The Antagonism of Corticotropin-Releasing Factor Receptor-1 in Brain Suppress Stress-Induced Propofol Self-Administration in Rats

Abstract

Propofol addiction has been detected in humans and rats, which may be facilitated by stress. Corticotropin-releasing factor acts through the corticotropin-releasing factor (CRF) receptor-1 (CRF1R) and CRF2 receptor-2 (CRF2R) and is a crucial candidate target for the interaction between stress and drug abuse, but its role on propofol addiction remains unknown. Tail clip stressful stimulation was performed in rats to test the stress on the establishment of the propofol self-administration behavioral model. Thereafter, the rats were pretreated before the testing session at the bilateral lateral ventricle with one of the doses of antalarmin (CRF1R antagonist, 100–500 ng/site), antisauvagine 30 (CRF2R antagonist, 100–500 ng/site), and RU486 (glucocorticoid receptor antagonist, 100–500 ng/site) or vehicle. The dopamine D1 receptor (D1R) in the nucleus accumbens (NAc) was detected to explore the underlying molecular mechanism. The sucrose self-administration establishment and maintenance, and locomotor activities were also examined to determine the specificity. We found that the establishment of propofol self-administration was promoted in the tail clip treated group (the stress group), which was inhibited by antalarmin at the dose of 100–500 ng/site but was not by antisauvagine 30 or RU486. Accordingly, the expression of D1R in the NAc was attenuated by antalarmin, dose-dependently. Moreover, pretreatments fail to change sucrose self-administration behavior or locomotor activities. This study supports the role of CRF1R in the brain in mediating the central reward processing through D1R in the NAc and provided a possibility that CRF1R antagonist may be a new therapeutic approach for the treatment of propofol addiction.

The excitatory transmission from basolateral nuclues of amygdala to nucleus accumbens shell regulates propofol self‐administration through AMPA receptors

“…The rats were implanted with chronically indwelling intravenous catheters as previously described 27 . This surgery was carried out under sodium pentobarbital anaesthesia (40 mg/kg ip), and the catheters were flushed with 0.2 ml saline‐heparin solution daily to maintain the patency.…”

“…Propofol used in this study was purchased from Fresenius Kabi (10 mg/ml, Beijing, China) and was daily prepared for self‐administration behavioural training. As described in the previous study, 27 a single dose of 1.7 mg/kg/injection of propofol was used for behavioural training. NBQX (0.25, 0.5 and 1.0 μg/0.3 μl/site) (Sigma‐Aldrich, St‐Louis, MO, United States), the AMPARs selective antagonist, was dissolved in sterile saline (NS), and the doses of the agent adopted in this study were determined refer to previous research 28 …”

“…The specification of the self‐administration behavioural training apparatus (Ningbo Addiction Research and Treatment Center, Zhejiang, China) has been described in the previous studies 27 . In brief, the apparatus adopted a custom‐made operant box with a size of 30 cm × 30 cm × 30 cm, and a lower hem of 5 cm above the floor.…”

“…The specification of the self-administration behavioural training apparatus (Ningbo Addiction Research and Treatment Center, Zhejiang, China) has been described in the previous studies. 27 In brief, the apparatus adopted a custom-made operant box with a size of 30 cm  30 cm  30 cm, and a lower hem of 5 cm above the floor. There were two nose-poke operandas (active nose-poke and inactive nose-poke) equipped and located 5 cm above the floor, each with a yellow LED light inside the nose-poke hole.…”

“…The rats were implanted with chronically indwelling intravenous catheters as previously described. 27 This surgery was carried out under sodium pentobarbital anaesthesia (40 mg/kg ip), and the catheters were flushed with 0.2 ml saline-heparin solution daily to maintain the patency. Moreover, the rats were treated with penicillin B through the catheter daily for at least 7 days during recovery period to prevent infection, and the microinjections at bilateral NASh (AP + 1.8 mm, ML ± 1.0 mm, DV -7.8 mm) were through the implanted guide cannulae (20-gauge, Small Parts Inc., United States).…”