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Neuroendocrine and circadian modulation by the menstrual cycle
662
FRIDAE MAY 20
BIOL PSYCtnATRY 1994:35:615-747
efficacy of bright (> 2500 lux) white moming (0630-0830), bright white evening (1900-2100) and dim (< tO lux) ~ i evening light. Studies of melatonin circadian rhythms during the menstrual cycle showed that in PMS compmed with control subjects, there was a significantly reduced area under the curve (now replicated in an additional 20 subjects), an earlier offset and a shorter duration of melatonin secretin in PMS vs. control subjects. In addition, we found in this study differential changes in melatonin onset and offset times during the menstrual cycle and after light therapy in PMS vs. control subjects.
170. NEUROENDOCRINE AND CIRCADIAN MODULATION BY THE MENSTRUAL CYCLE IE. Leibenluft, Ip. L. Fiero, & 2D. R. Rubinow 1Clinical Psychobiology Branch and 2Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892 Biologi,:al studies of patients with mood disorders do not generally conuel for menstrual cycle phase, and most investigators are unaware of whether, and how, the dependent variables that they measure may be affected by the hormonal fluctuation over the menstrual cycle. This presentation will review the existing literature on the fluctuation over the menstrual cycle of the following variables: prolactin, growth hormone, melatonin, sleep, body temperature, neurotransmitter activity, and measures of the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes. Studies are included in the review if they meet the following criteria: (i) bubjects were normal, healthy, spontaneously menstruating women, studied in two or more menstrual phases; (2) ovulation was determined; (3) circadian variation was at least partially accounted for either by sampling during the same time period each day or by sampling at regular intervals over a 24-hour period, it is concluded that body temperature and plasma and urinary norepinephrine vary predictably over the menstrual cycle. Prolactin, adrenocorticotropic hormone, and ~.endorphin may have peaks in the periovulatory phase, while serotonin levels in platelct.poor plasma may reach a nadir at that time. Triiodothyronine, thyroxine, cortisol, and melatonin do not appear to vary systematically over the course of the menstrual cycle, while the data for growth hormone, thyroid stimulating hormone, and sleep are inconclusive. The implications of the literature for the design of clinical studies will be discussed.
171. NEUROPSYCHIATRIC EFFECTS OF PERIMENOPAUSAL ESTROGEN REPLACEMENT P. J. Schmidt, C. A. O!1o, & D. R. Rubinow Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892
ity, and Beck Depression Inventory scores (ANOVA-R). An extensive neuropsychiatric test battery revealed no differences in performance in depressed women at baseline, compared with scores after three weeks or six weeks of estrogen, nor in comparison with scores obtained in a group of non-depressed perimenopausal controls (n - 10). These data suggest a role for estrogen replacement in the treatment of depression occurring in the context of the perimenopause, but do not suggest the occurrence of estrogen responsive cognitive impairment during the perimenopanse.
172. D2 SUBSTRATES OF A MEASURE THAT PREDICTS ATYPICAL ANTIPSYCHOTIC POTENCY N.R. Swerdlow, F.J. Wan, S.B. Caine, D.S. Zisook, N. Taaid, & M.A. Geyer Department of Psychiatry, UCSD School of Medicine, La Joila, C A 92093-0804
Startle is inhibited when the startling stimulus is prec~led30-s00 msee by a weak prepulse. Prepulse inhibition (PPI) is impaired in neuropsychiatric disorders characterized by deficient sensorimotor or cognitive gating, and in rats treated with dopamine (DA) agonists, competitive NMDA antagonists or serotonin (51-rr) IA agonists. The ability of antipsychotics to restore PPI in DA agonist-treated rats correlates (R=0.991) with their clinical potency. We have continued to investigate the DAcrgic subs;~atcs of PPI. PPI is disrupted by systemic or intra-accumbens treatment with the D2 agonist quinpirole but not the relative D1 agonist (DI :D2=50: ~) $KF 38393. Intra.accumbens quinpirole disrupts PPl after infusions into either "core" or "shell" regions, with a small but demonstrable gradient favoring "core" D2 substrates. A synergistic reduction of PPl by systemic quinpirole and SKF 38393 is blocked by the D2 antagonist raclopride but not the DI antagonist SCH 23390. The relative DI agonist (DI :D2-10: l) SKF 82958 disrupts PPI, but this effect is reversed by raclopride and not SCH 23390. The disruption of PPI by quinpirole, the mixed DA agonist apomorphine (APO), and the DS/D2 agonist 70H-DPAT correlate with their D2 affinity, and is reversed in all cases by haloperidol but not the D3 antagonist UH 232. The APO-disruption of PPl is reversed by the novel DA/5HT antipsychotic Seroquel (IC! 204,636) with a potency similar to that of ciozapine. The modulation of sensorimotor gating in the rat is a fertile model for pharmacological and anatomical investigations of DAergic mechanisms with predictive value for novel antipsychotics.
173. EFFECT OF TESTING FREQUENCY ON MK-801 INDUCED "POPPING" AND ATAXIA IN MICE A. Hitri, M. Stambuk, & S.I. Deutsch NIDA Research, DVAMC, Washington, DC 20422
Despite long-standing medical interest, alterations of mood and behavior associated with the perimenopause have been poorly characterized, if not dismissed, largely as a product of investigators failing to carefully characterize reproductive status and affective state. Moreover, the iole of estrogen replacement in the treatment of symptoms of depression during the perimenopause remains to be determined. We performed a double-blind, placebo-controlled trial of estrogen replacement in women with depression, in the absence of hot flushes, during the pefimenopause. Subjects (n - i 3) trot RDC criteria for depression and demonstrated serial elevated FSH levels > 20 IU/L consistent with the perimenopause. Preliminary resuits demonstrated significant improvement on estrogen compared with placebo in symptoms of tearfulness, emotional numbness, mood instabil-
A single injection of MK-801 ((+)-5-methyi-10,l l-dihydro5Hdibenzo[a,d!rycloheptane-5,10-imine maleat ); (Dizolcipine) is known to induce, a prominent ataxia and episodic "popping" behavior in mice. "Popping" occurs in discrete episodes of variable duration. The least intense example of this behavior consists of spasmodic contractions without "popping", while the most intense examples of this behavior, are the spasmodic contractions that propel the mouse into the air, an episode of repetitive "'popping" into the air could continue for several seconds. Since, the "popping" behavior may be potentially useful as a screening test for novel antipsychotic medications (Deutsch and Hitri 1993), we investigated the effect of repeated MK-801 testing in the ataxia and "pop-
FRIDAE MAY 20
BIOL PSYCtnATRY 1994:35:615-747
efficacy of bright (> 2500 lux) white moming (0630-0830), bright white evening (1900-2100) and dim (< tO lux) ~ i evening light. Studies of melatonin circadian rhythms during the menstrual cycle showed that in PMS compmed with control subjects, there was a significantly reduced area under the curve (now replicated in an additional 20 subjects), an earlier offset and a shorter duration of melatonin secretin in PMS vs. control subjects. In addition, we found in this study differential changes in melatonin onset and offset times during the menstrual cycle and after light therapy in PMS vs. control subjects.
170. NEUROENDOCRINE AND CIRCADIAN MODULATION BY THE MENSTRUAL CYCLE IE. Leibenluft, Ip. L. Fiero, & 2D. R. Rubinow 1Clinical Psychobiology Branch and 2Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892 Biologi,:al studies of patients with mood disorders do not generally conuel for menstrual cycle phase, and most investigators are unaware of whether, and how, the dependent variables that they measure may be affected by the hormonal fluctuation over the menstrual cycle. This presentation will review the existing literature on the fluctuation over the menstrual cycle of the following variables: prolactin, growth hormone, melatonin, sleep, body temperature, neurotransmitter activity, and measures of the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes. Studies are included in the review if they meet the following criteria: (i) bubjects were normal, healthy, spontaneously menstruating women, studied in two or more menstrual phases; (2) ovulation was determined; (3) circadian variation was at least partially accounted for either by sampling during the same time period each day or by sampling at regular intervals over a 24-hour period, it is concluded that body temperature and plasma and urinary norepinephrine vary predictably over the menstrual cycle. Prolactin, adrenocorticotropic hormone, and ~.endorphin may have peaks in the periovulatory phase, while serotonin levels in platelct.poor plasma may reach a nadir at that time. Triiodothyronine, thyroxine, cortisol, and melatonin do not appear to vary systematically over the course of the menstrual cycle, while the data for growth hormone, thyroid stimulating hormone, and sleep are inconclusive. The implications of the literature for the design of clinical studies will be discussed.
171. NEUROPSYCHIATRIC EFFECTS OF PERIMENOPAUSAL ESTROGEN REPLACEMENT P. J. Schmidt, C. A. O!1o, & D. R. Rubinow Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892
ity, and Beck Depression Inventory scores (ANOVA-R). An extensive neuropsychiatric test battery revealed no differences in performance in depressed women at baseline, compared with scores after three weeks or six weeks of estrogen, nor in comparison with scores obtained in a group of non-depressed perimenopausal controls (n - 10). These data suggest a role for estrogen replacement in the treatment of depression occurring in the context of the perimenopause, but do not suggest the occurrence of estrogen responsive cognitive impairment during the perimenopanse.
172. D2 SUBSTRATES OF A MEASURE THAT PREDICTS ATYPICAL ANTIPSYCHOTIC POTENCY N.R. Swerdlow, F.J. Wan, S.B. Caine, D.S. Zisook, N. Taaid, & M.A. Geyer Department of Psychiatry, UCSD School of Medicine, La Joila, C A 92093-0804
Startle is inhibited when the startling stimulus is prec~led30-s00 msee by a weak prepulse. Prepulse inhibition (PPI) is impaired in neuropsychiatric disorders characterized by deficient sensorimotor or cognitive gating, and in rats treated with dopamine (DA) agonists, competitive NMDA antagonists or serotonin (51-rr) IA agonists. The ability of antipsychotics to restore PPI in DA agonist-treated rats correlates (R=0.991) with their clinical potency. We have continued to investigate the DAcrgic subs;~atcs of PPI. PPI is disrupted by systemic or intra-accumbens treatment with the D2 agonist quinpirole but not the relative D1 agonist (DI :D2=50: ~) $KF 38393. Intra.accumbens quinpirole disrupts PPl after infusions into either "core" or "shell" regions, with a small but demonstrable gradient favoring "core" D2 substrates. A synergistic reduction of PPl by systemic quinpirole and SKF 38393 is blocked by the D2 antagonist raclopride but not the DI antagonist SCH 23390. The relative DI agonist (DI :D2-10: l) SKF 82958 disrupts PPI, but this effect is reversed by raclopride and not SCH 23390. The disruption of PPI by quinpirole, the mixed DA agonist apomorphine (APO), and the DS/D2 agonist 70H-DPAT correlate with their D2 affinity, and is reversed in all cases by haloperidol but not the D3 antagonist UH 232. The APO-disruption of PPl is reversed by the novel DA/5HT antipsychotic Seroquel (IC! 204,636) with a potency similar to that of ciozapine. The modulation of sensorimotor gating in the rat is a fertile model for pharmacological and anatomical investigations of DAergic mechanisms with predictive value for novel antipsychotics.
173. EFFECT OF TESTING FREQUENCY ON MK-801 INDUCED "POPPING" AND ATAXIA IN MICE A. Hitri, M. Stambuk, & S.I. Deutsch NIDA Research, DVAMC, Washington, DC 20422
Despite long-standing medical interest, alterations of mood and behavior associated with the perimenopause have been poorly characterized, if not dismissed, largely as a product of investigators failing to carefully characterize reproductive status and affective state. Moreover, the iole of estrogen replacement in the treatment of symptoms of depression during the perimenopause remains to be determined. We performed a double-blind, placebo-controlled trial of estrogen replacement in women with depression, in the absence of hot flushes, during the pefimenopause. Subjects (n - i 3) trot RDC criteria for depression and demonstrated serial elevated FSH levels > 20 IU/L consistent with the perimenopause. Preliminary resuits demonstrated significant improvement on estrogen compared with placebo in symptoms of tearfulness, emotional numbness, mood instabil-
A single injection of MK-801 ((+)-5-methyi-10,l l-dihydro5Hdibenzo[a,d!rycloheptane-5,10-imine maleat ); (Dizolcipine) is known to induce, a prominent ataxia and episodic "popping" behavior in mice. "Popping" occurs in discrete episodes of variable duration. The least intense example of this behavior consists of spasmodic contractions without "popping", while the most intense examples of this behavior, are the spasmodic contractions that propel the mouse into the air, an episode of repetitive "'popping" into the air could continue for several seconds. Since, the "popping" behavior may be potentially useful as a screening test for novel antipsychotic medications (Deutsch and Hitri 1993), we investigated the effect of repeated MK-801 testing in the ataxia and "pop-