Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol

Abstract

Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. In vivo GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.

Phasic and Tonic Locus Coeruleus Stimulation Associated Valence Learning Engages Distinct Adrenoceptors in the Rat Basolateral Amygdala

“…Our work demonstrates positive and negative valence signaling associated with phasic and tonic LC activity, respectively [see also Ghosh et al (2021) ]. This is in line with recent findings suggesting the role of tonic LC activity in negative valence signaling ( McCall et al, 2015 , 2017 ; Hirschberg et al, 2017 ; Llorca-Torralba et al, 2019 ), as well as findings of positive valence associated with LC activation ( Chen et al, 2021 ). Synaptic plasticity in the BLA mediates the formation of associative memories of both positive and negative valences ( Namburi et al, 2015 ).…”

“…The roles of adrenoceptors in reward/appetitive learning are much less understood. The hedonic value of LC-NE was first proposed in the 70’s ( Ritter and Stein, 1973 ) and has been supported by recent evidence ( Chen et al, 2021 ; Ghosh et al, 2021 ). Our work provides some of the first evidence of specific BLA adrenoceptor involvement in positive valence formation.…”

Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure

“…To uncover the effect of different doses of Propofol on cognitive function, 4 mg.kg −1 (L-Propofol, sub-anesthesia dose reported) (Chen et al, 2021 ) and 50 mg.kg −1 (H-Propofol, anesthesia dose used previously) (Jiang et al, 2018 ) of Propofol were delivered by intraperitoneal (i.p.) injection on PND 7 C57BL/6N mice, and behavioral tests were conducted according to the workflow ( Figure 1A ).…”

“…To explore the effect of Propofol applied in sedation or anesthesia in pediatrics on brain development, we first tested the sub-anesthesia dosage, 4 mg.kg −1 (L-Propofol) (Chen et al, 2021 ) along with the frequently used dosage in mice and 50 mg.kg −1 (H-Propofol) in cognitive function of neonatal mice (Jiang et al, 2018 ). As reported before, under 50 mg.kg −1 , slightly impaired spatial learning function in the acquisition test was observed (Zhong et al, 2018 ).…”

Effect of Intraoperative Propofol-Induced Sedation on the Neurotransmitter Levels (Pilot Study)

“…Другой мишенью пропофола является вентральная покрышка (ВП) среднего мозга, которая служит началом мезокортикального и мезолимбического дофаминовых путей, участвующих в поведенческих реакциях и поддержании состояния бодрствования [14]. Например, в эксперименте повреждение ВП или применение антагонистов дофаминовых рецепторов приводило к увеличению времени пробуждения при использовании пропофола [15,16].…”