Analysis Tools
behavior/neurological
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• at 8 weeks of age, homozygotes are viable, fertile and show no significant differences in motor activity (open field and elevated plus maze), exploratory behavior (hole board), motor learning and coordination (rotarod) or body weight relative to wild-type controls
• upon chronic high-dose midazolam addiction, homozygotes show no differences in the preference for midazolam over sucrose, body weight, or basic behaviors (e.g. locomotion and scratching) relative to wild-type controls
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• following diazepam treatment, male homozygotes display significantly faster improvement of performance on the rotarod, consistent with a more rapid development of tolerance to diazepam relative to similarly treated wild-type males
• in contrast, female diazepam-treated homozygotes show no differences in rotarod performance relative to wild-type controls
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• diazepam-naive homozygotes display a higher pentylenetetrazole (PTZ)-induced seizure propensity relative to wild-type controls (significant in females, strong tendency in males)
• flumazenil-induced diazepam withdrawal does not further increase PTZ-induced seizure propensity in either sex; under conditions of diazepam withdrawal, female homozygotes show a seizure propensity that is similar to that in wild-type females, pointing to a ceiling effect
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• in the open field, both male and female homozygotes exhibit an increased latency to reach the wall upon release in the center zone relative to wild-type controls
• when placed in a novel chamber (fear-conditioning box), both male and female homozygotes display an increased (unspecifc) novelty-induced freezing response relative to wild-type controls
• however, no differences in anxiety-related behavior are observed in the elevated plus-maze or light-dark box test
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• in the open field test, female (but not male), homozygotes make fewer visits to the center and spend significantly more time in the periphery walls
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• homozygotes show a heightened novelty-induced anxiety level, with a more pronounced effect noted in females
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nervous system
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• diazepam-naive homozygotes display a higher pentylenetetrazole (PTZ)-induced seizure propensity relative to wild-type controls (significant in females, strong tendency in males)
• flumazenil-induced diazepam withdrawal does not further increase PTZ-induced seizure propensity in either sex; under conditions of diazepam withdrawal, female homozygotes show a seizure propensity that is similar to that in wild-type females, pointing to a ceiling effect
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• under vehicle (DMSO) control conditions, mutant ventromedial hypothalamus slices show a significantly increased action potential (AP) frequency relative to wild-type slices, with no further increase under diazepam withdrawal conditions; in contrast, wild-type slices show a significant increase in AP frequency under diazepam withdrawal conditions relative to vehicle-treated WT slices
• however, no significant differences in the resting membrane potentials, AP rise times, decay times or half-widths are observed
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• under diazepam withdrawal conditions, mutant ventromedial hypothalamus slices fail to exhibit an increase in IPSC amplitude and frequency relative to vehicle-treated mutant slices
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• under diazepam withdrawal conditions, wild-type mIPSC amplitudes are 27% smaller than in mutant hypothalamus slices, and wild-type mIPSC rise times are 13% longer than in mutant slices, suggesting lack of a homeostatic adaptation to diazepam treatment in mutant slices
• however, no significant differences in mIPSC decay times or frequencies are observed
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