Serotonin in the ventral hippocampus modulates anxiety-like behavior during amphetamine withdrawal.

Withdrawal from amphetamine is associated with increased anxiety and sensitivity to stressors which are thought to contribute to relapse. Rats undergoing amphetamine withdrawal fail to exhibit stress-induced increases in serotonin (5-HT) release in the ventral hippocampus and show heightened anxiety-like behaviors. Therefore, we tested the hypothesis that reducing 5-HT levels in the ventral hippocampus is a causal mechanism in increasing anxiety-like behaviors during amphetamine withdrawal. First, we tested whether reducing 5-HT levels in the ventral hippocampus directly increases anxiety behavior. Male rats were bilaterally infused with 5,7-dihydroxytryptamine (5,7-DHT) into the ventral hippocampus, which produced a 83% decrease in ventral hippocampus 5-HT content, and were tested on the elevated plus maze (EPM) for anxiety-like behavior. Reducing ventral hippocampus 5-HT levels decreased the time spent in the open arms of the maze, suggesting that diminished ventral hippocampus 5-HT levels increases anxiety-like behavior. Next, we tested whether increasing 5-HT levels in the ventral hippocampus reverses anxiety behavior exhibited by rats undergoing amphetamine withdrawal. Rats were treated daily with either amphetamine (2.5-mg/kg, i.p.) or saline for 2weeks, and at 2weeks withdrawal, were infused with the selective serotonin reuptake inhibitor paroxetine (0.5µM) bilaterally into the ventral hippocampus and tested for anxiety-like behavior on the EPM. Rats pre-treated with amphetamine exhibited increased anxiety-like behavior on the EPM. This effect was reversed by ventral hippocampus infusion of paroxetine. Our results suggest that 5-HT levels in the ventral hippocampus are critical for regulating anxiety behavior. Increasing 5-HT levels during withdrawal may be an effective strategy for reducing anxiety-induced drug relapse.

The evolution of modern lineages of mouse L1 elements.

There are three known families of L1 elements in the Mus genome, V, F, and A. An individual L1 element is classified as a member of one of these families based on which of three different types of transcription promoters is at its 5' end. Initial evidence suggested that the only actively transposing L1 elements in the modern mouse genome were a young subfamily of A-type elements. That belief was overturned when a transposing F subfamily, T(F), was discovered. We used molecular phylogenetic methods to investigate the emergence of the two currently transposing L1 lineages, young A's and T(F)'s. Both of these subfamilies appear to be direct descendants from a specific clade of F-type L1's. Our results imply that recombination between L1 sequences occurred in the lineage from which the T(F) subfamily evolved. We also found that phylogenetic analysis of a L1 3' untranslated region (UTR) is diagnostic for the promoter type at the 5' end of the sequence and, therefore, for the family to which it belongs. As part of this investigation, we developed a set of full-length L1 sequences, which may serve as a general reference set for phylogenetic analyses in Mus. Our analyses included 21 full-length L1 elements from the GenBank nonredundant database that had not been phylogenetically analyzed previously.

Two distinct mutations in a single dystrophin gene: chance occurrence or premutation?

We report on a kindred segregating 2 distinct mutations of a dystrophin gene. DNA analysis showed that the second mutation, a deletion, arose in the same gene carrying the primary defect which produced a Becker phenotype in the affected males. The DNA data for this family are reported and the alternative explanations of chance occurrence and premutation are discussed to explain these unusual findings.

Identification of Duchenne muscular dystrophy genomic probe P20 constant Taql fragment corresponding to the EcoRV and Mspl polymorphisms.

The majority of Duchenne and Becker muscular dystrophy cases are caused by deletions observable in Southern blots with cDNA probes for the gene. When the deletion includes polymorphic probes, they may be used to determine carrier status by deletion segregation analysis: non-inheritance of parental alleles, or heterozygosity. The polymorphic genomic probe P20 is deleted in a large percentage of probands. P20 hybridizes with two constant fragments of 6.7 and 0.8 kb in Taql digests. In a number of probands, only the larger P20 Taql fragment is deleted. This study demonstrates that this fragment corresponds with the polymorphic EcoRV and Mspl fragments of P20. Families in which the upper Taql fragment is deleted may be screened for carrier status using non-inheritance of parental alleles or heterozygosity of P20 in EcoRV or Mspl digests.

The diagnosis of Duchenne and Becker muscular dystrophies: two years' experience in a comprehensive carrier screening and prenatal diagnostic laboratory.

This article describes the diagnostic algorithm being used for the management of the 148 families affected by Duchenne or Becker muscular dystrophy who are known to the Molecular Neurogenetics Laboratory in the Department of Neuropathology, Royal Perth Hospital. In 60 families from whom DNA has been obtained, 41 mutations (39 deletions and two duplications) of the Duchenne muscular dystrophy gene (DMD) have been identified by means of complementary DNA (cDNA) probes. DNA-based screening has clarified the carrier status of 45 at-risk women, and 13 pregnancies have been monitored. In addition, cDNA screening of all relevant patients with autosomal recessive muscular dystrophy, spinal muscular atrophy or limb-girdle muscular dystrophy facilitated the correct diagnosis of Becker muscular dystrophy in three patients.

Differentiation of Becker muscular dystrophy from limb-girdle muscular dystrophy and Kugelberg-Welander disease using a cDNA probe.

A 31-year-old man previously investigated for a neuromuscular disorder was diagnosed as having either limb-girdle dystrophy, spinal muscular atrophy, or Becker muscular dystrophy. Extensive clinical and special neurological investigations failed to clarify this differential diagnosis. However, recent DNA studies have shown a deletion of the dystrophin gene, thereby providing an unequivocal diagnosis of Becker muscular dystrophy. The application of molecular genetic techniques in the diagnosis of inherited neuromuscular disorders is discussed.