Effect Of Exercise During Abstinence On Cognitive Function In Nicotine Dependent Individuals And Its Mechanism

Objective Nicotine abuse has already become a world-wide public health issue. The biggest obstacle to treat nicotine dependence is high relapse rate after nicotine withdrawal. Cognitive deficits during abstinence are key reasons that cause relapse. Exercise can improve cognitive function in normal healthy person, brain sufferers and drug abusers. However, very little research has addressed the relationship between cognitive function of nicotine dependent individuals and exercise, especially whether exercise can improve cognitive deficits, and what are the neural mechanisms underlying exercise-induced improvements. Therefore, firstly, we observed characteristics of cognitive deficits in nicotine withdrawal from the angle of behavior, and explored whether moderate acute exercise could relieve the deficits. What’s more, we also evaluated the carving after nicotine withdrawal and during exercise intervention by scales. Secondly, we investigated the molecular mechanisms underlying different intensities exercise-induced improvements in nicotine withdrawal rats, by the way of replicating cognitive deficits in rats experienced nicotine withdrawl.Methods In the behavior study, 20 nicotine dependence and 20 couterparts among undergraduates were recruited for a between-subject design. Participants who had abstained from smoking for 24 h were asked to complete modified Sternberg task, Go/No Go task and VAS to evaluate working memory, inhibition ability and carving, respectively. Then, extra 30 nicotine dependence among undergraduates who had abstained from smoking for 24 h were recruited. They were randomized to sedentary group(SED, n=15) and moderate exercise group(EX, n=15). All participants were asked to complete modified Sternberg task, Go/No Go task and VAS following 15 min moderate treadmill running, which assessed the cognition and nicotine carving.In the mechanism research, 40 four-week SD male rats were trained for Go/Nogo task after one-week adaptation. conditioned place preference(CPP) paradigm was applied to establish nicotine-dependent rats. All selected rats were then randomly divided into four groups: Sedentary(SED), High-intensity Exercise(HE), Moderate-intensity Exercise(ME) and Low-intensity Exercise(LE). Rats in the exercise groups ran on a treadmill for 30 min daily for 10 days. At the end of the exercise regimen, all the rats were tested for CPP, Go/No Go task, Ymaze, Open field and Morris water maze(MWM), respectively. All the rats were sacrificed by anesthesia to get hippocampus and the prefrontal cortex after 24 h for behavior test. Expression of α7 n ACh Rs protein and downstream signal molecules in the hippocampus and prefrontal cortex were confirmed by Western blot.Results(1) Compared with control group, nicotine withdrawal group completed Sternberg task with longer reaction time and lower accuracy(P<0.01); completed Go/No Go task with lower accuracy(P<0.01); self-reported VAS with higher scores after 12h-, 24h-nicotine withdrawal(P<0.001).(2) Compared with SED group, nicotine withdrawal group completed Sternberg task with higher accuracy(P<0.01), but with similar reaction time; completed Go/No Go task with higher accuracy(P<0.01); self-reported VAS with lower scores during exercise, immediately after exercise and 10 min after exercise(P<0.001), but returned to baseline levels by 20 min after exercise.(3) Compared with SED group, ME and HE groups completed CPP task with lower scores(P<0.01 and P<0.05, respectively) except LED, but these groups did not differ with each other; In Y maze test, only ME group showed greater increase of spontaneous alternation behavior(P<0.01). ME and HE groups entered more frequently into and spent more time in the novel arm(P<0.05), which both groups showed same exploration to the the novel arm; In MWM test, the escape latency of place navigation test was only significantly shortened in ME group(P<0.05). The time and distance of swim in the platform quadrant significantly increased in ME and HE groups on the 5th day(P<0.05), but there was no difference between the two groups. In addition, the number of shuttling target quadrant increased significantly only in ME group rats(P<0.05); In Go/No Go test, ME and HE groups completed No Go task with higher accuracy(P<0.05), but the two groups did not differ in No Go accuracy. The accuracy of Go task was higher than No Go task in all groups(P<0.01); In open field test, the total distance, numbers of central crosses, and numbers of total crosses increased(P<0.01), immobile time reduced significantly, only in ME group(P<0.01).(4) Compared with SED group, the expression of α7 n ACh Rs was only up-regulated significantly in the prefrontal cortex of ME group(P<0.01), while it did not change in the hippocampus.(5) The expression of α7 n ACh Rs in the prefrontal cortex was positively associated with the No Go accuracy, with the indicators of Y maze such as spontaneous alternation behavior, number and time of entering the novel arm, with the indicators of WMW such distance, time and crossings in target quadrant of the probe test, while it was negatively correlated to CPP scores.(6) Compared with SED group, the downstream signal molecules of α7 n ACh Rs, such as relative expression of Epac2, Rap1, SYN, p-Akt and Bcl-2, were significant upregulated in rats’ prefrontal cortex(P<0.05), as well as the ratio of p-Ca MKII/Ca MKII, p-ERK/ERK and p-CREB/CREB(P<0.05), while the relative expression of p-PKA did not differ between all groups. The ratio of p-ERK/ ERK was increased significantly in HE rats’ prefrontal cortex(P<0.05).Conclusion(1) Nicotine withdrawal showed working memory and inhibition ability deficits, and nicotine craving increased gradually over abstinent period(0-24h).(2) Both moderate- and high-intensity exercise during nicotine abstinence can ameliorate cognitive deficits, reduce dependence. But the positive effect of moderateintensity exercise on cognitive improvement and nicotine dependence may be better than high-intensity exercise. And only moderate-intensity exercise can reduce anxietylike behavior.(3) Moderate-intensity treadmill exercise during nicotine abstinence may improve cognitive function, reduce anxiety-like behavior and low nicotine dependence, by the way of up-regulating the expression of α7 n ACh Rs specifically in the prefrontal cortex, as well as many downstream signal transduction pathways synergistically, rather than relying on a certain signal alone.