No abstract

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT + TT) gained more weight (5.96%), than the CC carriers (2.76%, p ¼ 0.008, FDR q-value ¼ 0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT + TT, 2.21±4.51 vs 4.33±3.89 kg; p ¼ 0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p ¼ 0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.

This paper reports the first characterization of the hydration properties of some amino acids and oligoglycines, low molecular weight analogues of proteins, in D2O. Specifically, the partial molar volumes, V°, and adiabatic compressibilities, K°S, of five α-amino acids and five oligoglycines have been determined in D2O at 25 °C. The resulting data have been used to estimate the volume and compressibility contributions of the component nonpolar (methylene group), polar (peptide group), and charged (oppositely charged amino and carboxyl terminal groups) chemical groups. It was found that the volume and compressibility contributions of these charged, polar, and nonpolar groups in D2O are “measurably” distinct from those in H2O. This distinction, in principle, may allow one to develop a method by which differential volumetric measurements of proteins in D2O and H2O can be used to gain insight into the nature of the solvent-exposed protein groups in the absence of detailed structural information.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

Abnormal development of the prefrontal cortex (PFC) is associated with a number of neuropsychiatric disorders that have an onset in childhood or adolescence. Although the basic laminar structure of the PFC is established in utero, extensive remodeling continues into adolescence. To map the overall pattern of changes in cortical gene transcripts during postnatal development, we made serial measurements of mRNA levels in mouse PFC using oligonucleotide microarrays. We observed changes in mRNA transcripts consistent with known postnatal morphological and biochemical events. Overall, most transcripts that changed significantly showed a progressive decrease in abundance after birth, with the majority of change between postnatal weeks 2 and 4. Genes with cell proliferative, cytoskeletal, extracellular matrix, plasma membrane lipid/transport, protein folding, and regulatory functions had decreases in mRNA levels. Quantitative PCR verified the microarray results for six selected genes: DNA methyltransferase 3A (Dnmt3a), procollagen, type III, alpha 1 (Col3a1), solute carrier family 16 (monocarboxylic acid transporters), member 1 (Slc16a1), MARCKS-like 1 (Marcksl1), nidogen 1 (Nid1) and 3-hydroxybutyrate dehydrogenase (heart, mitochondrial) (Bdh).