized that abnormal memory formations are responsible for generation of PTSD symptoms. Brain bhx)d flow changes, following activation of traumatic memories, might reflect this mechanism. Subjects are subjected to two types of auditory stimuli 48 hours apart--white noise and combat sounds--while their electrophysiological responses are monitored. 30mCi of 99m-Tc-HMPAO is injected after the termination of the stimulus. Acquisition is performed using a triple-headed Siemense gamma camera. Semiquantitative assessment and subtraction method are used in data analysis. Preliminary results reveal an increase in regional cerebral blood flow following the combat sounds activation (minus the white noise activation) in three regions of the brain. These regions were: 1) left and right parahippocampal gyms, 2) left striatum, and 3) area of the upper brain stem structures. (Z score - 3.6, 3.2m and 3.1, respectively). The changes observed in parahippocampal gyri are of particular interest because of the proposed role of hippocampus and parahippocampal structures in formation, assessment, and storage of memory. Upper brain stem activation might reflect activation of centers responsible for increased arousal and autonomic responses.
106. REM DURING NAPS IN COMBATRELATED PTSD T.A. Mellman, J. Hebding, D. David, & B. Nolan University o f Miami, School o f Medicine, Departments o f Psychiatry and Neurology and the Miami VA Medical Center, Miami, FL 33125 A relationship of post-traumatic stress disorder (PTSD) and dysfunctional mechanisms involving rapid eye-movement (REM) sleep has been suggested in the literature. There are theories as well as empirical support for an adaptive function for REM toward emotional desensitization of traumatic memories. Research to date, however, has not revealed many consistent or robust findings regarding REM in PTSD. Ross et al have reported increased phasic activity (muscle twitches and eye movements) during REM in combat-related PTSD. Our overnight polysomnographic evaluations of 25 combat veterans with PTSD versus controls have not revealed differences in REM timing or percentage. We, like Ross et al, f'md increased REM eye movement density, as well as a trend for awakenings with anxiety, and for the awakenings with autonomic arousal, to have been preceded by REM. In order to evaluate daytime "pressure" for sleep and REM, we have been conducting multiple sleep latency testing (MSLT) in a preliminary combat veteran sample. Four of the five PTSD patients studied to date have demonstrated "REM onset" naps. In two of the four patients, REM during naps was associated with anxious awakenings interrupting REM during the previous night's recording; in another,
FRIDAY, MAY 19
nocturnal REM was reduced, in the other increased. Thus our preliminary finding is consistent with increased daytime pressure for REM, variably related to disrupted or inhibited REM at night.
107. ANTIDEPRESSANT AND GLUCOCORTICOID RECEPTOR MODULATION OF STARTLE AND ANXIETY RESPONSES S. Beaulieu s, J. Rochford 2, I. Rousse 2, J. Glowa 3, & N. Barden 4 1NIMH, Biological Psychiatry Branch; 3 N I D D K , Bethesda, M D 20892-1272; ZMcGill University, Montreal, Canada; 4Laval University, Quebec, Canada
A transgenic mouse model of impaired type II glucocorticoid receptor function (GRF) and hypersecretion of ACTH and corticosterone has recently been developed. We have studied the effect of the impaired type II G R F on the responses of transgenic animals in comparison to controls in a novelty conflict task and in an acoustic startle paradigm before and after chronic treatment with the antidepressant desipramine (20 mg/kg) or saline 0.9% delivered either by daily IP injection for 4 weeks (novelty conflict studies) or by infusions (20 and 10 mg/kg/day) using ALZET osmotic minipumps implanted subcutaneously for 2 weeks (startle studies). In the novelty conflict task, mice were food deprived for 24 hr and placed into a novel open field with food pellets placed in the center. The latency to begin eating was measured. Saline treated transgenic mice displayed a significantly longer latency to eat than control mice treated with either saline or desipramine; however, desipramine given to transgenic mice decreased the latency to levels not significantly different than those of control animals. In the acoustic startle paradigm (8 random exposures to a 110 dB noise of 100 msec duration spaced by 15-30 sec), we measured the startle response before beginning any treatment and then randomly assigned the animals to saline or desipramine treatment. Transgenic mice had a significantly higher startle response than control animals before treatment (p < 0.0001 ). Saline did not change the magnitude of response in control and in transgenic animals, while both doses of desipramine reduced the startle response of transgenic mice to levels indistinguishable from those of saline treated controls. Acute desipramine treatment (20 mg/kg IP) given 2 hr prior to startle did not reduce the higher startle response of transgenic animals. However, similar acute desipramine treatment given 30 min prior to testing in the open field paradigm increased the latency to begin eating for both control and transgenics animals. Overall, these data indicate that an impaired type II glucocorticoid receptor function leads to an increased response to two different anxiogenic stimuli and that long-term antidepressant treatment can reverse this phenomenon. We are currently characterizing the molecular changes associated with this response.
108. CARDIAC AUTONOMIC FUNCTION IN PANIC DISORDER: ANALYSIS OF 24-HOUR HEART RATE TIME SERIES V.K. Yeragani, E. Sobolewski, S. Vempati, S. Yeragani, J. Kay, V.C. Jampala, A. Liggett, S. Krabill, & G. Igel Wright State University School o f Medicine and the VA Medical Center, Dayton, O H Several studies suggest an association between panic anxiety and sudden death and significant cardiovascular morbidity. Decreased cardiac cholin-
FRIDAY, MAY 19
ergic and an increased sympathetic function have been linked to significant cardiovascular morbidity. Our previous findings suggest decreased heart rate variability in patients with panic disorder, especially in the frequency band of 0.0143.05 Hz. We also found a significantly higher relative low-frequency (0.07-0.15 Hz) power in these patients; however, heart rate variability analysis from the 24-hour records has some unique advantages in that these records reflect real life more closely and would allow one to quantify heart rate variability during sleep. This preliminary report used Holter records of ECG in 5 normal controls (3 females, 2 males; age: 37.8 + 10.4 years) and 4 patients with panic disorder (2 females and 2 males; age: 32 + 6.2 years). We used customized software to download and edit the R-R interval data from the Delmar 750 Holter system. All data were visually inspected to make sure there were no missed or premature beats. From these data, two 20,000 second segments were analyzed, one reflecting the daytime activities and the other, predominantly sleep records. We used complex demodulation, a technique which correlates highly with spectral analysis but has the advantage of being useful even when the data are nonstationary; however, we used a linear detrend before subjecting the data to complex demodulation. We demodulated the time series at center frequencies of 0.09 and 0.31 Hz for the low-frequency (LF) and the high-frequency (HF) bands with pass frequencies of 0.05 and 0.15 Hz. A least squares filter with a 61 point filter term was used. The mean amplitudes for the LF and HF are as follows: patients: 4.4 + 0.9 and 1.18 _+0.26 bpm; controls: 4.4 _+ 1.3 and 1.9 + 0.98 bpm. The sympathovagal ratios (LF/HF) during sleep were significantly higher in the patient group (3.8 _+0.3 vs. 2.5 + 0.6; p < 0.01 ). These findings are in agreement with our previous reports of a relative increase in cardiac sympathetic activity in these patients, and higher sympathovagal ratios in these patients during lactate and isoproterenol infusions. We will present data with a larger sample at the meeting.
BIOL PSYCHIATRY 1995;37:593 683
623
110. RESTRICTION FRAGMENT LENGTH POLYMORPHISMS IN 5-HTF GENE SEQUENCE J. Rausch, Y. Fei, G. Ganapathy, & F. Leibach A u g u s t a VA and T h e Medical College o f Georgia, A u g u s t a , GA 30912-3810 Previous studies of oligonucleotides derived from placental consensus transporter sequences have served to identify human cDNAs shown to be highly related to, but not identical to, the rat brain 5-HT transporter (5HTT). The rat protein contains an additional site for protein kinase recognition in the cytoplasmic N-terminal region, not conserved in the human form. Unlike the rodent, where a single mRNA appears to encode the transporter, multiple hybridizing RNAs are observed in the human transporter, as evident in studies from the human placenta and lung. These observations underscore the importance of human studies to determine the possibility of genetic variation in the human serotonin transporter gene. In the present study we report the presence of restriction fragment length polymorphisms (RFLPs) in the serotonin transporter gene indicated by the restriction endonuclease enzyme, Xba I. From nine DNA samples tested in normal controls, five were Xba I-positive on both chromosomes, whereas four were Xba I-positive on only one chromosome. An expansion of these RFLP studies may identify linkage analysis of particular phenotypes to a specific RFLP, to determine whether potential genetic variation in the code for the serotonin transporter could be linked to differences in 5-HT transport expression relevant to antidepressant response phenotypes we have previously identified.
111. OVARIAN STEROIDS ANTAGONIZE GLUCOCORTICOID EFFECTS ON HPA AXIS 109. SAFETY AND EFFICACY OF CI-988 IN GAD JoJ. Sramek l, J.F. Costa l, J. Adams 2, A. MacPherson l, & N.R. Cutler I ICalifornia Clinical Trials, Beverly Hills, C A 90211; 2ParkeDavis Division of W a r n e r - L a m b e r t , A n n Arbor, MI 48105 CI-988 is a novel peptide CCK B antagonist being developed for treatment of anxiety and panic disorders. The present results are those of one site (n = 32) from a multicenter study (n = 88) which investigated the efficacy of CI-988 in patients with generalized anxiety disorder. The primary efficacy measures were the Hamilton Rating Scale for Anxiety (HAM-A) and the Clinical Global Impression (CGI) scale. At our site, 16 patients were randomized to placebo and 16 to CI-988, and 29 patients completed all 4 weeks of study treatment. Patients on CI-988 showed a greater decrease (p -0.06) in HAM-A scores than did patients on placebo at the end of the study, with mean change in HAM-A total at week 4 of-7.69 (-32.0%) for CI-988 and -4.19 (-18.6%) for placebo. There were no significant differences on the CGI between the two treatment groups. All adverse events were rated mild or moderate. One patient on CI-988 discontinued due to moderate abdominal pain; two patients on placebo discontinued for personal reasons. Our positive findings were not reflected in the overall multicenter results, as there was a significant treatment by center interaction for HAM-A scores such that the other two centers favored placebo and neither group, respectively. Considering the acceptable tolerability and potential anxiolytic efficacy of CI-988 demonstrated at this site, however, testing of higher oral doses may be warranted.
E.A. Young M e n t a l Health R e s e a r c h Institute and D e p a r t m e n t o f Psychiatry, University of M i c h i g a n , A n n Arbor, MI 48109 In the course of our studies on HPA axis dysregulation in depression, we noted that premenopausal women appear to be resistant to the sequelae of hypercortisolemia. We hypothesized that ovarian steroids modulate the HPA axis by acting as glucocorticoid antagonists in women. To test this in an experimental condition, we compared the effects of implantation of exogenous corticosterone pellets in gonadally intact male and female rats and ovariectomized (ovx) female rats. Despite achievement of higher plasma corticosterone concentrations in the intact female rats, exogenous corticosterone resulted in no decrease in thymus or adrenal weight and less inhibition of ACTH secretion. Previous studies in male rats had demonslaated that the increase in morning plasma corticosterone from the corticosterone pellets resulted in an elimination of the PM circadian drive. AM and PM plasma corticosterone concentrations were compared before and after corticosterone pellet implantation in male and female rats to determine if this same treatment resulted in inhibition of the circadian drive in female rats. Statistical comparison of intact males to intact females indicated: a) significant sex difference overall (F = 22.4, df = 1, p = 0.0001), b) significant effect of AM VS. PM (F = 96, df = 1, p = 0.0001), and c) sign interaction between sex and A~'PM (F = 10.6, df = 1, p = 0.0001). Overall, the ovx females resembled male rats in the effects of corticosterone pellet treatment on HPA axis measures. Ovx resulted in a restoration of the effects of exogenous corticosterone on adrenal weight, and on plasma ACTH secretion, and ovx female rats were no longer different from male rats on AM and PM plasma corticosterone secretion following implantation of corticosterone pellets. These studies support our hypothesis that ovarian steroids function as a buffer against elevated circulating glucocorticolds, as might be seen during episodes of depression.
BIOL PSYCHIATRY 1995;37:593-683
FRIDAY, MAY 19
105. BRAIN BLOOD FLOW IN POST TRAUMATIC STRESS DISORDER: SPECT ACTIVATION I. Liberzon 1,2, L.M. Fig 1,3, & T.D. Jung JPsychiatry and Nuclear Medicine, Veteran Affairs Medical Center, Ann Arbor, MI 48105; 2Department o f Psychiatry, University o f Michigan, A n n Arbor, MI 48104; 3Nuclear Medicine Division Department o f Internal Medicine, University of Michigan, Ann Arbor, MI 48104 The study describes patterns of brain blood flow in post traumatic stress disorder (PTSD), using single photon emission computed tomography (SPECT). PTSD patients exhibit symptoms of abnormal memory, and it was hypothesized that abnormal memory formations are responsible for generation of PTSD symptoms. Brain bhx)d flow changes, following activation of traumatic memories, might reflect this mechanism. Subjects are subjected to two types of auditory stimuli 48 hours apart--white noise and combat sounds--while their electrophysiological responses are monitored. 30mCi of 99m-Tc-HMPAO is injected after the termination of the stimulus. Acquisition is performed using a triple-headed Siemense gamma camera. Semiquantitative assessment and subtraction method are used in data analysis. Preliminary results reveal an increase in regional cerebral blood flow following the combat sounds activation (minus the white noise activation) in three regions of the brain. These regions were: 1) left and right parahippocampal gyms, 2) left striatum, and 3) area of the upper brain stem structures. (Z score - 3.6, 3.2m and 3.1, respectively). The changes observed in parahippocampal gyri are of particular interest because of the proposed role of hippocampus and parahippocampal structures in formation, assessment, and storage of memory. Upper brain stem activation might reflect activation of centers responsible for increased arousal and autonomic responses.
106. REM DURING NAPS IN COMBATRELATED PTSD T.A. Mellman, J. Hebding, D. David, & B. Nolan University o f Miami, School o f Medicine, Departments o f Psychiatry and Neurology and the Miami VA Medical Center, Miami, FL 33125 A relationship of post-traumatic stress disorder (PTSD) and dysfunctional mechanisms involving rapid eye-movement (REM) sleep has been suggested in the literature. There are theories as well as empirical support for an adaptive function for REM toward emotional desensitization of traumatic memories. Research to date, however, has not revealed many consistent or robust findings regarding REM in PTSD. Ross et al have reported increased phasic activity (muscle twitches and eye movements) during REM in combat-related PTSD. Our overnight polysomnographic evaluations of 25 combat veterans with PTSD versus controls have not revealed differences in REM timing or percentage. We, like Ross et al, f'md increased REM eye movement density, as well as a trend for awakenings with anxiety, and for the awakenings with autonomic arousal, to have been preceded by REM. In order to evaluate daytime "pressure" for sleep and REM, we have been conducting multiple sleep latency testing (MSLT) in a preliminary combat veteran sample. Four of the five PTSD patients studied to date have demonstrated "REM onset" naps. In two of the four patients, REM during naps was associated with anxious awakenings interrupting REM during the previous night's recording; in another,
FRIDAY, MAY 19
nocturnal REM was reduced, in the other increased. Thus our preliminary finding is consistent with increased daytime pressure for REM, variably related to disrupted or inhibited REM at night.
107. ANTIDEPRESSANT AND GLUCOCORTICOID RECEPTOR MODULATION OF STARTLE AND ANXIETY RESPONSES S. Beaulieu s, J. Rochford 2, I. Rousse 2, J. Glowa 3, & N. Barden 4 1NIMH, Biological Psychiatry Branch; 3 N I D D K , Bethesda, M D 20892-1272; ZMcGill University, Montreal, Canada; 4Laval University, Quebec, Canada
A transgenic mouse model of impaired type II glucocorticoid receptor function (GRF) and hypersecretion of ACTH and corticosterone has recently been developed. We have studied the effect of the impaired type II G R F on the responses of transgenic animals in comparison to controls in a novelty conflict task and in an acoustic startle paradigm before and after chronic treatment with the antidepressant desipramine (20 mg/kg) or saline 0.9% delivered either by daily IP injection for 4 weeks (novelty conflict studies) or by infusions (20 and 10 mg/kg/day) using ALZET osmotic minipumps implanted subcutaneously for 2 weeks (startle studies). In the novelty conflict task, mice were food deprived for 24 hr and placed into a novel open field with food pellets placed in the center. The latency to begin eating was measured. Saline treated transgenic mice displayed a significantly longer latency to eat than control mice treated with either saline or desipramine; however, desipramine given to transgenic mice decreased the latency to levels not significantly different than those of control animals. In the acoustic startle paradigm (8 random exposures to a 110 dB noise of 100 msec duration spaced by 15-30 sec), we measured the startle response before beginning any treatment and then randomly assigned the animals to saline or desipramine treatment. Transgenic mice had a significantly higher startle response than control animals before treatment (p < 0.0001 ). Saline did not change the magnitude of response in control and in transgenic animals, while both doses of desipramine reduced the startle response of transgenic mice to levels indistinguishable from those of saline treated controls. Acute desipramine treatment (20 mg/kg IP) given 2 hr prior to startle did not reduce the higher startle response of transgenic animals. However, similar acute desipramine treatment given 30 min prior to testing in the open field paradigm increased the latency to begin eating for both control and transgenics animals. Overall, these data indicate that an impaired type II glucocorticoid receptor function leads to an increased response to two different anxiogenic stimuli and that long-term antidepressant treatment can reverse this phenomenon. We are currently characterizing the molecular changes associated with this response.
108. CARDIAC AUTONOMIC FUNCTION IN PANIC DISORDER: ANALYSIS OF 24-HOUR HEART RATE TIME SERIES V.K. Yeragani, E. Sobolewski, S. Vempati, S. Yeragani, J. Kay, V.C. Jampala, A. Liggett, S. Krabill, & G. Igel Wright State University School o f Medicine and the VA Medical Center, Dayton, O H Several studies suggest an association between panic anxiety and sudden death and significant cardiovascular morbidity. Decreased cardiac cholin-
FRIDAY, MAY 19
ergic and an increased sympathetic function have been linked to significant cardiovascular morbidity. Our previous findings suggest decreased heart rate variability in patients with panic disorder, especially in the frequency band of 0.0143.05 Hz. We also found a significantly higher relative low-frequency (0.07-0.15 Hz) power in these patients; however, heart rate variability analysis from the 24-hour records has some unique advantages in that these records reflect real life more closely and would allow one to quantify heart rate variability during sleep. This preliminary report used Holter records of ECG in 5 normal controls (3 females, 2 males; age: 37.8 + 10.4 years) and 4 patients with panic disorder (2 females and 2 males; age: 32 + 6.2 years). We used customized software to download and edit the R-R interval data from the Delmar 750 Holter system. All data were visually inspected to make sure there were no missed or premature beats. From these data, two 20,000 second segments were analyzed, one reflecting the daytime activities and the other, predominantly sleep records. We used complex demodulation, a technique which correlates highly with spectral analysis but has the advantage of being useful even when the data are nonstationary; however, we used a linear detrend before subjecting the data to complex demodulation. We demodulated the time series at center frequencies of 0.09 and 0.31 Hz for the low-frequency (LF) and the high-frequency (HF) bands with pass frequencies of 0.05 and 0.15 Hz. A least squares filter with a 61 point filter term was used. The mean amplitudes for the LF and HF are as follows: patients: 4.4 + 0.9 and 1.18 _+0.26 bpm; controls: 4.4 _+ 1.3 and 1.9 + 0.98 bpm. The sympathovagal ratios (LF/HF) during sleep were significantly higher in the patient group (3.8 _+0.3 vs. 2.5 + 0.6; p < 0.01 ). These findings are in agreement with our previous reports of a relative increase in cardiac sympathetic activity in these patients, and higher sympathovagal ratios in these patients during lactate and isoproterenol infusions. We will present data with a larger sample at the meeting.
BIOL PSYCHIATRY 1995;37:593 683
623
110. RESTRICTION FRAGMENT LENGTH POLYMORPHISMS IN 5-HTF GENE SEQUENCE J. Rausch, Y. Fei, G. Ganapathy, & F. Leibach A u g u s t a VA and T h e Medical College o f Georgia, A u g u s t a , GA 30912-3810 Previous studies of oligonucleotides derived from placental consensus transporter sequences have served to identify human cDNAs shown to be highly related to, but not identical to, the rat brain 5-HT transporter (5HTT). The rat protein contains an additional site for protein kinase recognition in the cytoplasmic N-terminal region, not conserved in the human form. Unlike the rodent, where a single mRNA appears to encode the transporter, multiple hybridizing RNAs are observed in the human transporter, as evident in studies from the human placenta and lung. These observations underscore the importance of human studies to determine the possibility of genetic variation in the human serotonin transporter gene. In the present study we report the presence of restriction fragment length polymorphisms (RFLPs) in the serotonin transporter gene indicated by the restriction endonuclease enzyme, Xba I. From nine DNA samples tested in normal controls, five were Xba I-positive on both chromosomes, whereas four were Xba I-positive on only one chromosome. An expansion of these RFLP studies may identify linkage analysis of particular phenotypes to a specific RFLP, to determine whether potential genetic variation in the code for the serotonin transporter could be linked to differences in 5-HT transport expression relevant to antidepressant response phenotypes we have previously identified.
111. OVARIAN STEROIDS ANTAGONIZE GLUCOCORTICOID EFFECTS ON HPA AXIS 109. SAFETY AND EFFICACY OF CI-988 IN GAD JoJ. Sramek l, J.F. Costa l, J. Adams 2, A. MacPherson l, & N.R. Cutler I ICalifornia Clinical Trials, Beverly Hills, C A 90211; 2ParkeDavis Division of W a r n e r - L a m b e r t , A n n Arbor, MI 48105 CI-988 is a novel peptide CCK B antagonist being developed for treatment of anxiety and panic disorders. The present results are those of one site (n = 32) from a multicenter study (n = 88) which investigated the efficacy of CI-988 in patients with generalized anxiety disorder. The primary efficacy measures were the Hamilton Rating Scale for Anxiety (HAM-A) and the Clinical Global Impression (CGI) scale. At our site, 16 patients were randomized to placebo and 16 to CI-988, and 29 patients completed all 4 weeks of study treatment. Patients on CI-988 showed a greater decrease (p -0.06) in HAM-A scores than did patients on placebo at the end of the study, with mean change in HAM-A total at week 4 of-7.69 (-32.0%) for CI-988 and -4.19 (-18.6%) for placebo. There were no significant differences on the CGI between the two treatment groups. All adverse events were rated mild or moderate. One patient on CI-988 discontinued due to moderate abdominal pain; two patients on placebo discontinued for personal reasons. Our positive findings were not reflected in the overall multicenter results, as there was a significant treatment by center interaction for HAM-A scores such that the other two centers favored placebo and neither group, respectively. Considering the acceptable tolerability and potential anxiolytic efficacy of CI-988 demonstrated at this site, however, testing of higher oral doses may be warranted.
E.A. Young M e n t a l Health R e s e a r c h Institute and D e p a r t m e n t o f Psychiatry, University of M i c h i g a n , A n n Arbor, MI 48109 In the course of our studies on HPA axis dysregulation in depression, we noted that premenopausal women appear to be resistant to the sequelae of hypercortisolemia. We hypothesized that ovarian steroids modulate the HPA axis by acting as glucocorticoid antagonists in women. To test this in an experimental condition, we compared the effects of implantation of exogenous corticosterone pellets in gonadally intact male and female rats and ovariectomized (ovx) female rats. Despite achievement of higher plasma corticosterone concentrations in the intact female rats, exogenous corticosterone resulted in no decrease in thymus or adrenal weight and less inhibition of ACTH secretion. Previous studies in male rats had demonslaated that the increase in morning plasma corticosterone from the corticosterone pellets resulted in an elimination of the PM circadian drive. AM and PM plasma corticosterone concentrations were compared before and after corticosterone pellet implantation in male and female rats to determine if this same treatment resulted in inhibition of the circadian drive in female rats. Statistical comparison of intact males to intact females indicated: a) significant sex difference overall (F = 22.4, df = 1, p = 0.0001), b) significant effect of AM VS. PM (F = 96, df = 1, p = 0.0001), and c) sign interaction between sex and A~'PM (F = 10.6, df = 1, p = 0.0001). Overall, the ovx females resembled male rats in the effects of corticosterone pellet treatment on HPA axis measures. Ovx resulted in a restoration of the effects of exogenous corticosterone on adrenal weight, and on plasma ACTH secretion, and ovx female rats were no longer different from male rats on AM and PM plasma corticosterone secretion following implantation of corticosterone pellets. These studies support our hypothesis that ovarian steroids function as a buffer against elevated circulating glucocorticolds, as might be seen during episodes of depression.