Strain-Dependent Modifier Genes Determine Survival in Zfp423 Mice.

Zfp423 encodes a transcriptional regulatory protein that interacts with canonical signaling and lineage pathways. Mutations in mouse Zfp423 or its human ortholog ZNF423 are associated with a range of developmental abnormalities reminiscent of ciliopathies, including cerebellar vermis hypoplasia and other midline brain defects. Null mice have reduced viability in most strain backgrounds. Here we show complete lethality on a C57BL/6J background, dominant rescue in backcrosses to any of 13 partner strains, with strain-dependent survival frequencies, and evidence for a BALB/c-derived survival modifier locus on chromosome 5. Survival data indicate both perinatal and postnatal periods of lethality. Anatomical data from a hypomorphic gene trap allele observed on both C57BL/6J and BALB/c congenic backgrounds shows an aggregate effect of background on sensitivity to Zfp423 loss rather than a binary effect on viability.

Cocaine-but not methamphetamine-associated memory requires de novo protein synthesis.

Context-induced drug craving and continuous drug use manifest the critical roles of specific memory episodes associated with the drug use experiences. Drug-induced conditioned place preference (CPP) in C57BL/6J mouse model, in this regard, is an appropriate behavioral paradigm to study such drug use-associated memories. Requirement of protein synthesis in various forms of long-term memory formation and storage has been phylogenetically demonstrated. This study was undertaken to study the requirement of protein synthesis in the learning and memory aspect of the conditioned place preference induced by cocaine and methamphetamine, two abused drugs of choice in local area. Since pCREB has been documented as a candidate substrate for mediating the drug-induced neuroadaptation, the pCREB level in hippocampus, nucleus accumbens, and prefrontal cortex was examined for its potential participation in the formation of CPP caused by these psychostimulants. We found that cocaine (2.5 and 5.0 mg/kg/dose)-induced CPP was abolished by the pretreatment of anisomycin (50 mg/kg/dose), a protein synthesis inhibitor, whereas methamphetamine (0.5 or 1.0 mg/kg/dose)-induced CPP was not affected by the anisomycin pretreatment. Likewise, cocaine-induced CPP was mitigated by another protein synthesis inhibitor, cycloheximide (15 mg/kg/injection) pretreatment, whereas methamphetamine-induced CPP remained intact by such pretreatment. Moreover, anisomycin treatment 2h after each drug-place pairing disrupted the cocaine-induced CPP, whereas the same treatment did not affect methamphetamine-induced CPP. An increase of accumbal pCREB level was found to associate with the learning phase of cocaine, but not with the learning phase of methamphetamine. We further found that intraaccumbal CREB antisense oligodeoxynucleotide infusion diminished cocaine-induced CPP, whereas did not affect the methamphetamine-induced CPP. Taken together, these data suggest that protein synthesis and accumbal CREB phosphorylation are essential for the learning and consolidation of the cocaine-induced CPP, whereas methamphetamine-induced CPP may be unrelated to the synthesis of new proteins.

4-Hydroxytamoxifen attenuates methamphetamine-induced nigrostriatal dopaminergic toxicity in intact and gonadetomized mice.

The present study was undertaken to assess the ability of 4-hydroxytamoxifen (4-OHT) to alter methamphetamine-induced nigrostriatal dopaminergic toxicity. Three daily doses of 4-OHT (6 micro g/day) effectively attenuated methamphetamine-induced nigrostriatal dopamine depletions in both sexes of intact and gonadectomized C57BL/6 J mice. 4-OHT alone did not alter the dopamine content levels in the striatum. Both male and female mice exhibited similar Cu, Zn-superoxide dismutase protein levels in the striata whether after gonadectomy or 4-OHT treatment. Furthermore, basal body temperature and methamphetamine-induced hyperthermia were not affected by 4-OHT treatment in either sex of mice. Using a lucigenen-derived chemiluminescence assay, we found that 4-OHT by itself can serve as a potent superoxide anion radical scavenger in vitro. The protective effects of 4-OHT against methamphetamine-induced nigrostriatal dopamine depletion can be, in part, due to its antioxidative characteristics. The free radical-scavenging ability of 4-OHT calls for further investigations for its uses in clinical practice.

Ovarian hormones do not attenuate methamphetamine-induced dopaminergic neurotoxicity in mice gonadectomized at 4 weeks postpartum.

The present study was undertaken to assess the ability of ovarian hormones to alter methamphetamine (MA)-induced dopaminergic toxicity in male and female mice gonadectomized at 4 and 6 weeks of age. None of the following three treatments, estradiol benzoate (EB, 3 x 0.47 microg), progesterone (Prog, 3 x 0.47 microg), or EB (2 x 0.47 microg) followed by Prog (0.47 microg), affected the dopamine (DA)-depleting effects of MA in male and female mice gonadectomized when they were 4 weeks old. However, in contrast to the findings that male mice are more sensitive to MA-induced DA depletion than female mice, no sexual differences in the sensitivity to MA treatment were observed in mice gonadectomized at this age. Moreover, three daily doses of EB (0.47 microg) and EB (0.47 microg) combined with 4-hydroxytamoxifen (4OHT, 6 microg) effectively attenuated striatal DA depletion produced by MA in female mice ovariectomized at 6 weeks of age. Three daily doses of Prog (0.47 microg) and EB (0.47 microg) combined with 4OHT (6 microg) significantly attenuated MA-induced striatal DA depletion in male mice gonadectomized at 6 weeks of age. Taken together, the modulating effects of ovarian hormones on MA-induced DA depletion in mouse striatum could be sex- and age-dependent. 4OHT did not block the protecting effects of EB on MA-induced DA depletion in female and male mice, suggesting that the estrogen receptor may not be involved in the protective effects of EB on attenuating MA-induced DA toxicity.