Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference,and delays morphine extinction in rats

Objective It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor （NMDAR）, play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 （GLT-1） （ceftriaxone） are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference （CPP） than either compound alone. Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory （acquisition, extinction, and reinstatement of morphine preference） in rats. Results A low dose of neither MK-801 （0.05 mg/kg, i.p.） nor ceftriaxone （25 mg/kg, i.p.） alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. Conclusion The combined action of a low dose of an NMDAR antagonist （MK-801） and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.

Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Background:Parkinson’s disease(PD)is a neurodegenerative disease characterized by intraneuronal Lewy Body(LB)aggregates composed of misfolded alpha-synuclein(α-syn).The spread of misfoldedα-syn follows a typical pattern:starting in the olfactory bulb(OB)and the gut,this pathology is followed by the progressive invasion of misfoldedα-syn to the posterior part of the brain.It is unknown whether the administration of human mutant alpha-synuclein(hm-α-syn,a human mutation which occurs in familial PD)into the OB of rats would trigger similarα-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD.Methods:hm-α-syn was overexpressed in the OB of rats with an AAV injection.Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection.In follow-up studies,pathological mechanisms ofα-syn spread were explored at the histological,biochemical and micro-structure levels.Results:The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection.1)overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope.2)The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra(SN)12 weeks after AAV injection.This was consistent with decreased levels of the DA neurotransmitter.Importantly,behavioral dysfunctions were found that included olfactory impairment after 3 weeks,motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3)The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB,prefrontal cortex(PFC),hippocampus(Hip)and striatum caudate putamen(CPU)were decreased.4)phosphorylatedα-syn,at Ser-129(pSer129),was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone,which was also found in the most of LB stained by the thioflavine S(ThS)in the SN field.5)A marker of autophagy(LC3B)was increased in serval fields,which was colacolizated with a marker of apoptosis in the SN field.Conclusions:These results demonstrate that expression of exogenous mutantα-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenicα-syn to adjacent fields.This method may be useful for establishing an animal model of prodromal PD.

Retraction Note: Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Retraction Note:Translational Neurodegeneration(2018)7:25 https://doi.org/10.1186/s40035-018-0128-6 The Editor-in-Chief has retracted this article.After pub-lication,concerns were raised regarding image overlap across various panels in Fig.8.The authors have stated that incorrect images were used,but have been unable to provide the full raw data.Additionally,the authors could not justify the anesthetic protocol used for rat stereotaxic surgery.The Editor-in-Chief therefore no longer has con-fidence in the presented data and ethics of this article.Author Haichen Niu has stated on behalf of all co-authors that they agree to this retraction.