The influence of phenotype on the outcome of linkage analysis of schizophrenia.
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Chromosomes, Human, Pair 2↗
Biomedical subjects
R D Todd
Publications and source records attributed to R D Todd.
Manic-depressive illness and tyrosine hydroxylase markers. Bipolar Disorder Working Group.
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Adult↗
PTX-sensitive regulation of neurite outgrowth by the dopamine D3 receptor.
Neurotransmitter receptors are known to have direct roles in the modulation of neuronal morphogenesis. Previous work showed that clonal mesencephalic MN9D cells individually transfected with D2-like dopamine receptors show increased neurite outgrowth following long-term exposure to the D2-like receptor agonist quinpirole. In the current study, brief stimulation of D3 receptor-expressing cells also elicited increased neurite outgrowth, which could be mimicked by the Gi/G(o) protein activator mastoparan. Pretreatment with the Gi/G(o) protein inhibitor pertussis-toxin blocked the quinpirole- and mastoparan-mediated increases in outgrowth. These results suggest that dopamine D3 receptor stimulation has an immediate, G-protein-mediated role in neuronal morphogenesis.
Animals↗
Treatment-resistant depression in children and adolescents.
Treatment resistance in depressed children and adolescents cannot yet be defined fully because of the paucity of controlled studies that demonstrate efficacy. Therefore, this article addresses several of the age-specific, developmental considerations that may impinge upon treatment response. Areas covered include familial-genetic, psychosocial, and neuroimaging studies in addition to a review of controlled studies to date.
Adolescent↗
Psychiatric diagnoses in the child and adolescent members of extended families identified through adult bipolar affective disorder probands.
OBJECTIVE: To investigate the type and distribution of psychiatric disorders in the child and adolescent members of extended pedigrees identified through bipolar probands. METHOD: The child and adolescent offspring (24 male, 26 female, aged 6 to 17 years) and the adult parents (60) of 14 bipolar pedigrees ascertained for the National Institutes of Mental Health Genetics Initiative Study of Bipolar Affective Disorder were personally assessed using structured psychiatric interviews. A parent was also interviewed about each child or adolescent offspring. RESULTS: Twelve of the 50 interviewed offspring received a lifetime DSM-III-R diagnosis of an affective disorder. This included six cases of bipolar disorder, five cases of major depressive disorder, and one case of dysthymia. Eight of the offspring who received an affective disorder diagnosis also qualified for an anxiety disorder (four), a disruptive behavior disorder (two), or both (two). Offspring who had a parent with an affective disorder had a 5.1-fold higher risk for receiving an affective disorder diagnosis than did offspring with healthy parents. CONCLUSIONS: In a consecutive series of families identified through a proband with bipolar disorder, there were significant increases in the prevalence of affective disorder diagnoses in the child and adolescent offspring. The distribution of illness in offspring was compatible with the presence of important genetic factors which contribute to early-onset affective illness.
Adolescent↗
Increased prevalence of alcoholism in relatives of depressed and bipolar children.
OBJECTIVE: Previous publications from the "Nortriptyline in Childhood Depression: Follow-up Study" reported increased prevalence rates of mood disorders and alcoholism in the relatives of prepubertal depressed subjects. This article presents data on the association versus independent transmission of alcohol and mood disorders in the families of these subjects. METHOD: The follow-up study included 6- to 12-year-olds with major depressive disorder (MDD) and matched normal controls. After 2 to 5 years of follow-up, bipolarity developed in 31.7% of the MDD subjects. Family history data for the first- and second-degree relatives and first cousins of the 76 nonadopted MDD subjects and the 31 controls were obtained from the subjects' mothers, using the Family History-Research Diagnostic Criteria. RESULTS: The prevalence of alcoholism among the relatives of the MDD and bipolar probands was two to three times that reported for control relatives and twice that reported for the relatives of adult MDD and bipolar probands. Mood disorders and maternal alcoholism were independently transmitted while paternal alcoholism increased the risk for mood disorder in offspring. CONCLUSIONS: The potential psychosocial and genetic effects of familial alcoholism need to be considered for the clinical management and investigation of childhood-onset mood disorders.
Adolescent↗
Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clinical Centers.
Adenylyl cyclase (AC) activity was measured in membrane preparations of platelets from control and alcoholic subjects. The sample consisted of 51 alcoholics who were categorized as type I or type II using the criteria of Gilligan et al. (Genet. Epidemiol. 4:395-414, 1987) and 54 normal controls. Alcoholic males exhibited significantly lower values than controls in basal and fluoride-stimulated platelet AC activity. When male alcoholics were segregated into type I and type II categories, the platelet AC activity did not differ between subtypes, and both subtypes had AC activity that was below control values. Western blot analysis of the quantity of Gs alpha and Gi alpha proteins in a subset of male controls and alcoholic subjects demonstrated no significant relationship between quantity of G proteins and AC activity. The results confirm lower platelet AC activity in male alcoholics, compared with controls. Given the lack of quantitative relations between Gs alpha and Gi alpha proteins and AC activity, the results support the contention that individual differences in platelet AC activity in the alcoholic subjects may reflect quantitative or qualitative differences in the AC catalytic units.
Adenylyl Cyclases↗
Inhibition of dopamine synthesis by dopamine D2 and D3 but not D4 receptors.
The goal of the current study was to determine which of the D2-like receptors (D2, D3 or D4) are involved in autoreceptor regulation of dopamine synthesis. We have derived a model system utilizing a mouse mesencephalic cell line, MN9D, which both synthesizes and releases dopamine, to characterize the modulation of tyrosine hydroxylase activity, the rate limiting enzyme in the conversion of tyrosine to dopamine, by the D2-like receptors. Previously, we have shown that stimulation of D2 and D3, but not D4, dopamine receptors transfected into MN9D cells inhibited the release of dopamine. In the current study, we show that quinpirole stimulation of transfected D2 and D3, but not D4, dopamine receptors inhibited K+-stimulated tyrosine hydroxylase activity in a pertussis toxin-sensitive manner, strongly suggesting G-protein coupling as a mechanistic pathway. The D2 receptor effect could be maintained for at least 60 min, whereas the D3 receptor effect desensitized. Treatment with 10 microM forskolin, which raises cyclic AMP levels or with 100 nM okadaic acid, a potent phosphatase inhibitor, had no effect on the D2-or D3-mediated inhibition, suggesting that these effects may be independent of both cyclic AMP- and okadaic acid-sensitive phosphatase activity. Taken together, these data confirm the hypothesis that dopamine D2 and D3 receptors can perform dual roles in autoreceptor regulation.
Animals↗
Dopamine D2L receptor couples to G alpha i2 and G alpha i3 but not G alpha i1, leading to the inhibition of adenylate cyclase in transfected cell lines.
Previously, we showed that both D2 and D4 dopamine receptors inhibited adenylate cyclase in a pertussis toxin (Ptx)-sensitive manner in the dopamine-producing MN9D cell line, whereas only D2 receptors did so in a fibroblast cell line, CCL1.3. Of the known Ptx-sensitive G proteins, MN9D cells expressed G alpha i2, G alpha oA and G alpha oB, whereas CCL1.3 cells expressed only G alpha i2. Here we cotransfected MN9D and CCL1.3 cells with either the long form of the D2 receptor (D2L) or the D4 receptor and a mutant Ptx-resistant G protein alpha-subunit. When cotransfected CCL1.3 cell lines were tested for the ability of Ptx to block receptor-mediated inhibition of cyclic AMP accumulation, D2 receptors were found to couple to mutant G alpha i2 and G alpha i3 but not G alpha i1 or G alpha oA. D2 also coupled to mutant G alpha i2 but not G alpha oA in MN9D cells. In contrast, D4 receptors did not couple to either mutant G alpha i2 or G alpha oA subunits in MN9D cells. These data suggest that D4 receptor-mediated inhibition of adenylate cyclase is not coupled via the same mechanisms used by D2 receptors. D2L receptors are capable of coupling to more than one G protein in the modulation of cyclic AMP.
Adenylyl Cyclases↗
Possible association between the dopamine D3 receptor gene and bipolar affective disorder.
A variety of studies have reported possible genetic associations between bipolar affective disorder and different loci using relative risk (case-control) comparisons. An alternative approach is to construct a contrast group using parental alleles which were not transmitted to an affected individual [Falk and Rubinstein, 1987: Ann Hum Genet 51:227-233]. We have used both approaches to test for possible associations between alleles of the dopamine D3 receptor gene and bipolar affective disorder. For relative risk studies, the probands of multiple incidence bipolar affective disorder families have been compared to alcoholic and psychiatrically normal contrast groups. Nontransmitted allele approaches have used bipolar affective disorder and alcoholic probands in which both parents were available for genotyping. Using the BalI restriction enzyme site polymorphism of Lannfelt et al. [1992: Psychiatr Genet 2:249-256], we have found no differences in the allele or genotype frequencies for bipolar vs. alcoholic or psychiatrically normal controls. In contrast, we have found evidence for an increased frequency of allele 1 and allele 1 containing genotypes in transmitted alleles from bipolar families.
Adult↗
Preliminary study of magnetic resonance imaging characteristics in 8- to 16-year-olds with mania.
OBJECTIVE: To examine magnetic resonance imaging (MRI) characteristics in children and adolescents with mania according to DSM-III-R criteria. METHOD: A convenience sample of consecutively referred 8- to 16-year-old manic (n = 10) and normal (n = 5) subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode Version, the Children's Global Assessment Scale, and the Family History-Research Diagnostic Criteria. MRI scans were obtained from unsedated subjects using a 1.5 T MR scanner to acquire T1-weighted coronal and sagittal images and T2-weighted axial images. Images were assessed by blind clinical interpretation, ratings of T2-weighted deep white matter hyperintensities and petalia, and computer-assisted volumetric analysis of ventricular and cerebral volumes. RESULTS: Eight of 10 manic subjects and all 5 controls completed the scans. Scans of 4 manic subjects and 1 control subject showed ventricular or white matter abnormalities by clinical interpretation. Significant findings were positive correlations between increasing age and both right and left ventricular volumes. Two of the 8 manic subjects and no controls had confluent subcortical hyperintensities. CONCLUSIONS: MRI brain scanning was feasible in 8- to 16-year-olds. Preliminary findings from clinical interpretations and structured ratings suggest structural differences between young manic and normal subjects. Investigations of larger samples are needed to better characterize the differences.
Adolescent↗
Bipolar disorder and the pseudoautosomal region: an association study.
From family, adoption, and twin studies it is clear that genetic factors play an important role in the etiology of bipolar disorder (McGuffin and Katz: The Biology of Depression, Gaskell, London, 1986). Recently Yoneda et al. (Am J Hum Genet 51:1172-1173, 1992) reported an association between an allele (A4) of a VNTR marker (DXYS20) for the pseudoautosomal region and bipolar disorder in a Japanese population. In order to test for this association in a Caucasian population, we have typed a sample of 52 subjects with bipolar disorder and 61 normal controls. The bipolar subjects are probands of multiple incidence families. The normal controls are an epidemiologically ascertained sample of middle-aged, unrelated individuals. The two groups were matched for sex and ethnic background. There were no significant differences in the allele or genotype frequencies of DXYS20 between the two groups. In particular, there was no significant difference in the frequency of the A4 allele in normal controls and bipolar patients (0.377 vs. 0.317, respectively). The prevalence of the A4 allele in bipolar patients and normal controls was 0.567 and 0.622, respectively. We were not able to replicate the results of the Yoneda et al. (1992) study.
Adult↗
Morphogenic potentials of D2, D3, and D4 dopamine receptors revealed in transfected neuronal cell lines.
Molecular cloning studies have defined a family of dopamine D2-like receptors (D2, D3, and D4), which are the products of separate genes. Our previous work has shown that stimulation of dopamine D2-like receptors in cultures of fetal cortical neurons increases the extension and branching of neurites. To determine which D2-like receptors possess morphogenic potentials, a clonal mesencephalic cell line (MN9D) was transfected with D2, D3, or D4 receptor subtypes and treated with quinpirole, an agonist of D2-like receptors, and changes in morphological characteristics were quantitated. Stimulation of D2 receptors increased the number and branching of neurites with little effect on neurite extension; stimulation of D3 and D4 receptors increased the branching and extension of neurites. Similar results were found for primary mesencephalic cultures stimulated with quinpirole. These results suggest that the known D2-like receptors have specific developmental roles in regulating neuronal morphogenesis of dopaminergic pathways.
Animals↗
Linkage disequilibria at the D2 dopamine receptor locus (DRD2) in alcoholics and controls.
Because of its central role in the neuromodulation of appetitive behaviors, the D2 dopamine receptor gene (DRD2) has received considerable scrutiny as a possible candidate that may affect susceptibility to additive behaviors--especially alcoholism. Association studies that compare the frequencies of anonymous restriction fragment length polymorphisms (RFLPs) in alcoholics and controls have yielded equivocal results, suggesting that any role played by this receptor will account for only part of the variation. Since these RFLPs are not located in coding regions, the hypothesis has been advanced that the association seen in some studies results from linkage disequilibrium between these markers and one or more functional DRD2 alleles that affect susceptibility. To test this hypothesis, we have assayed four DRD2 RFLPs that span coding regions as well as a 3' flanking RFLP in an expanded sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these samples was observed, although for one marker (phD2-244), the alcoholic sample showed a significant departure from the Hardy-Weinberg equilibrium. The pattern of pairwise composite disequilibrium coefficients is broadly similar in the two samples, although when the five-marker haplotype frequencies are compared, a significant difference is revealed. This difference appears to be due to greater linkage disequilibrium of the control sample. These results do not support the involvement of the DRD2 region in the etiology of alcoholism.
Adult↗
Characterization of the human dopamine D3 receptor expressed in transfected cell lines.
A full-length cDNA clone of the human dopamine D3 receptor was obtained by the polymerase chain reaction (PCR) using reverse-transcribed RNA from human brain as the template. The cDNA was inserted into an expression vector which was then stably transfected into either Chinese hamster ovary (CHO), SK-N-MC human epithelioma or mouse CCL1.3 fibroblast cell lines. Post-transfection, the Bmax for D3 receptor expression was 1.9, 1.1 and 0.4 pmol/mg protein in the CHO-K1, SK-N-MC and CCL1.3 cell lines, respectively. The D3 receptor expressed in CHO-K1 and CCL1.3 cells exhibited similar radioligand binding profiles, especially for the D3-selective compound, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT). Radioligand-binding competition curves of presumed D3 agonists were shifted to the right by the addition of guanine nucleotides and Na+ to the assay buffer. Presumed D3-receptor agonists had no effect on cAMP accumulation in any of the D3-transfected cell lines although cAMP accumulation was inhibited by dopamine D2 receptor activation in D2-transfected CHO and CCL1.3 cells and by activation of the exogenously expressed neuropeptide Y receptor in SK-N-MC cells. Also, D3 receptor activation neither potentiated ATP-stimulated arachidonic acid release from CHO cells nor stimulated inositol phosphate production in CCL1.3-cells although both of these responses were elicited by D2 agonists in D2-transfected cells. We conclude that the signalling properties of the D3 receptor differ from those of its closest homolog, the D2 receptor.
Animals↗
Prevalence of affective disorder in the child and adolescent offspring of a single kindred: a pilot study.
OBJECTIVE: The study determined the prevalence of psychiatric disorders among the child and adolescent offspring of an extended family identified through a proband with bipolar affective disorder. METHODS: All of the not mentally retarded offspring (ages 6 to 17 years) of a single extended bipolar affective disorder pedigree were studied. Data regarding psychiatric diagnoses, intelligence, school achievement, temperament, and family functioning were collected using structured and standardized instruments. RESULTS: When the child and adolescent offspring were stratified by degree of genetic relationship to an adult with an affective disorder, there were no differences in demographic variables, IQ, school achievement, or most temperamental and family characteristics. In contrast, there were increases in the rates of affective disorders and disruptive behavior disorders in the offspring that correlated with the degree of genetic relationship to an affected adult. CONCLUSIONS: The risk of developing an early onset affective disorder is correlated with the degree of genetic relatedness to affected adults in this single, extended family. This pilot study demonstrates that the inclusion of extended relatives in high-risk studies can enhance the discrimination of genetic and environmental contributions to the development of affective disorders.
Adolescent↗
Dopamine D2 and D3 receptors inhibit dopamine release.
D2-like dopamine receptors are thought to control presynaptic dopamine synthesis and release. Because these receptors comprise a family which includes D2, D3 and D4 dopamine receptors, the question arises as to which subtype performs what role(s). To investigate the potential autoreceptor roles of these proteins, D2, D3 and D4 receptors were transfected into a mesencephalic clonal cell line which synthesizes and releases dopamine. Here we report that stimulation of transfected D2 and D3 receptors, but not D4 receptors, inhibits dopamine release from this dopaminergic cell line. This is the first report of a functional role for D3 receptors and establishes these cell lines as a convenient in vitro model system to study signal transduction mechanisms associated with autoreceptor function.
4-Aminopyridine↗
Pharmacological and functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines.
In order to study the properties of the D2-like dopamine receptors, D2, D3 and D4 clones were transfected into mouse Ltk- fibroblasts, CCL1.3, and a neuronal mesencephalic cell line, MN9D. Most of the derived antagonist and agonist inhibition constants were the same for a given receptor in either cell line as determined by saturation and competition binding experiments. The rank order potencies for antagonists are: eticlopride, D2 > D3 > D4; YM-09151-2, D2 = D4 > D3; spiperone, D2 = D3 > D4; (+)-butaclamol, D2 > D3 > D4; clozapine, D4 > D2 > D3; and for agonists, quinpirole, D3 = D4 > D2; 7-hydroxy-2-(di-n-propyl)-aminotetralin, D3 > D2 = D4. Functionally, D2 stimulation increases inositol phosphate levels in CCL1.3 cells but not in MN9D, whereas D2 activation inhibits forskolin-stimulated cyclic AMP levels in both cell lines. D4 stimulation has no effect on inositol phosphate metabolism in either cell type, but inhibits adenylate cyclase in MN9D cells. Both the D2 and D4 mediated decreases in cyclic AMP can be blocked by preincubation with pertussis toxin. D3 does not couple to these pathways in either cell line. Reverse transcription/polymerase chain reaction techniques were used to determine the availability of cellular signalling systems. Both CCL1.3 and MN9D cells have high levels of G alpha i2 expression, whereas neither cell expresses G alpha i1 or G alpha i3. These data imply that the D2 receptor couples to the G alpha i2 subtype in both cell lines, whereas D4 does not.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclase Inhibitors↗