Dopamine D1 receptor in the NAc shell is involved in delayed emergence from isoflurane anesthesia in aged mice

Abstract

Background Delayed emergence after general anesthesia tends to occur in the elderly population, but the mechanism remains unclear. Apart from age‐related pharmacokinetic changes, the aging‐induced structural and functional alterations in the arousal‐promoting neural substrates should be considered. The nucleus accumbens (NAc) is a crucial arousal‐related nucleus, in which activating medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) could facilitate the arousal from natural sleep. Meanwhile, the dopaminergic systems decline with aging in multiple brain regions. However, whether the age‐related decline in D1R in the NAc shell attenuates its arousal‐promoting capacity from general anesthesia remains to be elucidated. Methods We first verified the delayed emergence from isoflurane anesthesia and examined the corresponding changes of electroencephalogram (EEG) power in aged mice. In turn, the arousal‐modulating capacity of D1R was characterized in the young and aged cohorts by microinjection of D1R agonist/antagonist into the NAc shell. Furthermore, to address the possible mechanism responsible for the attenuated arousal‐modulating capacity of the aged NAc, the expression of D1R in the NAc shell was measured and compared between young and aged mice. Results Our data indicated that compared with young mice, the emergence time in aged mice was notably longer, while EEG power in δ band (1‐4Hz) was significantly higher and power in β band (12‐25Hz) was lower. Activating or inhibiting D1R in the NAc shell by microinjection D1R agonist/antagonist promoted or delayed the emergence process in young mice. Nevertheless, this modulation capacity of D1R in the NAc shell declined in aged mice, respectively. Meanwhile, downregulation of D1R expression in the NAc shell was detected in the aged brain. Conclusion Together, these results suggest that aging attenuates the arousal‐modulating capacity of D1R in the NAc shell probably through downregulation of D1R expression therein, which may provide a potential explanation and a therapeutic target for increased sensitivity to anesthetics in the elderly patients.

Dopaminergic Projections From the Ventral Tegmental Area to the Nucleus Accumbens Modulate Sevoflurane Anesthesia in Mice

“…The NAc participates in maintaining consciousness, and activation of the NAc potentiates the response to a general anesthetic (Ma and Leung, 2006). A previous study found that NAc-D1R in the NAc was involved in regulating the process of emergence from general anesthesia in aged mice (Zhang et al, 2020(Zhang et al, , 2021. These findings suggest that the NAc apparently regulates general anesthesia.…”

“…Our above results show that VTA-DA neurons are involved in modulating the state of sevoflurane anesthesia. In our previous study, we found that D1 receptors in the NAc were involved in modulating the process of emergence from general anesthesia (Zhang et al, 2020(Zhang et al, , 2021. To investigate whether sevoflurane had an influence on the change in the level of dopamine neurotransmitters in VTA-related downstream NAc areas, we measured the dynamics of the extracellular dopamine concentrations during sevoflurane anesthesia in the mouse NAc.…”

“…Using intracerebral microdialysis, Léna et al (2005) show that extracellular dopamine levels in the NAc are higher during arousal states than during slow-wave sleep. In addition, our previous studies indicate that microinjection of a D1 receptors (D1R) agonist into the NAc shell accelerates the emergence process from isoflurane anesthesia in mice (Zhang et al, 2020). Now, the most commonly used volatile anesthetic agent is sevoflurane which is an ideal drug for its pleasant smell, non-irritant effect on the airways and low blood-gas partition coefficient, especially for children (Boonmak et al, 2016;Brioni et al, 2017;Xu et al, 2020) Therefore, we speculate that VTA-DA neurons modulate the process of sevofluraneinduced general anesthesia through projections to the NAc.…”

The role of intracerebral dopamine D1 and D2 receptors in sleep‐wake cycles and general anesthesia

“…In another study, microinjecting D1R agonist or antagonist facilitated or delayed the awakening from isoflurane anesthesia in young mice by activating or inhibiting D1Rs in the NAc shell, respectively. Nonetheless, this modulation capacity of D1Rs in the NAc shell declined in aged mice 37 . Meanwhile, downregulation of D1R expression in the NAc shell was detected in the aged brain, which was associated with delayed awakening in aged mice under isoflurane anesthesia 37 .…”

Activation of Dopamine 4 Receptor Subtype Enhances Gamma Oscillations in Hippocampal Slices of Aged Mice

“…Studies about the DA levels and DA synthesis capacity are controversial, some reported DA synthesis capacity are relatively preserved in aging ( Karrer et al, 2017 ; Von Linstow et al, 2017 ), but Norrara et al, 2018 reported a significant decrease in the tyrosine hydroxylase immunoreactivity across nucleus accumbens in aged animals ( Norrara et al, 2018 ). The expression of D1-like dopamine receptors is reduced in the hippocampus of aged rodents ( Guo et al, 2017 ; Zhang et al, 2021 ) and humans ( Karrer et al, 2017 ), whereas the expression of D2-like receptors is less or not age-dependent ( Dang et al, 2017 ; Karrer et al, 2017 ; Seaman et al, 2019 ). Interestingly, the expression of DR4, a major D2-like receptor, prominently expressed in PV-expressing interneurons ( Andersson et al, 2012b ), is preserved in the aged mouse hippocampus ( Guo et al, 2017 ).…”