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R D Todd

Publications and source records attributed to R D Todd.

At least 73 records · Page 4Linked to original sources
PubMed1993

No proof of linkage between schizophrenia-related disorders including schizophrenia and chromosome 2q21 region.

We examined linkage between schizophrenia and schizophrenia-related disorders and five genetic markers on chromosome 2 in fourteen families ascertained through affected probands in St. Louis and Vienna. The chromosomal region 2q21 was considered a candidate locus for schizophrenia because of a report of a balanced translocation 2;18 (q21;q23) in a schizophrenia family. Linkage analyses were conducted for three disease models: a narrow model including schizophrenia only; an intermediate model including a spectrum of schizophrenia-related disorders; and a broad model including major affective disorders. Multipoint linkage analyses excluded linkage across the region (about 50 cM) for the intermediate disease model. The same was generally true for the broad affection status model. None of the two-point and multipoint analyses showed definite linkage of schizophrenia to any marker. The most prominent positive association was between D2S44 and a broad affection status model, giving a two-point lod score of 1.71 at 0.20 recombination fraction.

Adult↗
PubMed1993

Genetic studies of affective disorders: should we be starting with childhood onset probands?

OBJECTIVE: The objective of this study is to test whether the presence of childhood onset affective disorder identifies families with increased incidence and severity of affective disorders. METHOD: Family history information was collected on the first and second degree relatives and first cousins age > or = 15 years of 22 children with bipolar affective disorder, 54 children with major depressive disorder, and 31 psychiatrically normal children. RESULTS: Compared with the relatives of normal children, relatives identified through children with bipolar affective disorder or major depressive disorder had elevated rates of affective disorders and increased severity of affective disorders as judged by earlier age of onset and increased suicide attempts. Segregation analyses could reject purely environmental transmission of illness. CONCLUSION: Ascertaining families through childhood onset affective disorder probands identifies extended pedigrees with high incidence and severity of affective disorders. These families may be more appropriate for genetic analyses than are families of adult probands.

Adolescent↗
PubMed1992

Photoreceptors of mouse retinas possess D4 receptors coupled to adenylate cyclase.

In the mouse, the light-sensitive pool of cAMP can be eliminated in the dark by application of the dopamine D2-like receptor agonists LY 171555 (quinpirole), (+)-N0437 (2-[N-(n-propyl)-N-2-(thienylethylamino)-5-hydroxytetralin]) , or (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride]. The rank-order affinity of the ability of the D2-like antagonists to block the action of LY 171555 matched that of the rat D4 receptor. Reverse transcription of retina mRNA followed by DNA amplification using D4-specific nucleotides demonstrates the presence of D4 mRNA in retina. In situ hybridization studies using D4-specific digoxygenin-labeled oligonucleotides or 35S-labeled UTP RNA probes demonstrate the presence of D4 mRNA in the photoreceptor cell layer and in the inner nuclear and ganglion cell layers. The modulation by D4 ligands of the dark level of light-sensitive cAMP in photoreceptors demonstrates the physiological coupling of the D4 receptor subtype.

Adenylyl Cyclases↗
PubMed1992

Neural development is regulated by classical neurotransmitters: dopamine D2 receptor stimulation enhances neurite outgrowth.

The classical neurotransmitters serotonin and dopamine are thought to be involved in the etiology or treatment of a variety of psychiatric disorders. Recent studies suggest that these neurotransmitters may also have roles as neural morphogens during brain development. Previously, we have demonstrated that stimulation of serotonin 5-HT1A receptors selectively inhibited neurite branching in an in vitro system (Sikich et al 1990). In the present study, the developmental role of dopamine D2 receptors in the control of neurite outgrowth has been investigated by quantitating the morphological response of cortical neurons to agonist stimulation in vitro. Cultures of fetal rat frontal, cortical neurons were shown to express both alternatively spliced forms of D2 receptor messenger RNA (mRNA). The larger mRNA form predominated (D2A444:D2A415 ratio of about 6:1). In a small but significant percentage of these neurons, culture in the presence of the D2 receptor selective agonist, quinpirole, resulted in a three-to ten-fold increase in the length of neurites and in the number of branch points per neurite. These effects were blocked by the D2 receptor antagonists eticlopride and spiperone. Early abnormalities in the stimulation of dopamine or serotonin receptor subtypes could lead to the types of neuroanatomical changes observed in studies of schizophrenia, bipolar affective disorder, and autism. These morphogenic effects of classical transmitters could unite neurodevelopmental and neurotransmitter theories of the etiology of severe psychiatric disorders.

Animals↗
PubMed1992

The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system.

Dopamine receptors have been implicated in a variety of neurological and neuropsychiatric disorders. Here we describe the use of the polymerase chain reaction and low stringency library screening to isolate a rat genomic clone encoding a novel dopamine receptor. Sequence data and pharmacological analysis reveal this clone to be the rat analog of the human D4 receptor, which exhibits a high affinity for the antipsychotic drug clozapine. The mRNA for this receptor shows a restricted pattern of expression in the central nervous system. Significant levels of expression were found in the hypothalamus, thalamus, olfactory bulb, and frontal cortex. However, 20-fold higher levels of D4 mRNA expression were observed in the cardiovascular system. Thus, this receptor appears to mediate dopamine function in the cardiovascular system as well as the central nervous system.

Amino Acid Sequence↗
PubMed1991

Differential expression of dopaminergic D2 receptor messenger RNAs during development.

To define the possible roles of multiple types of dopamine D2 receptors, mRNA levels for two forms of D2 receptor were determined during a variety of developmental stages. Transcripts encoding the 444 amino acid form appear as early as embryonic day 14. In contrast, the mRNA encoding the 415 amino acid form of the receptor does not appear until embryonic day 17, and remains a minor form throughout prenatal development. The adult levels of the mRNAs of these two D2 receptor forms are not attained until long after birth.

Animals↗
PubMed1991

Alcoholism and alleles of the human D2 dopamine receptor locus. Studies of association and linkage.

The association of the A1 allele of the D2 dopamine receptor gene with alcoholism was examined by comparing 32 unrelated white alcoholics with 25 unrelated white controls and by analysis of 17 nuclear families in multigenerational pedigrees of alcoholics in whom the A1 allele was segregating. All subjects had structured psychiatric interviews. Clinical assessment and genotyping were carried out independently. Thirteen (41%) of the 32 alcoholics carried the A1 allele compared with three (12%) of the 25 controls. The association with the A1 allele was significant when controls were compared with a subset of 10 alcoholics with severe medical problems (60% vs 12%), but not less severe cases. However, regardless of clinical severity or subtype, there was no evidence of linkage or cosegregation of the A1 allele and increased susceptibility to alcoholism in informative pedigrees. The possible association in the general population without linkage in families may be explained either by chance variation in our small samples or a modifying effect of the A1 allele that increases severity. Further study of the role of the D2 receptor gene in alcoholism is warranted.

Alcoholism↗
PubMed1991

Analysis of the structure and expression of the human dopamine D2A receptor gene.

In order to study the possible involvement of dopamine receptors in the pathophysiology of various neurological and psychiatric disorders, we have isolated the human D2A gene. Like the rat D2A gene, the human gene contains at least eight exons and spans at least 52 kb. Exons 2-8 are clustered within 14 kb of genome. Exon 1 is separated from exon 2 by at least 38 kb. We and others have shown that alternative utilization of exon 6 gives rise to alternative D2A transcripts. Despite the extreme size of intron 1, no alternative transcription between exons 1 and 2 can be detected in basal ganglia and pituitary using polymerase chain reaction analysis. The relative abundance and tissue distribution of the alternative D2A transcripts were examined in 18 human brain regions. The relative expression of the transcripts varied by at least 70-fold across the brain regions surveyed. As expected, high levels of transcripts were detected in caudate, putamen, and pituitary. Moderate levels were detected in regions of catecholamine-containing cell bodies and in the amygdala. In contrast to the rat brain, very low levels of transcripts were detected in cortical regions.

Base Sequence↗
PubMed1991

The mouse dopamine D2A receptor gene: sequence homology with the rat and human genes and expression of alternative transcripts.

To understand the possible involvement of dopamine receptors in the pathogenesis of various neurological disorders, we have cloned and sequenced a dopamine D2A receptor gene from the mouse. A mouse genomic library was screened with probes derived from the published sequence of a rat D2A receptor cDNA. Using restriction endonuclease mapping, Southern blotting, and DNA sequencing, we have determined the cDNA sequence and genomic organization of the mouse D2A receptor gene. Unlike other guanine nucleotide-binding protein-coupled receptors, but similar to its rat and human counterparts, the mouse D2A receptor gene has seven introns and spans at least 30 kb of genomic DNA. The mouse D2A sequence shows 99% amino acid homology with the rat and 95% amino acid homology with the human sequence. As would be predicted, sequence differences are significantly more frequent outside of the hypothesized transmembrane spanning domain regions of the protein. Using the polymerase chain reaction with primers made from neighboring exons, we have identified two alternatively spliced D2A transcripts in the mouse. However, in contrast to the other species studied, the mouse expresses primarily the mRNA representing the larger, 444-amino-acid form of the receptor. Mouse pituitary expresses only the mRNA of the 444-amino-acid form of the D2A receptor. Hence, the mouse may offer the best model to study the in vivo physiology of the long form of the D2A receptor.

Amino Acid Sequence↗
PubMed1991

Non-steady-state measurement of in vivo radioligand binding with positron emission tomography: specificity analysis and comparison with in vitro binding.

We previously have developed a non-steady-state method for in vivo measurement of radioligand-receptor binding in brain using positron emission tomography (PET) and 18F-spiperone (18F-SP). This method has proven to be highly sensitive to the detection of decreases in the apparent number of available specific binding sites. The purposes of this investigation are to demonstrate the specificity of this PET assay and compare findings to in vitro binding assays. Three to six studies were performed in each of five male baboons. Each animal was pretreated with either ketanserin [serotonergic (S2)], eticlopride [dopaminergic (D2)], or unlabeled SP to compete with 18F-SP for specific binding sites. Sequential PET scans and arterial-blood samples were collected for 3 hr after intravenous injection of 18F-SP. Data were analyzed with a three-compartment model that considered the accumulation of radiolabeled metabolites in arterial blood. Five baboons were killed, and radioligand-receptor binding in vitro was measured by homogenate techniques. There was no detectable in vitro or in vivo specific binding of SP in cerebellum. The specific binding of SP in striatal tissue in vitro was approximately 74% to D2 sites and 26% to S2 sites, whereas ketanserin displaced all specific binding in frontal cortex. In close agreement, specific binding measured in vivo with PET revealed that 68% of apparent striatal binding could be blocked by pretreatment with eticlopride, and 34% by ketanserin. The small apparent difference between receptor binding in vitro and in vivo may result from the relatively poor resolution of PET.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

5-HT1A receptors control neurite branching during development.

Serotonin (5-HT) is known to affect the motility and structure of responsive growth cones and to influence synaptic density in vitro. Whether these effects are produced via membrane bound serotonin receptors or another mechanism has been unknown. We demonstrate that high-affinity 5-HT receptors, present prenatally in rat brain, are asymmetrically distributed among cultured cortical neurons. Stimulation of the 5-HT1A receptors of these neurons in vitro specifically decreases the branching of neurites by 70% and reduces total neuritic length by more than half. These results are compatible with subtypes of serotonin receptors having important roles in mammalian neurodevelopment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Organization and expression of the rat D2A receptor gene: identification of alternative transcripts and a variant donor splice site.

We have recently reported the creation of a cell line expressing D2 receptors encoded by a gene distinct from that described by Bunzow et al. [Bunzow, J. R., Van Tol, H. H. M., Grandy, D. K., Albert, P., Salon, J., Christie, M., Machida, C. A., Neve, K., & Civelli, O. (1988) Nature 336, 783-787]. To provide a framework for understanding structural differences between these and other G-protein-coupled receptors, the structure of the rat gene coding for the Bunzow et al. cDNA (called D2A here) was delineated. The D2A gene contains eight exons and spans at least 50 kb. Sets of oligonucleotide primers were used in combination with the polymerase chain reaction (PCR) to determine the presence of alternative transcripts within the introns. In contrast to other G-protein-coupled receptors, the D2A gene undergoes alternative RNA processing within intron 5, resulting in an insertion of 29 amino acids to the predicted 415 amino acid sequence of the D2A protein. By use of the PCR assay the relative abundance and tissue distribution of the alternative D2A transcripts (herein termed D2A415 and D2A444) were determined. A variant donor splice site was also identified at the end of exon 4, a GC dinucleotide instead of the canonical GT. The variant dinucleotide was also present in the mouse but not in the human D2A gene.

Animals↗
PubMed1990

Acute psychosis in a patient with Epstein-Barr virus infection.

A case study is presented of an adolescent female who became psychotic and attempted suicide during an acute Epstein-Barr Virus infection. Resolution of the infection resulted in the patient returning to her previous normal mental status. The adolescent's ingestion of acetaminophen masked the signs and symptoms of infection and delayed proper diagnosis.

Acute Disease↗
PubMed1990

No evidence for linkage between chromosome 5 markers and schizophrenia.

Linkage between chromosome 5 markers and schizophrenia has been proposed for a small number of Icelandic and English families. Three subsequent reports have failed to replicate this report. To increase the number of tested kindreds, we collected seven North American families with schizophrenia and genotyped them at 4 loci that span the region 5p13-5q11-14, including the two markers used in the single positive linkage report. The data were analyzed with models of affection status similar to those utilized in the positive report. We observed no evidence of linkage between these markers and psychiatric disorders, regardless of the definition of affection status. Additionally, we can exclude most of the region for linkage with schizophrenia in these families. This and other negative reports of linkage between schizophrenia and chromosome 5 markers suggest that genetic defects in this region are rarely, if ever, etiologically related to schizophrenia.

Chromosomes, Human, Pair 5↗