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.

Enhancement of Aggression Induced by Isolation Rearing is Associated with a Lack of Central Serotonin

Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.

Parkin promotes proteasomal degradation of p62： implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson＇s disease

Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.

Burning products of TA15 titanium alloy by friction oxygen concentration method

The microstructural characteristics, elemental distribution law and microscopic formation mechanism of the burning products of TA15 titanium alloy were investigated by friction oxygen concentration method, associated with in situ observation, X-ray diffraction(XRD),scanning electron microscopy(SEM) and energy-dispersive spectroscopy(EDS) analyses, providing the thoughts to improve fireproof property. The results show that, when the friction contact pressure(p) is 0.20 MPa and oxygen concentration of premixed air flow(c) is 60 vol%, TA15 titanium alloy produces violent sparks and presents dazzling white light during combustion. The generated products after burning are mainly TiOand small amount of AlOoxides. Four distinct zones form from the combustion surface to the alloy matrix, and they are in the sequence of combustion zone, fusion zone, heat-affected zone and transition zone. Further, combustion zone is composed of TiOand A1203 compounds, containing obvious cracks. In the fusion zone, discontinuous oxygenrich Al-based solid solution forms, and the elemental distribution has strong volatility. In the heat-affected zone,there are abundant of Ti-based solid solution and small amount of Al-and Mo-based solid solution. Transition zone is made of lamellar structure. Two technical approaches are given to prevent oxygen diffusion inside the reaction zone and reaction-affected zone. On the one hand,the content of Al is designed as the upper limit of alloy composition; on the other hand, fireproof coatings are deposited on the surface of the alloy.