Dopaminergic Hypothesis Research Articles

Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population

The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P=0.0010, odds ratio=1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis.

The dopaminergic hypothesis of attention-deficit/hyperactivity disorder needs re-examining

Although psychostimulants alleviate the core symptoms of attention-deficit/hyperactivity disorder (ADHD), recent studies confirm that their impact on the long-term outcomes of ADHD children is null. Psychostimulants enhance extracellular dopamine. Numerous review articles assert that they correct an underlying dopaminergic deficit of genetic origin. This dopamine-deficit theory of ADHD is often based upon an overly simplistic dopaminergic theory of reward. Here, I question the relevance of this theory regarding ADHD. I underline the weaknesses of the neurochemical, genetic, neuropharmacological and imaging data put forward to support the dopamine-deficit hypothesis of ADHD. Therefore, this hypothesis should not be put forward to bias ADHD management towards psychostimulants.

Dopamine and Migraine: Biology and Clinical Implications

In the last 30 years dopamine has been considered as playing a role in the pathogenesis of migraine. The literature indicates that migraineurs are hypersensitive to dopamine agonists with respect to some of the premonitory symptoms of migraine such as nausea and yawning. There are various non-specific dopamine D(2) receptor antagonists that show good clinical efficacy in migraine, and also a number of polymorphisms of dopaminergic genes related to migraine. Animal studies have also shown that dopamine receptors are present in the trigeminovascular system, the area believed to be involved in headache pain, and neuronal firing here is reduced by dopamine agonists. There appears to be little effect of dopamine on peripheral trigeminal afferents. We assess some of the limitations of the clinical studies with regard to the therapeutics, and those found in the studies that discovered differences in genetic polymorphisms in migraine, and consider the implications of this on a dopaminergic hypothesis of migraine.

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Association analysis of polymorphisms in the N-methyl- d-aspartate (NMDA) receptor subunit 2B ( GRIN2B) gene and tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a neurological disorder characterized by irregular, non-rhythmic, choreoathetotic and involuntary movements in single or multiple body regions. Chronic administration of typical antipsychotic agents, which predominantly act on dopamine receptors, implicates the dopamine system in susceptibility to TD. An alternative to this dopaminergic supersensivity hypothesis in understanding the pathogenesis of TD is the glutamatergic neurotoxicity hypothesis, which implicates the N-methyl- d-aspartate (NMDA) receptor in TD pathogenesis. In the present study, the association between three polymorphisms (T-200G, C366G and C2664T) of the GRIN2B gene, which encodes the 2B subunit of the NMDA receptor, and the occurrence and severity of TD were investigated in 273 Chinese schizophrenic patients receiving long-term antipsychotic treatment (TD: 142, non-TD: 133). There was no significant association between patients' genotype and allele frequencies and TD occurrence. Among the TD patients, the differences in the total scores on the Abnormal Involuntary Movement Scale (AIMS) among the three genotypes of each polymorphism were not significant. Because the three studied markers are in weak linkage disequilibrium with each other, haplotype-based association was not carried out. We conclude that genetic variations in the human GRIN2B gene probably do not play a major role in susceptibility to, or severity of TD.

Effect of educational intervention on medication timing in Parkinson's disease: a randomized controlled trial

BackgroundMedicine usage in Parkinson's disease patients is often imperfect, in particular irregular timing of medication. The effect of informing Parkinson's disease patients about the continuous dopaminergic hypothesis (to encourage regular medicine intake) on medication adherence and motor control was tested.MethodsPatients were randomised either to the active group (receiving the intervention) or control group (no extra information). Antiparkinson medicine usage was monitored for 3 months before and after the intervention using electronic pill bottles which record the date and time of opening (MEMS®, Aardex, Switzerland) and data used to calculate the percentage of doses taken at correct time intervals.Results43 patients (52%) were randomised to active counselling, and 40 (48%) were controls (standard management). The intervention effect (difference in timing adherence pre- to post-intervention between the 2 groups) was 13.4% (CI 5.1 to 21.7), p = 0.002. Parkinson motor scores did not change significantly (active group 0.1, CI -3.4 to 3.7) versus controls (4.5, CI 1.6 to 7.1), p = 0.06.ConclusionTiming adherence, but not motor scores, improves by providing patients with extra information. Therapy timing is of potential importance in Parkinson's disease management.Trial registration numberNCT00361205

Apomorphine-induced neurodegeneration in Mongolian gerbil hippocampus

Animal experiments using pharmacological agents acting on the dopaminergic system, such as apomorphine, have been used as suitable models of schizophrenia, based on the dopaminergic hypothesis of this disorder. To determine whether dopaminergic hyperactivity may produce neuropathological changes, young Mongolian gerbils were treated with apomorphine (0.45 mg/kg) and the hippocampal CA1 region was subsequently studied by transmission and scanning electron microscopy. Acute subcutaneous administration of apomorphine induced pronounced degenerative changes in hippocampal neurons, such as swollen dendrites and axons in the neuropil and swelling of synaptic endings with a decrease in the number of synaptic vesicles. In conclusion, we think that this animal model may provide important indications about a possible dopaminergic hyperactivation mechanism, that could produce pathological changes in the hippocampus similar to those encountered in psychotic patients.

Dopamine and Reward Prediction Error: An Axiomatic Approach to Neuroeconomics

Reinforcement learning theory has produced important insights into economic behavior. Intriguingly, neuroscientists recently discovered a plausible mechanism through which reinforcement may be encoded in the brain. Yet their resulting dopaminergic reward prediction error hypothesis has not yet been incorporated into economics. We develop an axiomatic model that characterizes the empirical implications of this theory for an idealized data set comprising both neuroscientific measurements and choices. Our axiomatization removes the language barrier between economics and neuroscience. This will allow neuroeconomic experimental protocols to be developed appropriate to the questions motivating economic, as opposed to purely neuroscientific, interest in learning.

Punding as a Complication of Brain Stem Stroke?

Stereotyped motor behaviors, known as "punding," originally described among amphetamine abusers have only recently been reported in Parkinson disease associated with both pro-(eg, levodopa) or anti-(eg, quetiapine) dopaminergic therapy. We describe a non-Parkinson disease case of nonpharmacologically induced punding as a complication of a brain stem cardiovascular accident. A 54-year-old man, after an episode of brain stem cardiovascular accident secondary to basilar artery thrombosis, was noted to endlessly purchase and hoard food items and to write, copy and organize recipes. His activity was excessive, disruptive and affected his interaction with family members. The patient's punding behaviors significantly improved with an increased dose of sertraline from 100 mg to 150 mg per day. Our patient's presentation was most consistent with punding, but interestingly was not a result of dopaminergic therapy. Moreover, improvement of his behavior was noted with a selective serotonin reuptake inhibitor, further questioning the dopaminergic hypothesis of punding.

Fisiopatologia da esquizofrenia: aspectos atuais

BACKGROUND: Schizophrenia is one of the most intriguing and studied psychiatric diseases and its physiopathology has advanced a lot in the last century. OBJECTIVE: To review the most important advances in the physiopathology of schizophrenia. METHOD: Review of the literature of each proposed topic by articles searched in Medline and/or chosen accordingly the authors’ experience. RESULTS: The dopaminergic hypothesis was one of the first ethiological theories and until today is among the ones that presents the most consistent evidences. However, it fails to explain important features found in schizophrenia, such as the natural history, the cognitive impairments and the structural abnormalities. Evidences provided by epidemiological studies of genetic and environmental risk factors, associated with the findings of neuropathological and neuroimaging studies, suggest an interactive model with several factors acting together to create a global alteration of the brain development. CONCLUSION: The physiophatology of schizophrenia has advanced a lot in the last century, evolving from unicausal theories towards more complex models that consider the interaction among several genetic and environmental factors.

Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects

Central dopaminergic activity is critical to the functioning of both motor and cognitive systems. Based on the therapeutic action of dopaminergic agents in treating attention deficit hyperactivity disorder (ADHD), ADHD symptoms may be related to a reduction in central dopaminergic activity. We tested the hypothesis that dopaminergic activity, as reflected by plasma homovanillic acid (pHVA), may be related to dimensional aspects of ADHD in adults. Subjects were 30 healthy volunteer and 39 personality disordered subjects, in whom morning basal pHVA concentration and a dimensional measure of childhood ADHD symptoms (Wender Utah Rating Scale: WURS) were obtained. A significant inverse correlation was found between WURS Total score and pHVA concentration in the total sample. Among WURS factor scores, a significant inverse relationship was noted between pHVA and history of “childhood learning problems”. Consistent with the dopaminergic dysfunction hypothesis of ADHD and of cognitive function, pHVA concentrations were correlated with childhood history of ADHD symptoms in general and with history of “learning problems” in non-ADHD psychiatric patients and controls. Replication is needed in treated and untreated ADHD samples to confirm these initial results.

Haplotype association study between DRD1 gene and bipolar type I affective disorder in two samples from Canada and Sardinia

Based on the dopaminergic hypothesis, the dopamine D(1) receptor gene (DRD1) is considered to be a good candidate gene involved in the susceptibility of bipolar disorder (BP). Genetic association between three DRD1 single nucleotide polymorphisms (SNPs) (-800T/C, -48A/G, and 1403T/C) and bipolar type I (BP I) disorder was performed in a case-control sample of Sardinian origin (170 BP I and 209 controls) and in an enlarged sample (229 families) of BP I trios from Toronto. The haplotype analyses generated significant global chi-square in both samples (P-value 0.024 in Toronto and 0.00042 in Sardinian). The main representative haplotypes in both samples were the -800T/-48A/1403C and the -800C/-48G/1403T. Considering each group individually, the -800C/-48G/1403T was transmitted more frequently from parents to BP I probands in Toronto sample (nominally P-value = 0.047) and was more frequent in cases than in control subjects in Sardinian sample although showing no significant evidence of association (nominally P-value = 0.16) When the estimated haplotype counts of both samples were combined, the global chi(2) was significant (P-value = 0.00085) and the nominal P-value for the haplotype -800C/-48G/1403T was 0.01. The fact that the same haplotype shows a similar trend for association in samples originating from different ethnic backgrounds seems to imply that the -800C/-48G/1403T haplotype may be considered as a risk factor for BP I disorder.

A dopaminergic deficit hypothesis of schizophrenia: the path to discovery

In contrast to the conventional view of dopamine involvement in schizophrenia, which posits hyperactive dopaminergic transmission, we propose that for unknown developmental and/or biochemical reasons, a primary defect occurs in efficient, tight dopaminergic synaptic transmission, triggering feedback activation and receptor upregulation, and resulting in the well-characterized increase in dopaminergic tone. This hypothesis is driven by suggestive evidence for subpopulations of dopamine D2 receptors delivering contrasting forms of dopaminergic transmission: synaptic receptors, responsible for basic dopaminergic function and subject to effective feedback control, and poorly controlled extrasynaptic receptors partly responsible for the positive symptoms of psychosis. Since the primary defect is dopamine deficiency, we term this theory the dopaminergic deficit hypothesis of schizophrenia. It is currently informing clinical studies with novel partial dopamine antagonists (dopamine stabilizers) such as ACR16, which preferentially target extrasynaptic receptors while leaving synaptic transmission and basic dopamine function intact.

Color naming deficits and attention-deficit/hyperactivity disorder: a retinal dopaminergic hypothesis.

BackgroundIndividuals with Attention-Deficit/Hyperactive Disorder (ADHD) have unexplained difficulties on tasks requiring speeded processing of colored stimuli. Color vision mechanisms, particularly short-wavelength (blue-yellow) pathways, are highly sensitive to various diseases, toxins and drugs that alter dopaminergic neurotransmission. Thus, slow color processing might reflect subtle impairments in the perceptual encoding stage of stimulus color, which arise from hypodopaminergic functioning.Presentation of hypotheses1) Color perception of blue-yellow (but not red-green) stimuli is impaired in ADHD as a result of deficient retinal dopamine; 2) Impairments in the blue-yellow color mechanism in ADHD contribute to poor performance on speeded color naming tasks that include a substantial proportion of blue-yellow stimuli; and 3) Methylphenidate increases central dopamine and is also believed to increase retinal dopamine, thereby normalizing blue-yellow color perception, which in turn improves performance on the speeded color naming tasks.Testing the hypothesisRequires three approaches, including:1) direct assessment of color perception in individuals with ADHD to determine whether blue-yellow color perception is selectively impaired; 2) determination of relationship between performance on neuropsychological tasks requiring speeded color processing and color perception; and 3) randomized, controlled pharmacological intervention with stimulant medication to examine the effects of enhancing central dopamine on color perception and task performanceImplications of hypothesisIf substantiated, the findings of color perception problems would necessitate a re-consideration of current neuropsychological models of attention-deficit/hyperactivity disorder, guide psycho-education, academic instruction, and require consideration of stimulus color in many of the widely used neuropsychological tests.

Syndrome catatonique et syndrome malin des neuroleptiques (à propos d’un cas)

We report the case of a young woman who deve-loped catatonic syndrome a few days after neuroleptic mali-gnant syndrome (NMS), arising the problem of the chronology of both affections. A 20-year old woman with an history of bipolar disorder, experienced an acute manic syndrome that made hospitalization necessary. Fourteen days after loxa-pine prescription, the patient developed a NMS (DSM IV criteria) dyskinesia, dysphagia, fever and alteration of cons-ciousness. Hepatic transaminases and muscular enzymes increased. Neuroleptic was immediately interrupted and benzodiazepines (Lorazepam) was started. Biological parameters were normalized after 7 days, hyperpyrexia decreased and extrapyramidal symptoms disappeared but manic symptoms persisted. Two weeks later, the patient presented nega-tivism, rigidity of the four limb, catalepsia and hyperpyrexia. She also had been anxious for death and presented auditory hallucinations. Bacteriological samples and computed tomography were normal. This catatonic symptoms did not decreased and electroconvulsive therapy (ECT) was necessary. After six ECT, she started standing up, walking, taking food and speaking. After 12 ECT, the clinical state was the same as it was before the acute episod. The patient was then treated with valproate and lorazepam for anxiety symptoms. Acute catatonie, a rare and life-threatening acute syndrome was described in psychosis before the advent of neuroleptic drugs. It's characterized by hyperexia, stupor alternated with exctement, rigidity. Many etiolologic factors have been reported for this affection: psychogenic, organic or toxic. Neuroletic malignant syndrome is a potentially fatal complication of neuroleptic treatment occuring in about 1% of patients treated with neuroleptic. This syndrome is characterised by consciousness alteration, extrapyramidal symptoms, autonomic and thermic disorders. Similar clinical and biological features in catatonia and neuroleptic malignant syndrome (NMS) suggest a relationship between both affections and common physiopathological mechanisms and neurochemical basis: a central dopamine deficiency. We believe like many authors that catatonia and NMS are two aspects of a same disease, arising the question of chronology of both affections: NMS precipitates catatonia evolution. In the same way, Revuelta reported a case of patient who presented a lethal catatonia worsened by neuroleptic malignant syndrome. Neuroleptic malignant syndrome may be related to a dopamine deficiency, predominantly in the basal ganglia and antérior hypothalamus. Dopaminergic impairment has also been postulated to explain hyperthermia and catatonic signs in acute catatonie. ECT increases cerebral concentrations of dopamine, GABA and noradrelanine. The efficacy of ECT also argues for the dopaminergic hypothesis. A relation between those syndromes are complexes. A catatonic syndrome is regard as an acute form of malignant syndrome. In the other way, a severity scores of malignant syndrome are correlated among catatonic signs. In this case report, we suggest that the neuroleptic malignant syndrome accelerate the evolution to catatonic syndrome.

Diethylstilbestrol-induced prolactinoma: dose-related tumor growth and effect of catecholaminergic cells on prolactin tumor cells

Background Prolactinoma is a pituitary adenoma originating from prolactin-secreting epithelial cells of the adenohypophysis. Unfortunately, there appears to be a relatively high recurrence rate despite all pharmacological, radiological, and surgical therapeutic interventions. The aim of the present study was to evaluate the extent of involvement of the dopaminergic dysregulation hypothesis of prolactinomas. We transplanted, in rats, DES-induced prolactinoma cells into the adrenal medulla or under the renal capsule, two tissues rich and poor in catecholaminergic innervation, respectively. Methods Prolactinoma was dose-dependently induced in ovariectomized female rats implanted with 10 and 20 mg DES, and tumor cells taken from prolactinoma induced by 20 mg DES were either transplanted under the renal capsule or into the adrenal medulla. Results Although the adrenal medulla, with its high dopamine content to inhibit prolactin secretion, was devoid of any tumoral development, a significant tumoral development was evident under the renal capsule, seemingly because of no inhibitory control over prolactin secretion coexisting with the dopamine deficiency of the tissue. Results are discussed for an alternatively possible regression and prevention of any relapse of prolactinoma, most possibly occurring because of tuberoinfundibular dopamine deficiency, by the implantation of another dopamine-rich tissue beside the tumoral mass. Conclusion Regression and prevention of any relapse of a tumoral outgrowth, most possibly occurring because of tuberoinfundibular dopamine deficiency, can well be alternatively achieved by the implantation of another dopamine-rich tissue beside the tumoral mass prolactinoma.

Esquizofrenia: quarenta anos da hipótese dopaminérgica sob a ótica da Química Medicinal

Schizophrenia is a devastating psychiatric illness that affects 1-2% of the world population and continues as a challenge to neuroscience. In this work, we describe an account about the historical evolution of the dopaminergic hypothesis of schizophrenia discussing, from the medicinal chemistry point of view all different classes of antipsychotic drugs, emphasizing the rational design, structure activity relationships (SAR) and physico-chemical properties related with its molecular mechanism of action.

Acute low single dose of apomorphine reduces periodic limb movements but has no significant effect on sleep arousals: a preliminary report

Study objectives. – To investigate the effects of apomorphine on the frequency of periodic limb movements during sleep (PLMS) and on sleep architecture. Design. – Nine patients presenting PLMS (including eight patients with restless legs syndrome) underwent three consecutive night sleep recordings. They received a single dose of 0.5 mg subcutaneous apomorphine at bedtime the third night. Results. – When computing PLMS during four 2-h periods of sleep, a significant period by apomorphine-effect was demonstrated, with a marked reduction of PLMS during the first 4 h post-injection ( P < 0.01). No significant differences were found in sleep macroarchitecture between the three recorded nights, excepted a slight reduction in sleep latency during the third night ( P < 0.05). Despite the decreased number of PLMS after apomorphine injection, there were significant changes neither in the total number of arousals nor in the index of arousals per hour of sleep. Conclusion. – Our results add further support to the dopaminergic hypothesis in the generation of PLMS. The persistence of arousals suggests that they are not simply the consequence of PLMS but a primary phenomenon, not related with the dopaminergic system.

High rates of periodic leg movements of sleep in REM-sleep behavior disorder raise more questions about the relationship between sleep-related movement disorders: Article reviewed: M.L. Fantini, M. Michaud, N. Gosselin, G. Lavigne, J. Montplaisir, Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation, Neurology, 59 (2002) 1889–1894

Objectives: Assess prevalence of periodic leg movements (PLMs) of sleep and the association of heart rate changes to these leg movements, in patients with REM behavior disorder (RBD) compared to patients with the restless legs syndrome (RLS). Study design: Case series. Study population: Forty consecutive patients with RBD and 15 patients with RLS. Methods: Polysomnography was performed in patients with RBD (without RLS) and a (presumably) historical age and gender-matched group with primary RLS. Of the 28 RBD patients with a PLM index greater than 10/h, 15 were randomly selected for further analysis of leg movement characteristics and consequences, and again compared to the RLS group. No patients in either group were taking medications known to affect sleep. Scoring of REM was performed without the EMG channel. Fifty leg movements from Stage II sleep were randomly selected for each patient. Change in heart rate from baseline for the 10 beats before, and 15 beats after, each leg movement onset was determined, and averaged within groups. Results: Seventy percent of patients with RBD had a PLM index greater than 10/h. Mean PLM index was no different between the RBD and RLS groups for wake or non-REM, though it was higher for the RBD group during REM sleep. Cardiac acceleration following PLM onset in the RBD group was over twice that seen in the RLS group, even though a smaller percentage of leg movements was associated with cortical arousal in those with RBD. Conclusions: PLM indices are the same in RBD and RLS, further supporting the dopaminergic hypothesis for generation or control of periodic leg movements during sleep (PLMS). PLMS are more common in RBD during REM sleep than observed in RLS. Reduced autonomic activation associated with leg movements in RBD may be related to idiopathic RBD or to a neurodegenerative disorder underlying the RBD. Similarly, the lack of cortical arousal seen with PLMS in RBD may indicate dysregulation of centers responsible for coordinating autonomic and cerebral activity during sleep.

Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable childhood-onset psychiatric condition characterized by developmentally inappropriate inattention, hyperactivity, and impulsiveness. The pathophysiology of ADHD is currently unknown. However, the therapeutic effects of stimulant medication together with findings from animal and neuroimaging studies as well as from several molecular genetic studies of the dopamine receptor D4 gene and dopamine transporter gene have implicated involvement of the dopaminergic system. To test the dopaminergic hypothesis further, we have looked for association between ADHD and alleles of seven dopamine-related candidate genes using a family-based association approach in a sample of 150 children diagnosed with ADHD. We tested polymorphisms in genes encoding three dopamine receptors (DRD3, DRD4, and DRD5) and four dopamine-relevant enzymes: tyrosine hydroxylase [tyrosine hydroxylase (TH)], dopamine beta hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). We were unable to detect a significant association with any of the polymorphisms genotyped, although there was a trend for preferential transmission of the DRD5 148 bp marker allele and the MAOA 122 bp marker allele. We conclude that none of the alleles we have tested makes a major contribution to ADHD, although much larger samples are required to exclude small effects.