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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The decreased sensitivity of animals to rewarding brain stimulation caused by pimozide has been interpreted as a selective pharmacologic blockade of central reward pathways rather than a nonspecific disruption of performance. In an attempt to confirm this hypothesis, the effects of pimozide on both reward and detection thresholds for intracranial stimulation delivered to the medial forebrain bundle-lateral hypothalamic area (MFB-LH) were determined in four animals. The drug caused a systematic increase in the reward threshold of each subject but had no such effect on the detection threshold. We conclude that pimozide selectively inhibits the rewarding effects of brain stimulation, and that therefore, the D2 dopamine receptor has a major role in activating central reward pathways subserving pharmacologic and electrical reinforcement. The dual anhedonic/antipsychotic effects of neuroleptic medication are discussed as a possible paradox of central importance to the psychopathology of schizophrenia.
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PMID:Dissociation of the attentional and motivational effects of pimozide on the threshold for rewarding brain stimulation. 213 97

The diverse physiological actions of dopamine are mediated by its interaction with two basic types of G protein-coupled receptor, D1 and D2, which stimulate and inhibit, respectively, the enzyme adenylyl cyclase. Alterations in the number or activity of these receptors may be a contributory factor in diseases such as Parkinson's disease and schizophrenia. Here we describe the isolation and characterization of the gene encoding a human D1 dopamine receptor. The coding region of this gene is intronless, unlike the gene encoding the D2 dopamine receptor. The D1 receptor gene encodes a protein of 446 amino acids having a predicted relative molecular mass of 49,300 and a transmembrane topology similar to that of other G protein-coupled receptors. Transient or stable expression of the cloned gene in host cells established specific ligand binding and functional activity characteristic of a D1 dopamine receptor coupled to stimulation of adenylyl cyclase. Northern blot analysis and in situ hybridization revealed that the messenger RNA for this receptor is most abundant in caudate, nucleus accumbens and olfactory tubercle, with little or no mRNA detectable in substantia nigra, liver, kidney, or heart. Several observations from this work in conjunction with results from other studies are consistent with the idea that other D1 dopamine receptor subtypes may exist.
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PMID:Molecular cloning and expression of the gene for a human D1 dopamine receptor. 214 34

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological properties and the intracellular responses they mediate. The cerebral D2 dopamine receptor is the target of drugs used to alleviate the main symptoms of schizophrenia. Although it is considered to be a single molecular entity, there is evidence that multiple D2-receptor subtypes exist. A complementary DNA encoding a D2 receptor has recently been cloned and the deduced 415-amino-acid sequence indicates that it belongs to the large superfamily of receptors coupled to G proteins, and that its topology consists of seven transmembrane domains. In this family, the genes are frequently without introns and each is believed to encode a unique polypeptide product. Here we show that the gene for the D2 receptor produces two receptor isoforms by alternative messenger RNA splicing, providing a route to receptor diversity in this family. One isoform corresponds to the D2(415) receptor, but the second contains an additional sequence encoding a 29-amino-acid fragment, defining a novel D2(444) receptor isoform. Expression of the two isoforms is tissue-specific, and both are regulated by guanyl nucleotides. As the extra sequence is located within a putative cytoplasmic loop that binds to G proteins, the two isoforms might interact with different G proteins and thereby initiate distinct intracellular signals.
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PMID:Alternative splicing directs the expression of two D2 dopamine receptor isoforms. 253 47

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.
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PMID:Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. 287 95

The best support for the hypothesized involvement of central nervous system dopamine systems in the pathophysiology of schizophrenia is the association between the affinity of neuroleptic drugs for the D2 dopamine receptor and their potency as antipsychotics. Discrepancy between the time course of receptor binding and the development of antipsychotic effects, however, limits this model. Preclinical studies have now shown that activation of presynaptic nigrostriatal and mesolimbic dopamine neurons by acute neuroleptic administration is reversed during chronic administration. Clinically, neuroleptic-induced time-dependent reductions in plasma levels of the dopamine metabolite, homovanillic acid (HVA), have been linked to the antipsychotic response in schizophrenic patients. These data support the notion that slowly developing alterations in presynaptic dopamine activity play a role in the mechanism of action of neuroleptic drugs. Differences between plasma and cerebrospinal fluid (CSF) HVA responses to neuroleptic treatment, although not fully explained, may be related to prominent contributions of mesocortical metabolism to CSF levels of HVA. A time-dependent dopaminergic model of neuroleptic action with implications for the pharmacotherapy of schizophrenia is presented.
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PMID:Perspectives on a time-dependent model of neuroleptic action. 290 94

We have investigated the radioligand binding properties of D1 and D2 dopamine receptors in postmortem brains from schizophrenic patients. Consistent with previous reports, the schizophrenic population demonstrated a significant 56% increase in D2 dopamine receptor density. Importantly, the D1 dopamine receptor density was significantly reduced by 43%. These alterations in dopamine receptor densities resulted in a highly significant difference in the ratio of D2/D1 dopamine receptors between schizophrenic patients and controls. A correlation between D1 dopamine receptor density and age was apparent in the schizophrenic patients: D1 dopamine receptor density decreased markedly with age and the linear regressions of D1 dopamine receptor density versus age in both the controls and schizophrenic patients had similar slopes. These results may have clinical implications for the treatment of schizophrenia and tardive dyskinesia.
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PMID:Dopamine receptor subtype imbalance in schizophrenia. 295 73

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological and biochemical characteristics. The D2 dopamine receptor has been implicated in the pathophysiology and treatment of movement disorders, schizophrenia and drug addiction. The D2 dopamine receptor interacts with guanine nucleotide-binding proteins to induce second messenger systems. Other members of the family of receptors that are coupled to G proteins share a significant similarity in primary amino-acid sequence and exhibit an archetypical topology predicted to consist of seven putative transmembrane domains. We have taken advantage of the expected nucleotide sequence similarities among members of this gene family to isolate genes coding for new receptors. Using the hamster beta 2-adrenergic receptor gene as a hybridization probe we have isolated related genes including a cDNA encoding the rat D2 dopamine receptor. This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.
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PMID:Cloning and expression of a rat D2 dopamine receptor cDNA. 253 46

Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125-4.0 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.
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PMID:Dopaminergic stimulation disrupts sensorimotor gating in the rat. 313 96

Brain dopamine receptors (type D2) mediate the psychomotor effects of dopamine. The D2 dopamine receptor can exist in either a high-affinity state for dopamine (nanomolar dissociation constant) or in a low-affinity state (micromolar dissociation constant). Both states of the receptor, however, have high affinity for neuroleptics (60 pM for spiperone). The postsynaptic receptor probably operates mainly in the D2 slow state. The presynaptic dopamine receptor, and also the dopamine receptors in the pituitary gland and the area postrema, probably function in the D2 high state. The density of brain D2 dopamine receptors is elevated in schizophrenia. The control densities were 10.5 pmol per g tissue. Half of the schizophrenic tissues (putamen, caudate nucleus, and nucleus accumbens) revealed densities of about 11.9 pmol per g, while the other half of the tissues revealed a density mode of 23.8 pmol per g. The bimodal distribution may support the concept of two types of schizophrenia. Future work must decide which group has more tardive dyskinesia.
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PMID:Brain dopamine receptors in schizophrenia and tardive dyskinesia. 315 8

It has been suggested that a combined blockade of 5-HT2 and D2 dopamine receptors may be superior to D2 dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT2 and D2 dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT2 and D2 dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [11C]N-methylspiperone ([11C]NMSP) was used as a radioligand for determination of 5-HT2 receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT2 receptor occupancy about 60%. [11C]raclopride was used as a radioligand for determination of D2 dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT2 receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT2 receptor occupancy should be very high at the dose level of 4-10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT2 and D2 dopamine receptor blockade in the treatment of schizophrenia.
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PMID:5-HT2 and D2 dopamine receptor occupancy in the living human brain. A PET study with risperidone. 753 Mar 76


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