General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity

Abstract

Accumulating evidence indicates that exposure to general anesthetics during infancy and childhood can cause persistent cognitive impairment, alterations in synaptic plasticity, and, to a lesser extent, increased incidence of behavioral disorders. Unfortunately, the developmental parameters of susceptibility to general anesthetics are not well understood. Adolescence is a critical developmental period wherein multiple late developing brain regions may also be vulnerable to enduring general anesthetic effects. Given the breadth of the adolescent age span, this group potentially represents millions more individuals than those exposed during early childhood. In this study, isoflurane exposure within a well-characterized adolescent period in Sprague-Dawley rats elicited immediate and persistent anxiety-and impulsive-like responding, as well as delayed cognitive impairment into adulthood. These behavioral abnormalities were paralleled by atypical dendritic spine morphology in the prefrontal cortex (PFC) and hippocampus (HPC), suggesting delayed anatomical maturation, and shifts in inhibitory function that suggest hypermaturation of extrasynaptic GABA A receptor inhibition. Preventing this hypermaturation of extrasynaptic GABA A receptor-mediated function in the PFC selectively reversed enhanced impulsivity resulting from adolescent isoflurane exposure. Taken together, these data demonstrate that the developmental window for susceptibility to enduring untoward effects of general anesthetics may be much longer than previously appreciated, and those effects may include affective behaviors in addition to cognition.

General Anesthetic Exposure During Early Adolescence Persistently Alters Ethanol Responses

“…Given the differential EtOH sensitivities observed across adolescent and adults, we next tested the effects of isoflurane exposure on EtOH‐induced memory impairment. We previously reported no differences in baseline memory performance 1 week following adolescent anesthetic exposure (Landin et al, ). However, in the present study, adolescent anesthetic‐exposed rats challenged with a dose of 1 g/kg EtOH were unable to distinguish the novel object from the familiar object, as indicated by the decrease in time spent exploring the novel object when compared with air‐exposed controls ( t 11 = 2.230, p < 0.05; Fig.…”

“…B ). However, memory impairment in isoflurane‐exposed adolescents given an EtOH challenge as adults did not differ from the age‐matched isoflurane‐exposed rats challenged with saline ( not shown—see Landin et al, ). Interestingly, air‐control rats when given an EtOH challenge as adults also had reduced time spent exploring the novel object ( t 15 = 4.348, p < 0.01; Fig.…”

“…Stress also increased EtOH consumption via GABA A ‐R activity in the VTA (Ostroumov et al, ). Our previously observed increases in extrasynaptic GABA A ‐Rs following adolescent anesthetic exposure likely contribute to increased intake (Landin et al, ), given that knockdown of these receptors has been shown to reduce EtOH intake (Nie et al, ). Future studies should identify whether enhancement of extrasynaptic GABA A receptor activity following adolescent GA alters dopaminergic neurons, and whether this is responsible for dysregulating the reward pathway and thus voluntary EtOH consumption.…”

“…Alterations in EtOH responsiveness following anesthetic exposure were not observed when rats were exposed to isoflurane as adults. For example, we previously observed that adult rats exposed to isoflurane did not exhibit alterations in novel object recognition or inhibitory GABA A receptor expression or function (Landin et al, ). In the current study, we observed no changes in EtOH‐induced loss of the righting reflex or CTA following adult isoflurane exposure.…”

“…The consequences of general anesthetic exposure in infants and children have been well investigated and have demonstrated consequent cognitive and behavioral abnormalities (see: Lin et al, , for review). However, the impact of such exposures on later developmental periods, including adolescence, is very limited, but convergent evidence has been observed with respect to memory and learning (see: Landin et al, ; Pavkovic et al, ). To our knowledge, the present study is the first to assess the contribution of developmental anesthetic exposure on behaviors related to substance use disorder vulnerability using an animal model, whereas no human data have directly assessed this association.…”