Effect of GNTI, a kappa opioid receptor antagonist, on MK-801-induced hyperlocomotion and stereotypy in mice.

AIM: To examine the effect of GNTI [5'-guanidinyl-17-(cyclopropylmethyl)-6,7- dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan], a selective antagonist for the kappa opioid receptor, in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia. METHODS: Two doses of MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis. RESULTS: GNTI inhibited MK-801-induced hyperlocomotion and stereotypy. In particular, GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg vs 0.6 mg/kg MK-801. CONCLUSION: Antagonism of kappa opioid receptors attenuates MK-801-induced behavior, suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia. GNTI appears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

SNAP-25 in hippocampal CA3 region is required for long-term memory formation.

SNAP-25 is a synaptosomal protein of 25 kDa, a key component of synaptic vesicle-docking/fusion machinery, and plays a critical role in exocytosis and neurotransmitter release. We previously reported that SNAP-25 in the hippocampal CA1 region is involved in consolidation of contextual fear memory and water-maze spatial memory (Hou et al. European J Neuroscience, 20: 1593-1603, 2004). SNAP-25 is expressed not only in the CA1 region, but also in the CA3 region, and the SNAP-25 mRNA level in the CA3 region is higher than in the CA1 region. Here, we provide evidence that SNAP-25 in the CA3 region is also involved in learning/memory. Intra-CA3 infusion of SNAP-25 antisense oligonucleotide impaired both long-term contextual fear memory and water-maze spatial memory, with short-term memory intact. Furthermore, the SNAP-25 antisense oligonucleotide suppressed the long-term potentiation (LTP) of field excitatory post-synaptic potential (fEPSP) in the mossy-fiber pathway (DG-CA3 pathway), with no effect on paired-pulse facilitation of the fEPSP. These results are consistent with the notion that SNAP-25 in the hippocampal CA3 region is required for long-term memory formation.

The negative cell cycle regulator, Tob (transducer of ErbB-2), is involved in motor skill learning.

Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647-659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam.

Identification and characterization of hmr19 gene encoding a multidrug resistance efflux protein from Streptomyces hygroscopicus subsp. yingchengensis strain 10-22.

The hmr19 gene was cloned from Streptomyces hygroscopicus subsp. yingchengensis strain 10-22, a bacterium strain producing agricultural antibiotics. Sequence similarity comparison indicates that hmr19 gene may encode a predicted protein with 14 putative transmembrane alpha-helical spanners, belonging to the drug:H(+) antiporter-2 family of the major facilitator superfamily. The expression of hmr19 in the mycelium of strain 10-22 was detected by Western blotting analysis. Gene replacement technology was employed to construct an hmr19 disruption mutant. The growth inhibition test against different antibiotics indicated that the mutant strain was 5-20 fold more susceptible to tetracycline, vancomycin and mitomycin C than the parental wild type strain. The mutant took up tetracycline much faster and accumulated more antibiotics than the wild type strain 10-22. While with the addition of an energy uncoupler, carbonyl cyanide m-chlorophenylhydrazone, the characteristics of the accumulation of [(3)H]tetracycline in these two strains were almost the same. It was thus concluded that hmr19 encoded a multidrug resistance efflux protein.

[Animal models of schizophrenia using different laboratory mouse strains].

Based on the glutamate dysfunction hypothesis for the pathophysiology of schizophrenia, MK801, a noncompetitive antagonist for the NMDA-type of glutamate receptors, was administered to mice by i.p. injection. We observed hyperlocomotion and stereotypy, two behavioral signs indicative of schizophrenic symptoms in human. Aided with automated movement measuring of locomotion and videotaping for off-line scoring of stereotypy, these two schizophrenia-like behaviors were readily evaluated. According to the result of dose-response measurements of serial MK801 dosages in the BALB/c inbred mice, 0.6 mg/kg MK801 was determined as the optimum dosage for these behaviors. Furthermore, the same experiments were performed in another inbred strain C57BL/6 and the outbred stock ICR, and similar results were obtained. These results show that MK801 induces schizophrenia-like symptoms in both inbred and outbred mice. Risperidone, an atypical antipsychotic drug for treating schizophrenia in human, was used in the schizophrenia models using BALB/c and C57BL/6 mice. The results indicated that risperidone dose-dependently inhibited the MK801-induced schizophrenia-like symptoms in BALB/c and C57BL/6 mice. Thus, our results indicate that the MK801-induced behaviors may serve as useful mouse models of schizophrenia.