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.

Propofol addictive properties have been demonstrated in humans and rats. The glutamatergic transmission from basolateral nucleus of amygdala (BLA) to the nucleus accumbens (NAc) modulates reward-seeking behaviour; especially, NAc shell (NAsh) is implicated in reward-seeking response. Previous studies indicated the interactions between AMPA receptors (AMPARs) and dopamine D1 receptor (D1R) in NAc mediated drug addiction, but whether the circuit of BLA-to-NAsh and AMPARs regulate propofol addiction remains unclear. We trained adult male Sprague-Dawley rats for propofol self-administration to examine the changes of action potentials (APs) and spontaneous excitatory postsynaptic currents (sEPSCs) in the NAsh. Thereafter, optogenetic stimulation with adeno-associated viral vectors microinjections in BLA was used to explore the effect of BLA-to-NAsh on propofol self-administration behaviour (1.7 mg/kg/injection). The pretreatment effects with NBQX (0.25-1.0 μg/0.3 μl/site) or vehicle in the NAsh on propofol self-administration behaviour, the expressions of AMPARs subunits and D1R/ERK/CREB signalling pathway in the NAc were detected. The results showed that the number of APs, amplitude and frequency of sEPSCs were enhanced in propofol self-administrated rats. Propofol selfadministration was inhibited in the NpHR3.0-EYFP group, but in the ChR2-EYFP group, there was a promoting effect, which could be weakened by NBQX pretreatment. NBQX pretreatment also significantly decreased the expressions of GluA2 subunit and D1R in the NAc but did not change the expressions of GluA1 and ERK/CREB signalling pathway. The evidence supports a vital role of BLA-to-NAsh circuit in regulating propofol self-administration and suggests this central reward processing may function through the interaction between AMPARs and D1R in the NAsh.

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