Neonatal allopregnanolone levels alteration: Effects on behavior and role of the hippocampus

Darbra, Sònia; Mòdol, Laura; Llidó, Anna; Casas, Caty; Vallée, Monique; Pallarès, Marc

doi:10.1016/j.pneurobio.2013.07.007

Cited by 21 publications

(14 citation statements)

References 144 publications

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“…Similarly neonatal rats treated with a single injection of allopregnanolone, a neurosteroid that enhances GABA A R activity, 22 later developed a reduced PPI of startle reactivity. 23,24 Given our findings that propofol stimulates the adrenal secretion of corticosterone in neonatal rats, it is plausible that propofol may enhance GABA A R activity not only through direct interaction with the receptor, but also through stimulation of the corticosterone secretion and an increase of corticosterone precursor-derived neurosteroids, allopregnanolone and tetrahydrodeoxycorticosterone. Furthermore, corticosterone may modulate the levels of neurosteroids in rats by increasing 3α-hydroxysteroid dehydrogenase expression, an enzyme involved in the synthesis of neurosteroids.…”

Section: Discussionmentioning

confidence: 94%

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats

Tan

Zhu

et al. 2014

Anesthesiology

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Background We studied whether neonatal propofol anesthesia affects development of the endocrine and neural systems. Methods Sprague-Dawley rats were anesthetized using intraperitoneal propofol for 5 h on postnatal days (P) 4, 5, or 6. Pups that received either saline or intralipid, but not those in the negative control groups, were also maternally separated for 5 h. Serum levels of corticosterone were measured immediately after anesthesia and in adulthood after prepulse inhibition (PPI) of acoustic startle testing (≥P80), followed by measurement of hippocampal neuronal activity. Results Propofol acutely increased corticosterone levels to 146.6 ± 23.5 ng/ml (n=6) vs 16.4 ± 3.5 ng/ml (n=6) and 18.4 ± 3.2 ng/ml (n=6) in saline- and intralipd-treated pups, respectively. In adulthood, the propofol group exhibited exacerbated endocrine responses to stress in a form of increased corticosterone levels (1171.58 ± 149.17 ng/ml (n=15) vs 370.02 ± 36.01 ng/ml (n=10) in the saline group). The propofol group had increased the frequency of miniature inhibitory postsynaptic currents in CA1 neurons of male and female rats, but reduced PPI of startle was detected only in males. The Na+–K+–2Cl− co-transporter inhibitor bumetanide, administered to pups prior to propofol, alleviated long-term endocrine and PPI abnormalities. Exogenous corticosterone, administered to naïve pups, induced synaptic and endocrine, but not PPI effects, similar to those of propofol. Conclusions Propofol-caused acute increases in corticosterone levels and gamma-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities.

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Section: Discussionmentioning

confidence: 94%

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats

Tan

Zhu

et al. 2014

Anesthesiology

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“…Data available in the literature indicate that THP treatment as well as its withdrawal (i.e., 24 h) transiently increases the expression of α4 subunit in the hippocampus [60]. A decrease of this GABA-A subunit has been reported after neonatal THP treatment [61] or following the development of acute THP tolerance [62]. Usually, the effect of THP on the expression of α4 subunit is associated with changes in the expression of δ subunit [60], which was not affected in our experimental model.…”

Section: Discussionmentioning

confidence: 99%

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

et al. 2015

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The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.

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“…The model has been extended to demonstrate that a variety of early developmental insults to the mesial temporal lobe are accompanied by PPI deficits that emerge in adulthood, including immune/inflammatory activation of the VH (e.g., Zhu et al 2014a, b;Ribeiro et al 2013), neonatal pilocarpine-induced seizures (Labbate et al 2014), and neonatal lesions of the basolateral amygdala (Vázquez-Roque et al 2012). Other in utero or neonatal neurotoxic manipulations also produce PPI deficits in adult rats, including methylazoxymethanol (MAM) exposure (Le Pen et al 2006), elevated neonatal allopregnanolone (Darbra et al 2014), and neonatal administration of NMDA antagonists (Uehara et al 2010). In some cases, the expression of PPI deficits induced by these early developmental manipulations can be blocked by acute treatments during adulthood, using antipsychotics (e.g., clozapine: Ribeiro et al 2013), putative neuroprotective agents (e.g., minocycline: Zhu et al 2014b), and glycinergic agents (Le Pen et al 2003).…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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Animal models of impaired sensorimotor gating, as assessed by prepulse inhibition (PPI) of startle, have demonstrated clear validity at face, predictive, and construct levels for schizophrenia (SZ) therapeutics, neurophysiological endophenotypes, and potential causative insults for this group of disorders. However, with the growing recognition of the heterogeneity of the schizophrenias, and the less sanguine view of the clinical value of antipsychotic (AP) medications, our field must look beyond "validity," to assess the actual utility of these models. At a substantial cost in terms of research support and intellectual capital, what has come from these models, that we can say has actually helped schizophrenia patients? Such introspection is timely, as we are reassessing not only our view of the genetic and pathophysiological diversity of these disorders, but also the predominant strategies for SZ therapeutics; indeed, our field is gaining awareness that we must move away from a "find what's broke and fix it" approach, toward identifying spared neural and cognitive function in SZ patients, and matching these residual neural assets with learning-based therapies. Perhaps, construct-valid models that identify evidence of "spared function" in neural substrates might reveal opportunities for future therapeutics and allow us to study these substrates at a mechanistic level to maximize opportunities for neuroplasticity. Such an effort will require a retooling of our models, and more importantly, a re-evaluation of their utility. For animal models to remain relevant in the search for schizophrenia therapeutics, they will need to focus less on what is valid and focus more on what is useful.

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Neonatal allopregnanolone levels alteration: Effects on behavior and role of the hippocampus

Cited by 21 publications

References 144 publications

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

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