Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety

Schroeder, Henri; Humbert, Anne-Claude; Desor, Didier; Nehlig, Astrid

doi:10.1016/s0006-8993(97)00538-6

Cited by 22 publications

(16 citation statements)

References 56 publications

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“…Despite the fact that the tests used in the present study do not allow for a clear dissociation between altered affect and cognition, they do suggest that both domains were impaired concurrently. Our results are in concordance with previously published data that demonstrate that changes induced by exposure to BZDs during gestation and infancy are related to changes in emotionality, to changes in levels of hyperactivity/hyperarousal and attention deficit (Frieder et al, 1984; Livezey et al, 1986; Schroeder et al, 1997) and to changes in memory function. This underscores the usefulness of ontogenetic CZP treatment as an animal model of neurodevelopmental disturbance in the GABAergic system, which may manifest in the domain of behavior.…”

Section: Discussionsupporting

confidence: 94%

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Mikulecká

Šubrt

Stuchlı́k

et al. 2014

Front. Behav. Neurosci.

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Clinical and experimental studies suggest possible risks associated with the repeated administration of benzodiazepines (BZDs) during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP) on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day) was administered from postnatal day (P)7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1) a homing response (HR) test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2) passive avoidance was tested in three trials (at 0, 2 and 24 h intervals) on P12, P15, P18, P25 and P32 rats; (3) within- and between-session habituation was tested in an open field (OF) at P70; and (4) a long-term memory (LTM) version of the Morris water maze (MWM) was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the HR and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test). The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to emotional/motivational responsiveness.

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Section: Discussionsupporting

confidence: 94%

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Mikulecká

Šubrt

Stuchlı́k

et al. 2014

Front. Behav. Neurosci.

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“…These regions include the mamillary body, ventrolateral thalamus, septal nucleus, medial striatum, and globus pallidus (Ableitner et al, 1985;Ableitner and Herz, 1987;Kelly et al, 1986). In addition, a number of anxiogenic pharmacological challenges have been reported to elicit increased LCMRglu in these structures (Pratt et al, 1988;Ableitner and Herz, 1987) and chronic prenatal treatment with diazepam, which produces an anxiolyticlike phenotype in the ''drug-free'' adult, is also associated with reduced LCMRglu in many of these brain regions (Schroeder et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Sex influences the effect of a lifelong increase in serotonin transporter function on cerebral metabolism

Dawson

Ferrington

Olverman

et al. 2009

J of Neuroscience Research

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Polymorphic variation in the human serotonin transporter (SERT; 5-HTT) gene resulting in a lifelong increase in SERT expression is associated with reduced anxiety and a reduced risk of affective disorder. Evidence also suggests that sex influences the effect of this polymorphism on affective functioning. Here we use novel transgenic mice overexpressing human SERT (hSERT OVR) to investigate the possible influence of sex on the alterations in SERT protein expression and cerebral function that occur in response to increased SERT gene transcription. SERT binding levels were significantly increased in the brain of hSERT OVR mice in a region-dependent manner. The increased SERT binding in hSERT OVR mice was more pronounced in female than in male mice. Cerebral metabolism, as reflected by a quantitative index of local cerebral glucose utilization (iLCMRglu), was significantly decreased in many brain regions in hSERT OVR female as compared with wild-type female mice, whereas there was no evidence for a significant effect in any region in males. The ability of hSERT overexpression to modify cerebral metabolism was significantly greater in females than in males. This effect was particularly pronounced in the medial striatum, globus pallidus, somatosensory cortex, mamillary body, and ventrolateral thalamus. Overall, these findings demonstrate that the influence of a lifelong increase in SERT gene transcription on cerebral function is greater in females than in males and may relate, in part, to the influence of sex on genetically driven increases in SERT protein expression.

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“…It is also pertinent to note that, when applied alone, THDOC failed to produce significant changes in most of the parameters of interest (at least, not in the dose used in this study). With regard to therapeutic implications of neurosteroids, the latter finding gains additional importance in view of reports suggesting that other GABA-ergic agonists (for example, benzodiazepines), may induce behavioral alterations, when administered during perinatal life (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

Patchev¹,

Montkowski²,

Rouskova³

et al. 1997

J. Clin. Invest.

118

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Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA A receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABAagonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life. ( J. Clin. Invest. 1997. 99:962-966.)

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Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety

Cited by 22 publications

References 56 publications

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

Sex influences the effect of a lifelong increase in serotonin transporter function on cerebral metabolism

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

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