Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl− cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats

Abstract

Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.

Neurodevelopment is Particular Vulnerable in Neonatal Male Rats Subjected to Maternal Separation

“…After repeated separation for 3 hours per day, rats showed a greater hypothalamic-pituitary-adrenal (HPA) axis response to acute restraint stress compared to non-separated control rats [6]. Before we found a brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala CRH and some gene expression in male rats [7]. Even 2h maternal separation showed abnormal electroencephalogram activity [8].…”

“…Early separation may act as a stressor and have adverse effects on adult neural and behavioral outcomes [7,22]. Maternal separation is an animal model of early life stress that modulates the HPA axis and studies the neurobiological underpinnings of disruption of the mother-infant relationship and loss of parental care, a highly prevalent condition in humans [23].…”

Repeated Sevoflurane Exposures in Neonatal Rats Increased the Brain Vulnerability to Future Stress Exposure and Resulted in Fear-extinction Deficit

“…Disturbing NKCC1/KCC2 balance was associated with brain circuit hyperexcitability and contributed to a wide spectrum of stress-related neurocognitive and psychosocial dysfunctions [21][22][23][24][25]. The peak expression of NKCC1 in rodents is around P5-P7 [18], which provide the driving force for depolarizing GABA A R-mediated responses in immature neurons [18,22,26].…”

Impact of Genetic Variation on Stress‐Related Ethanol Consumption

“…Corticotropin‐releasing hormone (Crh) is one of the main peptide hormones responsible for transduction of stress responses and HPA axis activation. Alterations in Crh signaling due to stress exposure or genetic modification are associated with changes in alcohol consumption or seeking behavior in rodent models (Broccoli et al., ; Yang et al., ). Neuroligins are synaptic cell adhesion proteins important for the organization of excitatory and inhibitory synapses.…”