Effects Of Anti-estrogen ICI182780on Methamphetamine Reinforcement, Reinstatement, And Cognitive Dysfunction

Objectives: Gender differs markedly with regard to methamphetamine (MA)addiction. In order to clear the possible role of estrogen in MA addiction, our study was tosystematically observed the effects of chronic treatment with ICI182780（ICI）, anestrogen antagonist affected methamphetamine (MA) self-administration and drug seekingbehavior and depressive and anxiety-like behavior and emotional memory after MAtraining.Methods: All of female Sprague-Dawley （SD）rats were trained under a fixed-ratio1(FR1) schedule for12days with intravenous MA (0.05mg/kg per infusion,1-h or6-hsession daily).Rats underwent10daily1-h extinction session, and then tested thereinstatement which induced by cue and drug (1mg/kg MA). At last, animals were testedby using elevated plus-maze test, forced swim test and fear condition memory task,respectively.Result: There were significantly differences in active nose-pokes, dose of MA intakebetween the long access （6h） and short access（1h）trained rats（P<0.01）. Chronictreatment with ICI reduced the active nose-pokes in the1h MA training rats(P<0.05), butnot affect the active responses in6h training rats (P>0.05). Morover, chronic treatmentwith ICI decreased the intake dose of MA in both long and short training rats（P<0.01）.The active nose-pokes in long access group were significantly higher than those of shortaccess group during the first day of extinction session（P<0.01）, in contrast, ICI treatmentdid not change the extinction behavior (P>0.05). Long access MA training rats appearedmore higher active responses induced by cues or MA than those in the short access MAtraining rats, but there were no significant differences between two groups (P>0.05). ICItreatment also failed to inhibit either cue-induced or MA induced-MA seeking behavior(P>0.05).In the elevated plus maze tests，there are not different significantly of the timespending in closed arms between6h MA training and1h MA training rats.While thepercent of time after ICI treatment was higher than that of normal control group(P<0.05).In forced swimming tests,6h MA training prolonged the amount of time spent immobile compared with the normal control group (P<0.01). ICI-treated groups exhibited asignificant different compared with training control group (P<0.01).In the24-hour contextual fear conditioning tests, the freezing time spent by6h MAtraining rats was shorter than that of the control group,(P<0.05), the freezing time spent byICI-treated rats was shorten than that of MA training control group(P<0.01).In one week after contextual fear conditioning, both long access and short access MAtraining rats exhibited a significant reduction of freezing time (P<0.01), while ICI-treatedrats exhibited a significant different compared with MA training control group (P<0.01).Conclusion: The present results showed that the female rats appear to take more doseof MA, but not enhance the MA seeking behavior when exposed more time to MA. MAintake was reduced by chronic treatment with anti-estrogen, and indicating thatendogenous estrogen may be related to the MA reinforcement. MA exposure produced thecognitive dysfunction, but MA exposure did not produce the anxiety-like and depressivebehavior. ICI treatment with MA exposure weakened the anxiety-like behavior andincreased the depression-like behavior, and also facilitated the consolidation of fearconditioning memory. Taken together，the data suggested that estrogen receptor may beinvolved in the MA reinforcement and cognitive dysfunction induced by MA.