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Temperature rhythms, depression, and cholinergic supersensitivity
78A
BIOL PSYCHIATRY 19ql ;29:43A-185A
Basic Science
receptor. Kappa receptor agonists can produce psychotomimetic effects in humans, thus dyorphin may be relevant in schizophrenia and mood disorders. Prodyn peptides have been previously studied in various brain regions such as ihe hippocampus and the basal ganglia; in primates, these pepfides also exist in fairly high concentrations in the cortex, but a detailed investigation of the distribution of these peptides in cortex has not yet been performed. To begin to understand the nature of cortical prodyn-derived peptid~ we studied the distributions of dyn A (1-17), dyn A 0 - 8 ) , dyn B, and ¢t-neo-endotphin in twelve c~..cal areas in six monkeys (macaca nemestrina). There were between-region diffe~nces in amount of each peptide in the twelve cortical areas studied, suggesting regional heterogeneity in the distribution of prod~n in primate cortex. Because dyn A (1-17) has greater kappa opiate receptor affinity than its processed product, dyn A (1-8), ratios of these two forms were determined. D~a A (l-I?)/dyn A (!-8) ratios were greater in cortex than found in the basal ganglia, suggesting the possibility of increased kappa tone in the cortex relative to the neostriatum. These results may have relevance to the study of a variety of psychotic disorders, especially schizophrenia. [Supported by Grants DA02265, MH00818, MH422251, and the Theophile Raphael Fund.]
77
CHOLINERG!C AI:qD SEROTONERGIC PARAMETERS OF BEHAVIOR IN TWO INBRED STRAINS OF MICE: C57BL/6J and DB~2J Charlie L. Swanson Jr., B.S., Joseph N. Hingtgen, Ph.D., Jay R. Simon, Ph.D., Jo ~ I. Nurnberger Jr., M.D., Ph.D. Department of Psychiatry, The Institute of Psychiatric Research, Indiana University Medical Center, Indianapolis, IN 46202-4887. Neur~ansmitter-behavior relationships in inbred strains of mice may relate to heritable behavioral disorders in man. Behavioral effec~'s of cholinergic and serotonergic manipulation in C57BL/KI a~d DBA/~ mice were studied. The mice were observed during three minute observation periods in an open field apparatus. Total crossings, center crossings, and rearings were counted. At baseline, the C57BL/tI strain had more total and center crossings than the DBAI2J strain. Scopolamine and 8-OH-DPAT, a 5-HTIA agonist, produced disparities between the strains significant enough to warrant evaluation in the recombinant mb~.d:, of these strains. The most consistent discriminator of the twos~",,ins wan the behavioral response to 8-OHDPAT (CS"BLJ-6J mice decreased center crossings while DBA/2J mice increased center crossings). Future studies will investigate receptor binding and neurotransmiVier levels in the parent and recombinant inbred strains of these mice. (Supported in part by the Indiana Deparm~nt of Menial Health.)
78
TEMPERATURE RHYTHMS, DEPRESSION, AND CHOLINERGIC SUPERSENSITIVITY David Overstreet, Ph.D., Peter Sh/remani~ Ph.D., Lynette Daws, B.Sc., Grant Schiller, Ph.D. School of Biological Sciences, Flinders University, Adelaide, S.A. 5001 Australia. The cholinergic arid circadian rhythm hypotheses of depression have generally been regarded as independent models with considerable experimental support. However, the fact that ~ e Hinders Sensitive Liue (FSL) rats, selectively bred for increased cholinergic function and resembling human depressives, exhibited changes in REM sleep suggested that these two models might be related. The present experiment examined circadian temperature rhythms in the FSL and control rats in order to explore this relationship further. The first experiment, conducted in San Diego, recorded temperatures from implanted mini-mitters in 6 FSL and control rats housed under a 12/12 fight/dark regime. The FSL rats reached peak temperature 2.6 hr earlier than the control rats, but there were no differences in the 24 hr mean temperature or the amplitude. The second study, conducted at Flinders University, used rectal thermistor probes to record temperature in 3045 rats of each strain and sex every 3 hr for 36 hr under a continuous lighting regime. The temperatures
BIOL ~YCh'IATRY 199| :29:43A- |85A
Basic Science
79A
in the four groups were quite similar, but the means were higher and the amp~mdes blunted compared to those in the firstexperiment. It was thought that handling-induced changes irLcore l,,-,o6ytemperat-ure the continuous lighting rcgi:,nemight obscure any differences in circadian rhyrahms. These results c~early established that the FSL rats exhibited a phase advance of their temperature ~ahrn when recordings wer~ done in undistutl~d rats on a 12/12 light/darkcycle. Thus, the circadian rhythm ~ ch~linergic supersensitivityhypotheses of depressive disorders may be overlapping.
79
OXOTREMORINE INDUCED HYPOTHERMIA AS AN P,IDEX OF POSTNATAL DEVELOPMENT OF CHOLINERGIC ~ N C ~ O N IN A GENETICALLY SELECTED P~AT MODEL OF DEPRESSION Lyn Daws, B.Sc., David Overstreet, Ph.D., Grant Schiller, Ph.D. School of Biological Sciences, Flinders University, Adelaide, S.A. 5001 Australia, Adult Flinder~ Sensitive Line (FSL) rats---selectively bred for increased cho~inergic function--satisfy basic criteria as a rodent model af depressive disorders. A study of the developmental profile of oxotremor~,aeinduced hypothermia in male FSL and Hinders Resistant Line {FRL, control line) rats ~ c a t e s that FSL rats are comparatively supersensitive to the hypothermic effects of oxotremorine (0.25 nmo[e/kg, sc, rain) as early as i0 days post partum (pp), which is around the time of the appearance of homeothermy. This suggests an innate cholinergic hyperfunction in FSL rats. Hov, ever, thereafter, the thermomodulatory profile becomes complex: between days 10 to 15 pp, there is a progressive reduction in the extent of oxotremorine-induced hypothermia; then, from day 18 pp into adulthood there is a clear and incremental supersensitivity of FSL rats to the hypothermic effects of oxotremorine compared to the FRL. Dose-response curves are paradoxically U-shaped at 13 days pp, but acquire the classic sigmoid appearance by 21 days pp. While a small comparative increase in muscarinic receptor number has been noted in the hypothalamus of adult FSL rats, the present results suggest post-receptor mechanisms may account for the ch~I[nergic sensitivity differences observed. The substantial differ.ace in choliner~c sensitivity between FSL and FRL rats, and its early ontogenefic appearance suggest that cho|inerg~= hyperfunction is a trait marker of the predisposition towards depressive tendencies in FSL rats.
80
BENZODIAZEPINE EFFECTS ON FLICKER DETECTION: NEW LOOK AT AN OLD MEASURE IN PSYCHOPHARMACOLOGY Richard J. Maddock, M.D., Evanne Casson, PhD., Cameron S Ca,qer, ~'~ n.B S Scott J Woodley, B°"o Chris A. Johnson, Ph.D. •
~.¥J.
JL3
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University of California Davis, School of Medicine, Sacramento, CA 95517. Flicker fusion threshold is a widely used measure of CNS drug effects. However, it assesses only a narrow bandwidth of temporal information processing in the visual system. Typically, flicker fusion threshold measures the threshold for flicker detect/on at high frequencies (>30 Hz). However, temporally modulated visual stimuli appear to be processed by two par~llel neuronal systems e~mnding from the retina through the visual cortex. The parvocellular system is most sensitive to flicker at low and intermediate frequencies, while the magnocellular system is most sensitive to k~termediate and high frequencies. Peak sensitivity of the whole system in humans occurs at intermediate frequencies (8-16 Hz). This study examines benzodiazepine effects on flicker sensitivity across a range of frequencies. Based on previous work, we hypothesized a ~eater drug effect on low, compared to high frequency flicker detection. Luminance modulation thresholds for the detection of flicker was assessed at l, 2, 4, 8, 16, and 32 Hz in eight subjects before and after 0.25 mg of triazolam (p.o.) and placebo using a stimulus (5 °, 100 c/m z) presented either to the fovea, right, or left visual field. Preliminary analysis on 6 subjects shows highly significant drug effects at all frequencies and locations. Drug effects are similar at each location. However, the triazolam-induced decrement in fovea! flicker sensitivity is greater at l and 2 Hz than at ~6 and 32 Hz. The final results will be presented and
BIOL PSYCHIATRY 19ql ;29:43A-185A
Basic Science
receptor. Kappa receptor agonists can produce psychotomimetic effects in humans, thus dyorphin may be relevant in schizophrenia and mood disorders. Prodyn peptides have been previously studied in various brain regions such as ihe hippocampus and the basal ganglia; in primates, these pepfides also exist in fairly high concentrations in the cortex, but a detailed investigation of the distribution of these peptides in cortex has not yet been performed. To begin to understand the nature of cortical prodyn-derived peptid~ we studied the distributions of dyn A (1-17), dyn A 0 - 8 ) , dyn B, and ¢t-neo-endotphin in twelve c~..cal areas in six monkeys (macaca nemestrina). There were between-region diffe~nces in amount of each peptide in the twelve cortical areas studied, suggesting regional heterogeneity in the distribution of prod~n in primate cortex. Because dyn A (1-17) has greater kappa opiate receptor affinity than its processed product, dyn A (1-8), ratios of these two forms were determined. D~a A (l-I?)/dyn A (!-8) ratios were greater in cortex than found in the basal ganglia, suggesting the possibility of increased kappa tone in the cortex relative to the neostriatum. These results may have relevance to the study of a variety of psychotic disorders, especially schizophrenia. [Supported by Grants DA02265, MH00818, MH422251, and the Theophile Raphael Fund.]
77
CHOLINERG!C AI:qD SEROTONERGIC PARAMETERS OF BEHAVIOR IN TWO INBRED STRAINS OF MICE: C57BL/6J and DB~2J Charlie L. Swanson Jr., B.S., Joseph N. Hingtgen, Ph.D., Jay R. Simon, Ph.D., Jo ~ I. Nurnberger Jr., M.D., Ph.D. Department of Psychiatry, The Institute of Psychiatric Research, Indiana University Medical Center, Indianapolis, IN 46202-4887. Neur~ansmitter-behavior relationships in inbred strains of mice may relate to heritable behavioral disorders in man. Behavioral effec~'s of cholinergic and serotonergic manipulation in C57BL/KI a~d DBA/~ mice were studied. The mice were observed during three minute observation periods in an open field apparatus. Total crossings, center crossings, and rearings were counted. At baseline, the C57BL/tI strain had more total and center crossings than the DBAI2J strain. Scopolamine and 8-OH-DPAT, a 5-HTIA agonist, produced disparities between the strains significant enough to warrant evaluation in the recombinant mb~.d:, of these strains. The most consistent discriminator of the twos~",,ins wan the behavioral response to 8-OHDPAT (CS"BLJ-6J mice decreased center crossings while DBA/2J mice increased center crossings). Future studies will investigate receptor binding and neurotransmiVier levels in the parent and recombinant inbred strains of these mice. (Supported in part by the Indiana Deparm~nt of Menial Health.)
78
TEMPERATURE RHYTHMS, DEPRESSION, AND CHOLINERGIC SUPERSENSITIVITY David Overstreet, Ph.D., Peter Sh/remani~ Ph.D., Lynette Daws, B.Sc., Grant Schiller, Ph.D. School of Biological Sciences, Flinders University, Adelaide, S.A. 5001 Australia. The cholinergic arid circadian rhythm hypotheses of depression have generally been regarded as independent models with considerable experimental support. However, the fact that ~ e Hinders Sensitive Liue (FSL) rats, selectively bred for increased cholinergic function and resembling human depressives, exhibited changes in REM sleep suggested that these two models might be related. The present experiment examined circadian temperature rhythms in the FSL and control rats in order to explore this relationship further. The first experiment, conducted in San Diego, recorded temperatures from implanted mini-mitters in 6 FSL and control rats housed under a 12/12 fight/dark regime. The FSL rats reached peak temperature 2.6 hr earlier than the control rats, but there were no differences in the 24 hr mean temperature or the amplitude. The second study, conducted at Flinders University, used rectal thermistor probes to record temperature in 3045 rats of each strain and sex every 3 hr for 36 hr under a continuous lighting regime. The temperatures
BIOL ~YCh'IATRY 199| :29:43A- |85A
Basic Science
79A
in the four groups were quite similar, but the means were higher and the amp~mdes blunted compared to those in the firstexperiment. It was thought that handling-induced changes irLcore l,,-,o6ytemperat-ure the continuous lighting rcgi:,nemight obscure any differences in circadian rhyrahms. These results c~early established that the FSL rats exhibited a phase advance of their temperature ~ahrn when recordings wer~ done in undistutl~d rats on a 12/12 light/darkcycle. Thus, the circadian rhythm ~ ch~linergic supersensitivityhypotheses of depressive disorders may be overlapping.
79
OXOTREMORINE INDUCED HYPOTHERMIA AS AN P,IDEX OF POSTNATAL DEVELOPMENT OF CHOLINERGIC ~ N C ~ O N IN A GENETICALLY SELECTED P~AT MODEL OF DEPRESSION Lyn Daws, B.Sc., David Overstreet, Ph.D., Grant Schiller, Ph.D. School of Biological Sciences, Flinders University, Adelaide, S.A. 5001 Australia, Adult Flinder~ Sensitive Line (FSL) rats---selectively bred for increased cho~inergic function--satisfy basic criteria as a rodent model af depressive disorders. A study of the developmental profile of oxotremor~,aeinduced hypothermia in male FSL and Hinders Resistant Line {FRL, control line) rats ~ c a t e s that FSL rats are comparatively supersensitive to the hypothermic effects of oxotremorine (0.25 nmo[e/kg, sc, rain) as early as i0 days post partum (pp), which is around the time of the appearance of homeothermy. This suggests an innate cholinergic hyperfunction in FSL rats. Hov, ever, thereafter, the thermomodulatory profile becomes complex: between days 10 to 15 pp, there is a progressive reduction in the extent of oxotremorine-induced hypothermia; then, from day 18 pp into adulthood there is a clear and incremental supersensitivity of FSL rats to the hypothermic effects of oxotremorine compared to the FRL. Dose-response curves are paradoxically U-shaped at 13 days pp, but acquire the classic sigmoid appearance by 21 days pp. While a small comparative increase in muscarinic receptor number has been noted in the hypothalamus of adult FSL rats, the present results suggest post-receptor mechanisms may account for the ch~I[nergic sensitivity differences observed. The substantial differ.ace in choliner~c sensitivity between FSL and FRL rats, and its early ontogenefic appearance suggest that cho|inerg~= hyperfunction is a trait marker of the predisposition towards depressive tendencies in FSL rats.
80
BENZODIAZEPINE EFFECTS ON FLICKER DETECTION: NEW LOOK AT AN OLD MEASURE IN PSYCHOPHARMACOLOGY Richard J. Maddock, M.D., Evanne Casson, PhD., Cameron S Ca,qer, ~'~ n.B S Scott J Woodley, B°"o Chris A. Johnson, Ph.D. •
~.¥J.
JL3
~
•
• ,
University of California Davis, School of Medicine, Sacramento, CA 95517. Flicker fusion threshold is a widely used measure of CNS drug effects. However, it assesses only a narrow bandwidth of temporal information processing in the visual system. Typically, flicker fusion threshold measures the threshold for flicker detect/on at high frequencies (>30 Hz). However, temporally modulated visual stimuli appear to be processed by two par~llel neuronal systems e~mnding from the retina through the visual cortex. The parvocellular system is most sensitive to flicker at low and intermediate frequencies, while the magnocellular system is most sensitive to k~termediate and high frequencies. Peak sensitivity of the whole system in humans occurs at intermediate frequencies (8-16 Hz). This study examines benzodiazepine effects on flicker sensitivity across a range of frequencies. Based on previous work, we hypothesized a ~eater drug effect on low, compared to high frequency flicker detection. Luminance modulation thresholds for the detection of flicker was assessed at l, 2, 4, 8, 16, and 32 Hz in eight subjects before and after 0.25 mg of triazolam (p.o.) and placebo using a stimulus (5 °, 100 c/m z) presented either to the fovea, right, or left visual field. Preliminary analysis on 6 subjects shows highly significant drug effects at all frequencies and locations. Drug effects are similar at each location. However, the triazolam-induced decrement in fovea! flicker sensitivity is greater at l and 2 Hz than at ~6 and 32 Hz. The final results will be presented and