Dopaminergic hypofunctions and prepulse inhibition deficits in mice lacking midkine.

Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(-/-)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(-/-) mice. The Mdk(-/-) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(-/-) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.

Inbred strains of mice with variable sensitivity to ethanol exhibit differences in the content and processing of beta-endorphin.

The content of beta-endorphin-like immunoreactivity (beta-EPLIR) in the anterior and neurointermediate lobe of the pituitary gland, the hypothalamus and the serum of the c57BL/6, BALB/C and DBA/2 inbred strains of mice was estimated at the resting state as well as 45 min after i.p. injection of either ethanol solution (3.0 g/kg.b.wt.) or saline. At the resting state, the neurointermediate lobe and the serum of the c57BL/6 mice showed the highest content of beta-EPLIR, while no statistically significant difference was noticed in the total beta-EPLIR content in the anterior lobe and hypothalamus. At 45 min post-ethanol treatment the beta-EPLIR content was increased in the serum of all three strains of mice studied and was decreased in the hypothalamus of the c57BL/6 mice only. Further analysis of the beta-endorphin peptides using sephadex G-75 chromatography and reverse phase high performance liquid chromatography indicated strain differences in the relative proportions of the various forms of beta-endorphin in the anterior lobe, neurointermediate lobe and the hypothalamus. These strain specific differences in the content and post-translational processing of beta-endorphin may be involved in some of the genetically determined differences in responses to ethanol by these inbred strains of mice.

Acute and chronic acetazolamide administration in DBA and C57 mice: effects of age.

The clinical utility of the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is limited because of rapid development of tolerance to its effects. Tolerance is thought to develop as a result of glial cell proliferation and/or increased CA synthesis. DBA mice, susceptible to audiogenic seizures (AGSs) in an age-dependent manner, have increased CA activity as compared with C57 (non-audiogenic seizure susceptible) mice at 21 and 110 days of age. The present work utilized ACTZ to help determine the relationship between increased CA activity in brain and AGSs in DBA mice. Also, minimal electroshock seizure threshold (EST) was measured at various ages in DBA and C57 mice to determine age-related changes in CNS excitability. EST was significantly lower in DBA as compared with C57 mice at 18 days and between 40 and 115 days of age, suggesting that DBA mice remain hyperexcitable to electrical stimulation after they develop resistance to AGSs. ACTZ ED50s against maximal electroshock seizures (MES) were significantly higher in DBA as compared with C57 mice at 26,36, and 115 days of age. This finding correlates with higher CA activity in this strain at 110 days of age, noted previously. However, at 21 days of age, when CA activity is also higher in DBA versus C57 mice, there were no significant differences in ACTZ ED50s against MES between the strains. ACTZ ED50s against AGSs in DBA mice were considerably lower than ACTZ ED50s against MES in either strain, suggesting that a particular fraction of CA is intimately involved in the production of AGSs.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional acetylcholine turnover rates in the brains of three inbred strains of mice: correlation with some interstrain behavioural differences.

The hypothesis that the genetically determined behavioural differences which exist between the inbred mouse strains Balb/c, DBA/2 and C57Bl/6 may be related to differences in acetylcholine metabolism in certain regions of the brain has been tested. In vivo ACh turnover rates have been measured in three regions (hippocampus, caudate nucleus and frontal-parietal cortex) of the brains of each strain by following the rate of formation of labelled ACh, in these regions, after a pulse intravenous injection of a tracer dose of 3H labelled choline. Focused microwave procedures were used for the rapid fixation of brain tissue and Ch and ACh radioactivities were determined following their electrophoretic separation. Steady-state concentrations of Ch and ACh were measured by a sensitive radio-enzymatic method. Significant interstrain differences in ACh turnover rates are reported for each of the brain regions studied with the order of metabolic activity being Balb/c greater than DBA/2 greater than C57 Bl/6 in each case. These results are interpreted as being in agreement with previous reports on correlations between learning ability or locomotor activity and regional activities of choline acetyltransferase in the brains of these inbred strains. The correlations between the in vivo ACh turnover rates and (1) interstrain differences in behavioural measures and (2) regional choline acetyltransferase activities are discussed.