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Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa. Molecular Psychiatry (2000) 5, 476-481.Keywords: food intake; food restriction; energy metabolism; neuroendocrine control of appetite; locomotor activity; running wheels Hyperactivity is observed in 40-80% of patients with anorexia nervosa (AN). 1,2 Caloric deprivation severe enough to result in significant weight loss possibly provokes sensations of behavioral arousal and activation in individuals with an innate vulnerability to develop AN. 3 Indeed, reduced food intake and enhanced activity have been viewed as the core symptomatology in AN, because only these behavioral measures consistently distinguish AN from other disorders. 4 Semi-starvation induced hyperactivity (SIH) is a well characterized phenomenon in laboratory animals. 5,6 Rats supplied with food for only 1 h per day manage to survive, but die within a short period of time when exposed to a running wheel. The enhancement of activity is related to the severity of food restriction; total food deprivation results in a disruption of the nocturnal activity pattern. 6 Leptin is assumed to be the major hormone underlying the regulatory phenomena that lead to an adaptation of an organism to reduced energy supplies. 7 Thus, in mice exogenously applied leptin has been shown to blunt the semi-starvation-induced downregulation of the hypothalamic-pituitary gonadal and thyroid axes as well as the upregulation of the hypothalamic-pituitary adrenal axis. 7 The rapid decline in leptin secretion associated with caloric restriction and weight loss 7,8 could represent the initial trigger underlying the hyperactivity observed in SIH and AN. As an initial step towards testing this hypothesis we investigated the effect of continuous leptin treatment via minipum...

Prevalence rates of comorbid psychiatric disorders and suicidal ideation are considerably lower among adolescents with AN compared with adults. An early and careful assessment, along with adequate treatment of the eating disorder, might prevent the development of severe psychiatric comorbidities.

Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5 0 region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P = 0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n = 3) tested blocks (P = 0.0048); (3) within block two we detected a nominal P = 0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P < 0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.