Role of mesocorticolimbic DA system in reinstatement induced by cue

OBJECTIVE Dopamine(DA)plays important roles in Pavlovian conditioning by mediating reward,learning and motivation.While the conditioning stimulation(CS) is the most important inducement for reinstatement in addiction.The present study investigated the specific role of the DA projections to nucleus accumbens(NAc) and medial prefrontal cortices(mPFC) from ventral tegmental area(VTA) in reinstatement induced by cue.METHODS(1)Optogenetic intracranial self-stimulation and reinstatement.DAT-Cre transgenic mice received an injection of adeno-associated viral vectors encoding channelrhodopsin2(ChR2) or control vector into the VTA resulting in the selective expression of these opsins in DA neurons.Then,we stimulated the VTA,NAc(core and shel) or mP FC [prelimbic cortex(PL) and infralimbic cortex(IL)] via an optical fiber.In the reinforcement test,the mice with ChR2 learned instrumental responses corresponding to the delivery of photostimulation into the VTA with multiple frequencies and during time;in the reinstatement phase,stimulation of the DA projections to NAc(core or shell) or mPFC(IL and PL) from VTA to induce reinstatement after 2 weeks of extinction of self-stimulation.(2)Reinstatement in cocaine self-administration.Virus encoding ChR2 or hM4 Di were injected into VTA of DAT-Cre transgenic mice.The mice with ChR2 and hM4 Di in DA neurons were trained to establish self-administration of cocaine.After 2 weeks of extinction,laser stimulation of the DA projections to NAc(core or shel) or mP FC(IL and PL) was conducted to induce reinstatement.After that,Clozapine was injected in NAc core to test the impacts of VTA-NAc core depression on the reinstatement induced by cue.(3) Photometry of VTA DA neurons in reinstatement.DAT-Cre transgenic mice were received an injection of AAV-DIO-Gcamp6 m into VTA.After cocaine self-administration and extinction,mice with Gcamp6 m were challenged by cue(paired with cocaine previously) and the photometry of VTA DA neurons was conducted during the reinstatement.RESULTS(1)The enhanced self-stimulation behavior was positive correlation with the stimulation of DA neurons in VTA according to the increasing frequency of stimulation and extent stimulation duration time.Furthermore,DA receptor antagonists significantly depressed the frequency curve.(2) Only stimulation of the projections to the NAc core from the VTA significantly induced reinstatement after extinction of self-stimulation,neither shell nor mPFC(PL or IL).(3) Depression of VTA-NAc core projection significantly inhibited the reinstatement induced by cue.(4) DA neurons in VTA were activated when the cue appeared during the period of reinstatement test.CONCLUSION Mesocorticolimbic DA system directly modulate the reinforcement dependant on DA receptor.The activity of DA neurons in VTA is necessary for cue induced relapse.Importantly,projections to NAc core from VTA perform the unique effects in reinstatement.

Morphine pre-exposure facilitates reinstatement but attenuates retention of morphine-induced place preference

BACKGROUND： Drug-associated conditioned stimuli are a key factor to induce morphine relapse. To date, limited evidence is available regarding the impact of drug history on propensity or vulnerability to relapse after long-term abstinence. OBJECTIVE： To determine the effect of morphine pre-exposure on acquisition, maintenance and reinstatement of morphine-induced conditioned place preference （CPP） in rats. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Behavior Pharmacology, Institute of Psychology, the Chinese Academy of Sciences, from March to September, 2006. MATERIALS： Morphine hydrochloride was purchased from Qinghai Pharmaceutical, China; CPP software was designed and developed by Taiji Software Company, Beijing, China. METHODS： A total of 64 Sprague Dawley rats were randomly assigned to eight groups （n = 8）. Four morphine pretreatment regimens were used （subcutaneous injections, twice daily for 5 consecutive days and a total of 10 times）： （1） ＂intensive＂ （morphine injections with doses escalating from 10 to 60 mg/kg; （2） ＂moderate＂ （one morphine injection at 5 mg/kg dose and one saline injection at 1 mL/kg daily for 5 days）; and （3） ＂single＂ （nine saline injections at 1 mL/kg followed by one morphine injection at 5 mg/kg; （4） control （ten saline injections at 1 mL/kg）. At 5 days after morphine pretreatment, animals were divided into two subgroups that underwent morphine conditioned or saline conditioned training. The test for acquisition of CPP was performed 24 hours after CPP training. The retention of morphine CPP was measured by repeated tests performed weekly for 1 month after the initial test of place preference. After extinction by pairing each chamber with saline, the reinstatement of place preference by low doses of morphine （0.05, 0.15, 0.45 mg/kg） was tested. MAIN OUTCOME MEASURES： Acquisition, maintenance, and recovery response of CPP behavior. RESULTS： The acquisition magnitude of morphine-induced CPP was not affected by prior morphine exposure （F3, 56=0.17, P 〉 0.05）. However, rats treated with moderate or intensive morphine pretreatment showed a less persistent CPP （t = -1.36, P 〉 0.05; t = -1.18, P 〉 0.05）, but their place preference was reinstated by a low dose of morphine priming （t = -2.55, P 〈 0.05; t = -2.54, P 〈 0.05）. The retention and reinstatement of morphine-induced CPP did not differ between rats with single morphine pre-exposure and control rats. CONCLUSION： Morphine pretreatment enhanced reinstatement of morphine-induced CPP but with less persistence. Individuals with heavy drug exposure are more susceptible to drug relapse when re-exposed to addictive drugs.

An Effort to Reinstatement Support for Truant Students

According to a report by the Ministry of Education,Culture,Sports,Science,and Technology-Japan(MEXT),the number of students who did not attend school in Japan in the fiscal year 2018 was 164,528,and the percentage of students who did not attend school was 1.7%.This is the highest number of students ever.MEXT has been providing various measures to support students’return to school,such as setting up adaptation classes and reviewing the school structure,intending to reduce the number of students who do not attend school.However,it is not always easy to help students return to school,since the problems they face may not be simply academic or psychological in nature.Besides,many students have returned to school,but who have not returned to school in the past.In this paper,we introduce a special needs classroom for truant students.Next,the results of a survey of teachers and assistants in this classroom are discussed.Finally,we will report on our current efforts.

Glu R2-3Y Inhibits the Acquisition and Reinstatement of Morphine-Induced Conditioned Place Preference in Rats

Accumulating evidence indicates that a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors（AMPARs） are involved in the relapse to abused drugs.However, the role of AMPARs containing the Glu R2 subunit in opiate addiction is still unclear. Glu R2-3Y,an interfering peptide, prevents the endocytosis of AMPARs containing the Glu R2 subunit. In this study, we explored the effect of intravenous injection of Glu R2-3Y on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference（m CPP） in rats. We found that infusion of Glu R2-3Y（1.5 nmol/g） one hour before morphine during the conditioning phase inhibited the acquisition of m CPP, while an identical injection one hour before the post-conditioning test had no influence on the expression of m CPP. Injection of Glu R2-3Y（1.5 nmol/g） after m CPP extinction blocked the morphine-induced reinstatement of m CPP. Our results strongly support the hypothesis that inhibition of AMPAR endocytosis provides a new target for the treatment of opiate addiction.

Optogenetic inhibition of medial prefrontal cortex projections to the nucleus accumbens core and methyl supplementation via L-Methionine attenuates cocaine-primed reinstatement

DNA methylation has been identified as a powerful and activity-dependent regulator of changes in the brain that may underlie neuroadaptations in response to various types of stimuli,including exposure to drugs of abuse.Indeed,the medial prefrontal cortex(mPFC)projections to the nucleus accumbens(NAc)are critically important for reinstated cocaine-seeking in a rodent model of cocaine relapse.This circuitry undergoes several epigenetic modifications following cocaine exposure,including changes in DNA methylation that are associated with drug-seeking behavior.We have previously shown that methyl supplementation via L-Methionine(MET)administration attenuates cocaine-seeking behavior and reverses expression and methylation patterns of the immediate early gene c-fos,suggesting that MET may act by altering the excitability of this circuitry during cocaine reinstatement.In the current study,male rats were microinjected with an adeno-associated virus overexpressing halorhodopsin in the mPFC,optical fibers were surgically implanted into the NAc,and the rats were given injections of MET daily.Rats underwent acquisition of cocaine self-administration(0.75 mg/kg/infusion,2-h sessions)followed by extinction training in the absence of drug-paired cues.Two reinstatement tests were conducted:cue-induced reinstatement without optogenetic manipulations and cocaine-primed reinstatement with optogenetic inhibition of mPFC-to-NAc projections.There were no group differences before the cocaine-primed reinstatement session,and all groups showed robust cue-induced reinstatement.Both rats treated with MET and rats that received mPFC-to-NAc inhibition showed an abolishment of cocaine-primed reinstatement,suggesting that systemic methyl supplementation may act through this critical circuity.

The identity of some taxa of Schizophragma (Saxifragaceae)

After examining a large number of type and authoritative specimens of Schizophragma Siebold ＆ Zucc., S. elliptifolium C. F. Wei and S. integrifolium var. glaucescens Rehder were reduced to synonyms of S. hypoglaucum Rehder and S. integrifolium f. cordatum S. Y. Wang was reduced to synonym of S. corylifolium Chun. Schizophragma crassum var. ellipticum J. Anthony was treated as the correct name of S. crassum var. hsitaoanum （Chun） C. F. Wei. The name S. integrifolium var. minus Rehder is reinstated. The taxonomic treatment is supported by leaf epidermal characters.