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.
Highlights
Propofol is the most commonly used intravenous general anesthetic that acts by facilitating the inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA)
Our results suggested that the euphoric effects of subanesthetic dose of propofol are mediated by the activation of locus coeruleus (LC) neurons, not ventral tegmental area (VTA) neurons
Previous studies looked into only one aspect of addiction such as reinforcing effect represented by conditioned place preference (Pain et al, 1996)
Summary
Propofol is the most commonly used intravenous general anesthetic that acts by facilitating the inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). It has been found that a very low concentration of propofol can activate glutamate transmission to dopamine neurons in the VTA (Li et al, 2008). An in vivo microdialysis experiment showed that propofol decreased the dopamine level in the ventral pallidum of free active rats (Grasshoff et al, 2005). Our previous study found that propofol significantly reduced the level of dopamine in the prefrontal cortex of rats (Wang et al, 2016b). These results do not support the idea that the euphoric effects of propofol are mediated by the dopaminergic nervous system
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