| Objective:Drug addiction is a chronic relapsing disorder,many clinical studies have shown that chronic heroin or methamphetamine(MA)use is associated with impaired cognitive function and consciousness control ability.Nowadays MA and heroin have become the two most popular addiction drugs in the world.Especially among the registered drug abusers in China,they accounted for 55.1%and 45%respectively,ranking the first two places steadily.the abuse of heroin or MA has become a public safety problem.Methadone maintenance treatment clinics always reported that the patients with opioid dependence often take MA secretly to alleviate their withdrawal symptoms.As a sadative,heroin has very different pharmacological effects from MA which considered as psychostimulant.Whether they can be substituted for each other among their abusers,and what is the consequence of the substitution,has become one of our research directions.Both of the drug abusers showed severe spatial learning and memory impairments.Drug addiction also involves a pathological usurpation of the neural mechanisms underlying learning and memory related to the pursuit of rewards under normal circumstances.As cognitive enhancers,both of Donepezil-one of the acetylcholinesterase inhibitor which is commonly used in clinic,and Roflupram-a new synthetic phosphodiesterase 4 inhibitor which also has anti-inflammatory effects might attenuate the effect of reward and relapse of heroin and MA?That's another directions of our researches.Meanwhile,we also studied whether the heroin affects the recent memory that after drug-administration or the remote memory that before drug-administration.Moreover to study if the heroin had the same effect on spatial reward memory and fearing condition memory.Methods:(1)In heroin groups,rats were trained to self-administer heroin for 10 days underwent different dose of heroin to gain the dose-response curves of heroin.Then used different dose of MA to substitute heroin,and obtained the dose-response curves of substitution.In MA groups,used the same way.Then the two groups of data were compared.Meanwhile,the effects of the substitution priming induced heroin or MA-seeking were compared.(2)Used different doses of Donepezil or Roflupram to pretreat with rats in the time of self-administration or withdraw to study if they had the effect on the heroin reinforcement,or on heroin relative motivational value under the progressive ratio schedule,or on heroin relapse.After behavior tests,all rats were sacrificed and the tissus samples(especially nucleus accumbens)were collected for Immunofluorescence and western-blot to find the changes of some biological markers.(3)In one group,eight-arm maze and Fearing condition were used to test the recent ability of spatial learning and memory and the fear memory which made after two weeks of heroin self-administration on rats.In another group,we used same way to test the remote spatial and fear memory which made before exposure to heroin.Results:(1)The dose-effect curve of heroin showed progressive linear increasing.When the dose was changed upward from 50?g/kg/infusion to 100 or 200?g/kg/infusion,the total dose of heroin which the rat consumed was increased significantly.However,when the dose was changed downward from 50?g/kg/infusion to 12.5 or 25?g/kg/infusion,the total dose of heroin which the rat consumed showed no significant change.When we used different doses of MA substituted for heroin,the dose-effect curve shifted left and upward.Meanwhile,The dose-effect curve of MA showed an irregular inverted U-shaped trend.When the dose was changed downward from 50?g/kg/infusion to 25?g/kg/infusion,the total dose of MA which the rat consumed was decreased significantly.However,when the dose was changed upward from 50?g/kg/infusion to 100 or 200?g/kg/infusion,the total dose of MA which the rat consumed showed no significant change.When we used different doses of heroin substituted for MA,the dose-effect curve shifted rightward.In the self-administration,every hour of MA intake by rats was not stable,the first hours'MA intake was significantly more than other hours.However the heroin intake by rats was stable and equal in every hour.The dose-effect curve of heroin and heroin for substitution were no significant difference at any dose,the same of the dose-effect curve of MA and MA for substitution.A lower dose 30?g/kg MA pretreatment could significantly decrease the reinstatement of heroin seeking of heroin dependent rats,but not the higher dose MA such as 75?g/kg-750?g/kg.Meanwhile 50?g/kg heroin pretreatment could not change the reinstatement of heroin seeking,and 250,1250?g/kg heroin pretreatment could significantly increase the reinstatement of MA seeking of MA dependent rats.(2)3 mg/kg Donepezil significantly inhibit herion self-administration under the FR1 schedule,and decreased the reward values under the progressive ratio schedule in a dose-dependent.In addition,3 mg/kg Donepezil decreased the reinstatement of heroin seeking induced by cues or heroin priming 2-3 weeks after withdraw.However,3 mg/kg Donepezil had no effect on the 25?g/kg/infusion MA substitute for heroin in self-administration under the FR1 schedule.Moreover,3 mg/kg Donepezil could not decrease the reinstatement of MA seeking induced by cues or MA priming 2-3 weeks after withdraw.The treatment with 3 mg/kg Donepezil before heroin priming drug-seeking increased TH,pCREB,D1R,D2R and AMPA expression in NAc after relapse.Among them,D1R and AMPA could be completely co-located.CHAT expression in NAc did not changed after Donepezil pretreated relapse but it increased in VTA.(3)0.03mg/kg Roflupram significantly decreased the reward values under the progressive ratio schedule.Moreover,Systemic 0.03mg/kg Roflupram injection or microinjection of Roflupram(0.2?g/0.5?L/side)into the NAc showed the tread to decrease the reinstatement of heroin seeking induced by cues or heroin priming but not significantly.However 0.01 or 0.03mg/kg Roflupram,failed to inhibit heroin self-administration under the FR1 schedule.TH?D1R?D2R?AMPA expression in NAc did not changed after 0.03mg/kg Roflupram pretreated relapse,but only pCREB expression increased a little.Unfortunately,raised up the pretreatment dose of Roflupram to 0.1 or 0.3 mg/kg did not made any effect on herion self-administration under the FR1 schedule,or on reward values under the progressive ratio schedule.The chronic treatment with Roflupram(0.1 or 0.3mg/kg)at least 5 days in could not decrease the reinstatement of heroin seeking induced by cues or heroin priming.However,we were excited to find that 0.1 mg/kg Roflupram significantly decreased the reinstatement of MA seeking induced by cues or MA priming in MA dependence rats.(4)After 2 weeks heroin self-administration,the reference memory errors,working memory errors and exploration time of each arm in the eight-arm maze in the first two weeks of withdrawal period were significantly less than heroin naive rats.Two weeks after withdrawal,when the maze reward position was reversed and reset,there was no difference in spatial learning and memory between the two groups.However,the recent fear memory in the heroin dependent rats was significantly weaker than the heroin naive rats when tested on the first and tenth days after fearing condition during withdrawal period.In addition,the remote special and fear memory which formed before the rats touched heroin were not significantly difference between the heroin dependent rats and the heroin naive rats,when the tests given once a week during first to fourth weeks on the withdrawal days.Conclusion:(1)Heroin and MA can replace with each other in drug taking.Heroin may need lower dose of MA to substitute whereas MA may need higher dose of herion to substitute.However herion and MA may have their own independent dose-effect response,and not interacting together.(2)Donepezil,an acetylcholinesterase inhibitor,could decrease reward enhancement and motivation enhancement of heroin in rats.Moreover it could significantly alleviate the relapse behavior in heroin dependent rats.The effects of Donepezil on heroin-seeking behavior were at least partially correlated with the increases in expression D1 and AMPA receptor which work together in neurons and up-regulating D2 receptor in the NAc.However,Donepezil could not inhibited MA reward and MA-seeking behavior in MA dependence rats.(3)As PDE4 inhibitor,A small dose of Roflupram could slightly decrease the reinforcement of motivation and relapse of heroin in rats,but had no effect on the heroin reward enhancement.However,chronic and higher doses of Roflupram could nether decrease reward and motivation enhancement of heroin,nor attenuate the reinforcement of relapse in heroin dependent rats.Meanwhile,0.1mg/kg Roflupram had the potential to significantly attenuate the reinforcement of relapse in MA dependent rats.(4)Rats In the stage of heroin withdrawal may suffer from spatial learning and memory impairment and feedback of memory enhancement.Moreover the ability of extracting fear memory may also impaired in that stage. |
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