An RT-PCR study of 5-HT(6) and 5-HT(7) receptor mRNAs in the hippocampal formation and prefrontal cortex in schizophrenia.

5-Hydroxytryptamine (5-HT; serotonin) 5-HT(6) receptors (5-HT(6)R) and 5-HT(7) receptors (5-HT(7)R) have been implicated in schizophrenia and as targets of atypical antipsychotic drugs. We have studied the expression of these receptors in the hippocampal formation and dorsolateral prefrontal cortex (DLPFC) of 17 subjects with schizophrenia and 17 controls using reverse transcription-polymerase chain reaction (RT-PCR) with cyclophilin co-amplification. In schizophrenia, 5-HT(6)R mRNA was decreased in the hippocampal formation, and 5-HT(7)R mRNA was decreased in the dorsolateral prefrontal cortex. The mRNAs were unchanged in rats treated for 2 weeks with haloperidol, chlorpromazine, risperidone, olanzapine or clozapine. Regional decreases in 5-HT(6)R and 5-HT(7)R expression in schizophrenia may contribute to the overall serotonergic alterations which occur in the disorder, in part through their interactions with other neurotransmitter systems including glutamate and acetylcholine

5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585.

The 5-hydroxytryptamine (5-HT; serotonin)-6 receptor (5-HT6R) is a putative target of atypical antipsychotic drugs and its mRNA expression is altered in schizophrenia. [125I]SB-258585 is a selective 5-HT6R antagonist which has been well characterized for use in the rat brain. The present study evaluated its suitability for receptor autoradiography in the human brain and its application to quantitative studies. The affinity (K(d) approximately 1.2 nM) and relative distribution of binding sites (striatum >> cortex approximately hippocampus) were similar to the rat. The distribution of [125I]SB-258585 binding in these regions was also consistent with that of 5-HT6R mRNA, determined in parallel using in situ hybridization. [125I]SB-258585 binding site densities were measured in dorsolateral prefrontal cortex of 20 patients with chronic schizophrenia and compared with 17 normal subjects. No differences were seen between groups. Neither were [125I]SB-258585 binding site densities affected in the frontal cortex or striatum of rats following 2 weeks' administration of the antipsychotic drugs haloperidol, chlorpromazine, olanzapine, risperidone, or clozapine. In summary, [125I]SB-258585 is a suitable radioligand for studies of human brain 5-HT6R binding sites and shows that their distribution is broadly similar to that of the rodent. The lack of effect of schizophrenia or antipsychotic drug administration on [125I]SB-258585 binding suggests that an altered receptor density does not contribute to any involvement which the 5-HT6R may have in the disease or its treatment

FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion.

Polyglutamine expansions in the ataxin-2 gene (ATXN2) cause autosomal dominant spinocerebellar ataxia type 2 (SCA2), but have recently also been associated with amyotrophic lateral sclerosis (ALS). We present clinical and pathological features of a family in which a pathological ATXN2 expansion led to frontotemporal lobar degeneration with ALS (FTLD-ALS) in the index case, but typical SCA2 in a son, and compare the neuropathology with a case of typical SCA2. The index case shares the molecular signature of SCA2 with prominent polyglutamine and p62-positive intranuclear neuronal inclusions mainly in the pontine nuclei, while harbouring more pronounced neocortical and spinal TDP-43 pathology. We conclude that ATXN2 mutations can cause not only ALS, but also a neuropathological overlap syndrome of SCA2 and FTLD presenting clinically as pure FTLD-ALS without ataxia. The cause of the phenotypic heterogeneity remains unexplained, but the presence of a CAA-interrupted CAG repeat in the FTLD case in this family suggests that one potential mechanism may be variation in repeat tract composition between members of the same family

The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585.

We used the highly selective 5-HT(6) receptor radioligand [(125)I]SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide) to perform autoradiographic binding studies on the rat brain. High levels of specific binding occurred in the corpus striatum, nucleus accumbens, Islands of Calleja and the olfactory tubercle. A high level of binding also appeared in the choroid plexus. Moderate levels occurred in several regions of the hippocampal formation and in certain regions of the cerebral cortex, thalamus, hypothalamus, and substantia nigra; and very low levels in the globus pallidus, cerebellum, other mesencephalic regions, and the rhombencephalon. Displacement of total binding with 10 microM unlabelled SB-214111 (4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), another selective 5-HT(6) receptor antagonist, or 10 microM unlabelled methiothepin, reduced binding to barely discernible levels. Some animals received unilateral injections of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle to lesion the nigro-striatal pathway before autoradiographic examination. Effectiveness of the 6-OHDA lesions in the substantia nigra and striatum was confirmed with tyrosine hydroxylase immunohistochemistry. Such lesions resulted in no significant changes in [(125)I]SB-SB258585 binding in any brain region examined, suggesting that 5-HT(6) receptors in the striatum are not located on dendritic, somatic or terminal elements of dopaminergic neurones. Thus, the striatal binding sites seen in this study may be on intrinsic GABAergic or cholinergic neurones, or on terminals of projection neurones from the thalamus or cerebral cortex. The 5-HT(6) receptor ligand binding seen here in the striatum, accumbens, olfactory tubercle, Islands of Calleja, cerebral cortex and hippocampus are in concordance with previous immunohistochemical studies, and suggest a possible involvement of 5-HT(6) receptors in locomotor control, cognition, memory, and control of affect. The high levels of binding observed in the choroid plexus in this study have not been reported before. This finding suggests that 5-HT(6) receptors could play a role in the control of cerebrospinal fluid dynamics

FTLD-ALS of TDP-43 type and SCA2 in a family with a full ataxin-2 polyglutamine expansion.

Polyglutamine expansions in the ataxin-2 gene (ATXN2) cause autosomal dominant spinocerebellar ataxia type 2 (SCA2), but have recently also been associated with amyotrophic lateral sclerosis (ALS). We present clinical and pathological features of a family in which a pathological ATXN2 expansion led to frontotemporal lobar degeneration with ALS (FTLD-ALS) in the index case, but typical SCA2 in a son, and compare the neuropathology with a case of typical SCA2. The index case shares the molecular signature of SCA2 with prominent polyglutamine and p62-positive intranuclear neuronal inclusions mainly in the pontine nuclei, while harbouring more pronounced neocortical and spinal TDP-43 pathology. We conclude that ATXN2 mutations can cause not only ALS, but also a neuropathological overlap syndrome of SCA2 and FTLD presenting clinically as pure FTLD-ALS without ataxia. The cause of the phenotypic heterogeneity remains unexplained, but the presence of a CAA-interrupted CAG repeat in the FTLD case in this family suggests that one potential mechanism may be variation in repeat tract composition between members of the same family

Prevalence and sociodemographic determinants of tobacco use among adults in Pakistan: findings of a nationwide survey conducted in 2012.

BACKGROUND: Smoking is one of the leading causes of preventable mortality. The World Health Organization recommends that countries should monitor tobacco use regularly. In Pakistan, the last national study on smoking in the general population was conducted in 2002 to 2003. METHODS: We conducted a cross-sectional survey of a nationally representative sample of men and women living in rural and urban areas of four main provinces of Pakistan from March through April 2012. Face-to-face in-house interviews were undertaken using a pre-tested structured questionnaire that asked about smoking and other forms of tobacco use. Multistage stratified random area probability sampling was used. To determine the national prevalence of tobacco use, the sample was weighted to correspond to rural-urban population proportions in each of the four provinces as in the 1998 census conducted by Pakistan's Population Census Organization. Associations between sociodemographic variables and tobacco use were investigated using multivariable robust regression. RESULTS: Out of 2,644 respondents (1,354 men and 1,290 women), 354 men and 4 women reported being current cigarette smokers. The weighted prevalence of current cigarette smoking was 15.2% (95% confidence interval [CI]; 11.2, 19.3) overall, 26.6% (95% CI: 19.1, 34.1) among males, and 0.4% (95% CI: -0.2, 1.0) among females. Among females, 1.8% (95% CI: 0.4, 3.1) used any smoked tobacco and 4.6% (95% CI: 1.8, 7.4) used any smokeless tobacco daily or on some days of the week. Among males, odds of current cigarette smoking decreased with increasing level of education (OR = 0.75; 95% CI: 0.68, 0.84) and increased with having a father who used tobacco (OR = 2.11; 95% CI: 1.39, 3.22) after adjusting for other sociodemographic characteristics. Lower household income was associated with current cigarette smoking among rural males only (odds ratio [OR] = 0.67; 95% CI: 0.48, 0.92 per category increase in monthly household income). CONCLUSION: A large proportion of males smoked cigarettes. Cigarette use was negligible among females, but they used other forms of tobacco. Low education was a determinant of cigarette smoking among males irrespective of socioeconomic status and area of residence. Tobacco control campaigns should target uneducated and rural poor men and monitor all forms of tobacco used by the population