A. J. Harmar

Polymorphism in serotonin transporter gene associated with susceptibility to major depression

UNLABELLED BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. METHODS A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders. FINDINGS We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.

Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder.

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y=T/C, R=G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65–11.95) and for bipolar disorder 3.22 (95% Cl, 1.15–9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.

Association of Short Alleles of a VNTR of the Serotonin Transporter Gene with Anxiety Symptoms in Patients Presenting After Deliberate Self Harm

The polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene consists of three alleles containing, respectively, 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. The frequencies of the three alleles in 384 individuals presenting after deliberate self harm were the same as a group of 346 controls. However, ratings of anxiety (and state anger) were higher in those patients with genotypes including the shorter repetitive elements. The findings support the hypothesis that, in this group of patients with low rates of severe psychiatric disorder, allelic variation in the serotonin transporter gene may contribute to the expression of anxiety symptoms.

Neuroendocrine molecular biology

Molecular Biology of the Nervous System.- Structure, Function and Expression of the Human Calcitonin /?-CGRP Gene.- Neuronal Specific Gene Expression in the Murine Hippocampus.- Hybridization Histochemistry - Locating Gene Expression.- The Identification and Function of Differentiation Antigens on Primary Sensory Neurons.- LHRH - New Perspectives.- The Physiological Actions of LHRH: Evidence from the Hypogonadal (hpg) Mouse.- The Biosynthetic Precursor of Gonadotropin - Releasing Hormone: A Multifunctional Prohormone.- Gonadotropin-Releasing Hormone: Differentiation of Structure and Function During Evolution.- The Biosynthesis of LHRH.- Evidence for Sex Differences in GnRH Receptors and Mechanism of Action.- The Role of Brain Peptides in the Control of Anterior Pituitary Hormone Secretion.- Phospholipid Turnover, Ca2+ Mobilization and Protein Kinase C Activation in GnRH Action on Pituitary Gonadotrophs.- Hormonal Regulation of Pituitary Gonadotropin Gene Expression.- Neuropeptides.- The Mammalian Tachykinins and Their Receptors: Structure-Activity Relationship of the Manmalian Tachykinins.- Biosynthesis of the Tachykinins and Somatostatin.- Biosynthesis of Somatostatin, Vasoactive Intestinal Polypeptide, and Thyrotropin Releasing Hormone.- Enzymes Processing Somatostatin - Precursors, The Somatostatin-28 Convertase of Rat Brain, A System Converting Somatostatin-28 to Both Somatostatins-14 and -28 (1-12).- Oxytocin and Vasopressin.- Oxytocin and Vasopressin Secretion: New Perspectives.- Organization and Expression of the Vasopressin and Oxytocin Genes.- Measurement of Expression of the Vasopressin and Oxytocin Genes in Single Neurons by In Situ Hybridization.- Neurohypophysial Peptides in the Gonads.- Molecular Biology of Ovarian Oxytocin.- Characterization, Regulation and Functional Activity of Specific Vasopressin Receptors in the Anterior Pituitary Gland.- Transcriptional and Post-Translational Regulation of Neuropeptide Synthesis.- The Regulation of Proopiomelanocortin Gene Expression by Estrogen in the Rat Hypothalamus.- Differential Regulation of ACTH and ?-Endorphin by Controlled Processing.- Strategies in the Regulation of Secretory Signals from Proopiomelanocortin-Producing Cells.- Expression of Preprosomatostatin Genes in Heterologous Cells.- Degradation of Luteinizing Hormone-Releasing Hormone (LHRH) by Pituitary Plasma Membrane and by Pituitary Cells in Culture.- Neuroendocrine Mechanisms at the Cellular Level.- Analysis of Hormone Secretion from Individual Pituitary Cells.- LHRH Priming in Gonadotrophs: A Model System for the Analysis of Neuroendocrine Mechanisms at the Cellular Level.- Membrane Traffic in Relation with Release Mechanisms in Neuroendocrine Cells in Culture.- Neuro-Steroids: 3?-Hydroxy-?5-Derivatives in the Rat Brain.- Ion Channels and the Control of Secretion in Normal Anterior Pituitary Cells.- Receptors - Cellular and Molecular Biology.- Biochemical and Functional Characterization of GnRH Receptors.- Hormonal Receptor Plasticity in the Brain as Shown by In Vitro Quantitative Autoradiography.- Cytosolic Factors Modulating Prolactin Binding.- Pituitary GnRH Receptors - Recent Studies and Their Functional Significance.- Effects of an LHRH Antagonist on Luteal Function in the Macaque.- Clinical Applications.- Comparison of Protein and Ribonucleic Acid Composition of Post Mortem Brain Tissue Between Controls and Cases of Alzheimer Type Dementia.- Neuroendocrine Changes in Alzheimers Disease: Raised Plasma Concentrations of Growth Hormone and Thyroid Stimulating Hormone and Reduced Concentrations of Oestrogen-Stimulated Neurophysin.- The Use of an LHRH Agonist in the Treatment and Investigation of the Premenstrual Syndrome.- Direct Effects of LHRH and Agonists on Human Breast Cancer Cells.

Neuropeptide—receptor interactions studied with the aid of fluorescence-activated cell sorting and video intensification microscopy

Studies of interactions between neurotransmitters and their receptors would be greatly facilitated by a method for obtaining cell fractions enriched with cells that contain a high density of receptors specific for the neutrotransmitter. Here we report the use of a fluorescence-activated cell sorter (FACS) to prepare fractions of pituitary cells that contain a high density of specific receptors for the decapeptide, luteinizing hormone-releasing hormone (LHRH). The fluorescence probe, an agonist of LHRH coupled to rhodamine isothiocyanate [(rhod-D-Lys6)-LHRH], was 75% as potent as LHRH in terms of releasing LH from dispersed pituitary cells. Cells, dispersed mechanically from the anterior pituitary glands of either immature rats or ovariectomized rats treated with oestrogen and progesterone, were exposed to (rhod-D-Lys6)-LHRH at 4 degrees C for 1 h and passed through a FACS. The pituitary cells sorted into two major peaks, one of which contained cells that fluoresced brightly and showed a significant LH response to LHRH, and a second which contained cells that did not fluoresce and showed no LH response to LHRH. Using photon counting techniques, the population of fluorescent cells was found to bind LHRH in a saturable and specific manner. In the immature rats the percentage of the large cell population that bound (rhod-D-Lys6)-LHRH was about 80%, approximately the same proportion of the cell population that is made up of gonadotrophs.