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In this review, we will examine the most recent preclinical evidence in support of the fact that both acute and chronic stress may have a detrimental impact on the normal function of the dopaminergic system. In recent decades, the term stress has changed its meaning from that of a 'non-specific body response' to a 'monitoring system of internal and external cues'; that is a modality of reaction of the mammalian central nervous system (CNS) which is critical to the adaptation of the organism to its environment. Compelling results have demonstrated that the dopaminergic system is important not only for hedonic impact or reward learning but also, in a broader sense, for reactivity to perturbation in environmental conditions, for selective information processing, and for general emotional responses, which are essential functions in the ability (or failure) to cope with the external world. In this, stress directly influences several basic behaviors which are mediated by the dopaminergic system such as locomotor activity, sexual activity, appetite, and cross sensitization with drugs of abuse. Studies using rat lines which are genetically different in dopamine (DA) physiology, have shown that even small alterations in the birth procedure or early life stress events may contribute to the pathophysiology of psychiatric disorders-in particular those involving central DA dysfunction-and may cause depression or psychotic derangement in the offspring. Finally, the fact that the dopaminergic system after stress responds, preferentially, in the medial prefrontal cortex (MFC), is thought to serve, in humans, as a protection against positive psychotic symptoms, since the increased DA activity in the MFC suppresses limbic DA transmission. However, excessive MFC dopaminergic activity has a negative impact on the cognitive functions of primates, making them unable to select and process significant environmental stimuli. Thus it appears that a critical range of DA turnover is necessary for optimal cognitive functioning after stress, in the response of the CNS to ever-changing environmental demands. Molecular Psychiatry (2000) 5, 14-21.
Mol Psychiatry 2000 Jan
PMID:The role of stress in the pathophysiology of the dopaminergic system. 1067 64

Increasing evidence now suggests that more than one subtype of dopamine receptors is co-expressed in some of the central neurons. The neurobiological effects on the host cells when these receptors are concurrently activated by their common physiological ligand, dopamine, however, remains elusive. Among the members of the family of dopamine receptors, coupling of D1-like dopamine receptors to Gs and D2-like receptors to Gi proteins are known to augment or suppress cellular functions respectively, through modulation of adenylyl cyclase activity and consequently cAMP generation. Simultaneous activation of D1 and D2 receptors in transfected cell lines expressing the two cloned receptors, however, produced antagonistic effects. This is in contrast to in vivo studies, in which concurrent activation of D1-like and D2-like receptors by their respective agonists may induce synergistic or antagonistic effects or both. We report here that in long-term rat hypothalamic cell cultures, activation of both D1-like (D1 and D5) and D2 receptors on atrial natriuretic factor-producing neurons by dopamine yields a biphasic response. The response is ligand concentration-dependent and involves type II adenylyl cyclases. This process is mediated primarily through antagonistic and synergistic interactions of D5 and D2 receptors as the event is mimicked by the concurrent activation of these two receptors co-transfected in CHO cells. Our present findings suggest a novel action of dopamine, and the biochemical processes involved may underlie some of the pharmacological actions of atypical anti-psychotic drugs. Molecular Psychiatry (2000) 5, 39-48.
Mol Psychiatry 2000 Jan
PMID:Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction. 1067 67

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.
Mol Psychiatry 2000 Jan
PMID:A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia. 1067 69

Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84.
Mol Psychiatry 2000 Jan
PMID:Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. 1208 58

Schizophrenia is a common and severe psychiatric disorder of unknown etiology. Numerous neuropathological studies have found subtle structural changes in limbic structures, especially medial temporal lobe structures and the gyrus cinguli. To test the hypothesis that synaptic disturbances are involved in the pathogenesis of schizophrenia, we studied the growth-associated protein 43 (GAP-43), a protein localized to presynaptic terminals, suggested to be involved in establishment and remodeling of synaptic connections, in postmortem brain tissue, using quantitative Western blotting immunohistochemistry. The material consisted of brain tissue from 17 schizophrenics (80 +/- 11 yr), diagnosed according to the DSM-III-R criteria, and 20 age-matched controls (75 +/- 13 yr). Quantitative analyses showed increased GAP-43 protein levels in schizophrenic compared to control brains, both in the hippocampus (2.43 +/- 0.78 vs 1.00 +/- 0.29; p < 0.0001) and in the gyrus cinguli (1.52 +/- 0.21 vs 1.00 +/- 0.35; p < 0.0001). Also by immunohistochemistry, increased GAP-43 staining was found in schizophrenic compared with control brains, throughout all layers of the gyrus cinguli and the hippocampus. Anomalous synaptic sprouting and reorganization, with resultant "miswiring," as well as a defect in synaptic pruning have been hypothesized to be pathogenetic factors in schizophrenia. We suggest that a decreased synaptic density, whether caused by disturbed development or damage/degeneration, may elicit a reactive synaptogenesis (reflected by an increase in GAP-43), which may be functional or anomalous. Synaptic pathology in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.
J Mol Neurosci
PMID:The growth-associated protein GAP-43 is increased in the hippocampus and in the gyrus cinguli in schizophrenia. 1069 Dec 97

Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs. Hence, it is essential to identify additional variants of dopamine receptors for which more selective antipsychotic drugs can be found. Although no family linkage has been found between the D2 receptor and schizophrenia, there can be brain region abnormalities in the RNA transcript expression of dopamine receptors. Therefore, in order to identify variant dopamine D2 receptors, we searched for mutations in the RNA transcripts for the dopamine D2 receptor in the striatum of post-mortem brains from individuals who died with psychosis, including schizophrenia. A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains.
Brain Res Mol Brain Res 2000 Mar 10
PMID:New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. 1071 23

The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses.
Mol Psychiatry 2000 May
PMID:Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. 1088 29

Aromatic L-amino acid decarboxylase (AADC) is a relatively non specific enzyme involved in the biosynthesis of several classical neurotransmitters including dopamine and 5-hydroxytryptamine (5HT; serotonin). AADC does not catalyse the rate limiting step in either pathway, but is rate limiting in the synthesis of 2-phenylethylamine (2PE) which is a positive modulator of dopaminergic transmission and a candidate natural psychotogenic compound.1 We and others have proposed that polymorphism in AADC resulting in altered 2PE activity might contribute to the pathogenesis of psychosis. In order to test this hypothesis, we have used denaturing high performance liquid chromatography (DHPLC)3 to screen 3943 bases of the AADC gene and its promoter regions for variants that might affect protein structure or expression in 15 unrelated people with schizophrenia, and 15 unrelated people with bipolar disorder. Three polymorphisms were identified by DHPLC: a insertion/deletion polymorphism in the 5' UTR of the neuronal specific mRNA (g.-33-30delAGAG, bases 586-589 of GenBank M77828), a T>A variant in the non-neuronal exon 1 (g. -67T>A, GenBank M88070), and a G>A polymorphism within intron 8 (g. IVS8 +75G>A, GenBank M84598). Case-control analysis did not suggest that genetic polymorphism in the AADC gene is associated with liability for developing schizophrenia or bipolar disorder.
Mol Psychiatry 2000 May
PMID:Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder. 1088 38

Dopamine (DA) plays an important role in cognition, neuroendocrine functions and psychosis.1,2 Whilst stress adversely affects some of these functions, its neurobiological basis remains unclear.3 In the rat hypothalamus, a concurrent activation of D5and D2 receptors by dopamine produces a biphasic effect on the function of atrial natriuretic factor (ANF) neurons.4 Whereas low doses (10-8 and 10-7 M) of DA suppress the release and pro-ANF mRNA expression, high doses (10-6 and 10-5 M) of the amine produce an opposite effect through the interaction of D5 and D2 receptors. We report here that the augmenting effect of DA on the hypothalamic neurons is inhibited by a synthetic glucocorticoid, dexamethasone (DM), in both time-dependent and dose-related manner with an EC50 of 0.1 nM. Furthermore, the inhibition is blocked by 100 nM of RU38486 (P<0.01), a glucocorticoid receptor antagonist, but not by an equivalent dose of RU28318, a mineralocorticoid receptor antagonist. In contrast, DM failed to modulate low doses (10(-8) to 10(-7) M) of DA-induced suppression of ir-ANF release and pro-ANF mRNA expression that was mediated primarily through D2 receptors. We conclude that glucocorticoids markedly alter DA-induced biphasic effects by down-regulating D5, but not D2, receptor-mediated neurobiological events. Hence, in severe stress, high levels of circulating glucocorticoids may render dopamine to act as a potent suppressor of neurons that possess both D5 and D2 receptors. The possibility that this novel mechanism of stress hormone or glucocorticoids may, in part, undermine DA-mediated neurophysiology in critical regions of the brain, which links to psychosis now needs to be considered.
Mol Psychiatry 2000 May
PMID:Glucocorticoid modulation of dopamine mediated effects on hypothalamic atrial natriuretic factor neurons. 1088 39

DiGeorge syndrome, velocardiofacial syndrome and various other malformations have been described in association with deletions and translocations involving human chromosome 22q11. Many of the structural malformations observed are also seen in animal models of neural crest disruption suggesting that the haplo-insufficiency resulting from the deletion somehow affects this group of cells or their interactions. Over the past few years it has been shown that the deletion predisposes to a range of psychotic conditions prompting the hypothesis that the deleted region may contain a predisposition locus for psychotic illness. The DiGeorge chromosomal region has been entirely sequenced and many of the genes mapping to the deletion interval have been studied in some detail. Despite these efforts, no gene has yet been proved to play a defined role in the pathogenesis of the syndrome. Current efforts are directed at the study of engineered chromosome mouse models which offer the potential to dissect at least some of the developmental pathways disrupted in this intriguing group of malformation syndromes.
Hum Mol Genet 2000 Oct
PMID:The 22q11 deletion syndromes. 1100 97


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