Assessment of lisdexamfetamine on executive function in rats: A translational cognitive research.

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.

Effect of aquaporin 4 gene knockout on neuropathic pain and its possible mechanism / 国际药学研究杂志

Objective: To investigate the effect of aquaporin 4(AQP4)in neuropathic pain and explore the rela- tionship with the activation of spinal astrocytes and release of proinflammatory cytokines. Methods: The effect of AQP4 gene knockout(KO)on the pain-related behavior was investigated using the sciatic nerve branch injury model(SNI)of AQP4 KO and wild type(WT)mice. The expression of astrocyte activation-related protein,glial fibrillary acidic protein(GFAP),and the level of proinflammatory cytokines,TNF-α and IL-6,all in the mouse spinal cord samples,were detect- ed by Western blot(WB)and ELISA,respectively. Results: After SNI surgery,compared with the WT group,a signifi- cant attenuation in mechanical allodynia was found in the KO group(P<0.01),however,no difference was detected be- tween two sham groups(Sham)of WT and KO mice(P>0.05). These results indicated that the AQP4 gene knockout re- lieved neuropathic pain. Fouteen days after SNI surgery,WB results showed that the GFAP level in mouse spinal cord was significantly higher in the WT-SNI group than in the WT-Sham group(P<0.01),whereas the GFAP level in the KOSNI group was significantly lower than that in the WT-SNI group(P<0.01). These results indicated that AQP4 KO inhib- ited activation of spinal astrocytes in SNI model mice. In addition,14 days after SNI surgery,ELISA results showed that the levels of mouse spinal cord proinflammatory cytokines,TNF-α and IL-6 in the WT-SNI group were significantly high- er than those in the WT-Sham group(P<0.05 and P<0.01,respectively),whereas the levels of TNF-α and IL-6 in the KO-SNI group were significantly lower than those in the WT-SNI group(P<0.05 and P<0.01,respectively). These re- sults indicated that AQP4 KO inhibited the level of mouse spinal cord proinflammatory cytokines in SNI model mice. Conclusion: The AQP4 gene knockout may relieve the neuropathic pain via the inhibition of the astrocyte activation and proinflammatory cytokine release.

Effect of different extinction methods on morphine-induced conditioned place preference in mouse / 国际药学研究杂志

Objective To compare the effect of extinction using different methods and the subsequent reinstatement of morphine-primed on morphine-induced conditioned place preference (CPP).