Selective effects on crf neurons and catecholamine terminals in two stress-responsive regions of adult rat brain after prenatal exposure to diazepam

Inglefield, Jon R.; Bitran, Daniel; Olschowka, John A.; Kellogg, Carol K.

doi:10.1016/0361-9230(93)90227-3

Cited by 11 publications

(3 citation statements)

References 47 publications

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“…The present findings that the expression of genes encoding GABA A R, A 1 R and A 2A R was altered in a region-specific manner but not that of 18SrRNA indicate that prenatal diaz-epam may interfere with the development of distinct neurotransmitter/neuromodulator systems (10,(33)(34)(35) rather than diffusely with DNA transcription or RNA stability. Our data on ␣1 GABA A R subunit mRNA expression are in agreement with adult data showing its downregulation in the cortex following chronic DZP exposure (36).…”

Section: Discussionmentioning

confidence: 59%

Prenatal Diazepam Exposure Alters Respiratory Control System and GABAA and Adenosine Receptor Gene Expression in Newborn Rats

et al. 2008

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In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies.

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Section: Discussionmentioning

confidence: 59%

Prenatal Diazepam Exposure Alters Respiratory Control System and GABAA and Adenosine Receptor Gene Expression in Newborn Rats

et al. 2008

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“…On the other hand, BDZs and neuro-steroids, like the tetrahydro metabolites of progesterone, that facilitate GABA-ergic transmission (Orchinik and McEwen, 1993), can counteract the effects of corticosterone on neuronal firing and antagonize the release and action of CRH on the amygdala (Dubrovsky et al, 1985;File et al, 1988;Davis et al, 1994). Prenatal administration of diazepam has also been reported to reduce the number of noradrenergic nerve terminals and that of CRH interneurones selectively in the hypothalamus of the adult offspring (Inglefield et al, 1993). The high lipid solubility of diazepam makes it very likely that the drug produced this effect by acting directly on the foetal brain.…”

Section: Effect Of Maternal Administration Of Modulators Of Gaba Actimentioning

confidence: 96%

Can the Behaviour Abnormalities Induced by Gestational Stress in Rats be Prevented or Reversed?

Weinstock

2002

Stress

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Gestational stress increases circulating maternal hormones that produce changes in behaviour and impair the feedback regulation of the hypothalamic pituitary adrenal axis of the offspring. Prenatally-stressed (PS) rats also release more corticotropin-releasing hormone (CRH) in the limbic system in response to stimulation than controls. This contributes to their exaggerated fear of intimidating situations and depressive-like behaviour. By using different treatments given to the pregnant mother, to neonatal or adult offspring, it has been possible to learn more about the mechanisms underlying the behavioural abnormalities induced by gestational stress. Many of these treatments were also able to prevent or reverse the abnormalities. They included maternal adrenalectomy and replacement of her basal hormone levels to avoid the prolonged elevation of plasma corticosterone, administration of anti-anxiety agents to reduce her reactions to the stress and continuous blockade of opioid receptors to prevent down-regulation of the foetal opioid system and subsequent alterations in behaviour. Hyperanxiety in the adult PS offspring could also be avoided if, as neonates, they were handled daily for 10 days, or given an antidepressant, amitriptyline for 4-5 weeks in the prepubertal period. Increased fear of novelty in adult PS rats could also be abolished by the intracerebro-ventricular administration of a CRH antagonist. This suggests that the new non-peptide CRH1 receptor antagonists that enter the brain might provide an effective treatment for the behaviour abnormalities in the offspring arising as a result of gestational stress.

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“…In prenatally exposed offspring in animal models, signs of abnormal behavior such as chronic anxiety, the inability to habituate to a novel environment, impaired complex discrimination (66,67), impaired learning and memory (68), and delayed suckling function have been observed (69,70). Furthermore, prenatal exposure to diazepam and other BZs appear to alter corticotropin and noradrenergic neuron function involved with stress response systems (9,71). Evidence of adverse neurobehavioral effects after prenatal BZ exposure in humans is limited and no studies of alerted pain reactivity following prenatal exposure have been reported.…”

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confidence: 99%

Prolonged Prenatal Psychotropic Medication Exposure Alters Neonatal Acute Pain Response

et al. 2002

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Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and ␥-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n ϭ 7), paroxetine (n ϭ 11), sertraline (n ϭ 4)]; 16 infants exposed to SSRIs and clonazepam (SEϩ) [paroxetine (n ϭ 14), fluoxetine (n ϭ 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups-[mean (range)] SE:SEϩ 183 (31-281):141 (54 -282) d (p Ͼ 0.05). Infants exposed to SE and SEϩ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied. (Pediatr Res 51: 443-453, 2002) Abbreviations 5HT, 5 hydroxytryptamine (serotonin) BZ, benzodiazepine C, control (nonexposed) infants DA, dopamine GABA, ␥-amino-butyric acid HFP, high-frequency power HRV, heart rate variability LFP, low-frequency power NE, norepinephrine NFCS, Neonatal Facial Coding System NICU, neonatal intensive care unit PKU, phenylketonuria RP, respiratory power RSA, respiratory sinus arrhythmia SE, SSRI-exposed infants SE؉, SSRI-and BZ-exposed infants SSRI, selective serotonin reuptake inhibitors Maternal anxiety and depression are frequently treated during pregnancy with psychotropic medications such as SSRIs and BZs (1). Given that all psychotropic medications diffuse easily across the placenta, clinicians caring for women with psychiatric illness during their pregnancies are faced with the difficult task of making recommendations regarding psychotropic medication use with unknown effects on the growing fetus. To date, none of these medications have been appr...

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Selective effects on crf neurons and catecholamine terminals in two stress-responsive regions of adult rat brain after prenatal exposure to diazepam

Cited by 11 publications

References 47 publications

Prenatal Diazepam Exposure Alters Respiratory Control System and GABAA and Adenosine Receptor Gene Expression in Newborn Rats

Prenatal Diazepam Exposure Alters Respiratory Control System and GABAA and Adenosine Receptor Gene Expression in Newborn Rats

Can the Behaviour Abnormalities Induced by Gestational Stress in Rats be Prevented or Reversed?

Prolonged Prenatal Psychotropic Medication Exposure Alters Neonatal Acute Pain Response

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