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Neurochemistry International Mar 1992
Review
Topics: Amino Acid Sequence; Animals; Humans; Molecular Biology; Molecular Sequence Data; Nervous System; Neurobiology; Receptors, Dopamine
PubMed: 1365419
DOI: 10.1016/0197-0186(92)90205-6 -
Nihon Yakurigaku Zasshi. Folia... Dec 1998There have been many efforts to develop novel antipsychotic drugs with improved clinical efficacy and reduced side effects such as extrapyramidal side effects and... (Review)
Review
There have been many efforts to develop novel antipsychotic drugs with improved clinical efficacy and reduced side effects such as extrapyramidal side effects and hyperprolactinemia. Recent evidences from studies on the effects of novel antipsychotic drugs such as clozapine on neurotransmitter receptors are prompting reconsideration of the dopaminergic hypothesis of schizophrenia. This paper gives an overview of the current understanding, including our data, of the effects of several antipsychotics on dopamine receptor subtypes. The recent cloning of dopamine receptors has revealed that multiple dopamine receptor subtypes are generated from at least five distinct dopamine receptor genes. Aripiprazole, a candidate for a novel antipsychotic, has an antagonistic activity against dopamine D2 receptors with a high affinity, but has a weaker potency to up-regulate D2 receptors than haloperidol in the striatum and inhibitory effects on D2-receptor binding activities and mRNA in the pituitary, when it is chronically administrated to rats. Thus the occupancy or influences in D2 receptors in the striatum are involved in the extrapyramidal side effects of typical antipsychotic drugs. These studies provide new leads to understand the pathophysiology and causes of schizophrenia and to develop more effective and safe methods of treatment.
Topics: Animals; Antipsychotic Agents; Aripiprazole; Haloperidol; Piperazines; Quinolones; RNA, Messenger; Rats; Receptors, Dopamine
PubMed: 10202760
DOI: 10.1254/fpj.112.351 -
Life Sciences 1997Recent advances in molecular biology have provided pharmacologists the opportunity of developing an entirely new type of agent for studying and treating a variety of... (Review)
Review
Recent advances in molecular biology have provided pharmacologists the opportunity of developing an entirely new type of agent for studying and treating a variety of biological disorders. These agents, termed antisense oligodeoxynucleotides, have as their target the messenger RNAs encoding specific proteins. They act by binding to selected portions of these mRNAs through complimentary interactions and thereby prevent the synthesis of these proteins. These novel pharmacological tools have the promise of being easier to design and being more selective and predictable in their actions. In addition, insofar as agents targeted to receptors for neurotransmitters are concerned, unlike the classical pharmacological agents, these new compounds may not lead to the upregulation of the very receptors the drugs are designed to inhibit. The present review summarizes briefly studies on the effect of oligodeoxynucleotides antisense to the mRNAs encoding the various subtypes of the dopamine receptor. The studies show that oligodeoxynucleotides antisense to the D2 dopamine receptor when intracerebroventricularly into brains of rodents are rapidly taken up into the brain tissue, distributed to brain cells, and produce effects characteristic of highly selective D2 dopamine antagonists. The compounds also produced specific reductions in the levels of D2 dopamine receptor mRNA and D2 dopamine receptors. Similarly, injecting an antisense oligodeoxynucleotide targeted to the D1 dopamine receptor mRNA produces effects characteristic of D1 dopamine receptor antagonists. Other studies using these agents has produced evidence that there is a small pool of receptors that turn over very rapidly and which constitute the functional pool of these receptors. The evidence suggests further that antisense oligodeoxynucleotides inhibit the synthesis of this small functional pool of dopamine receptors, thereby providing an explanation of why there is often a discordance between changes in dopaminergic function and changes in the levels of dopamine receptors. Studies of antisense oligodeoxynucleotides targeted to the other subtypes of dopamine receptor may help reveal the biological roles that these and other newly discovered subtypes of neurotransmitter receptors have. They may also provide an entirely new and potentially more selective therapeutic regimen for altering the functions of these receptors.
Topics: Animals; Behavior, Animal; Dopamine; Oligonucleotides, Antisense; RNA, Messenger; Receptors, Dopamine
PubMed: 9042372
DOI: 10.1016/s0024-3205(96)00566-8 -
Psychopharmacology Series 1987
Review
Topics: Animals; Carps; Cattle; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 2950520
DOI: 10.1007/978-3-642-71288-3_24 -
Journal of Pineal Research Apr 2005D1- and D2-dopamine receptors in the bovine pineal gland were previously identified and characterized. The data indicate that the density of D1-dopamine receptors far...
D1- and D2-dopamine receptors in the bovine pineal gland were previously identified and characterized. The data indicate that the density of D1-dopamine receptors far exceeded that of D2-dopamine receptors. In our previous study, the mRNA for both the D1- and D2-dopamine receptors which elucidated the status of dopamine and its possible involvement in the pineal function was identified. A selective D1-agonist enhanced N-acetyltransferase (NAT) activity and increased the melatonin level, whereas, a selective D2-agonist inhibited NAT activity and decreased the melatonin level. An attempt has been made in the present study to clarify the mechanism of dopamine in controlling melatonin production in bovine pineal. The level of intracellular cyclic 3',5'-adenosine monophosphate (cAMP) was determined after a 2-hr incubation of bovine pinealocytes with selected combinations of drugs. SKF 38393, a selective D1-agonist, enhanced intracellular level of cAMP, and its effect was blocked by SCH 23390, a D1-selective antagonist. In contrast quinpirole, a selective D2-agonist, inhibited forskolin-stimulated intracellular level of cAMP while its effect was blocked by a D2-selective antagonist, spiperone. In addition, the dopamine-dependent phosphorylation of the transcription factors, cAMP responsive element-binding protein (CREB) was investigated. Immunoblots showed that SKF 38393 enhanced CREB phosphorylation and the stimulatory effect was abolished by SCH 23390 whereas quinpirole inhibited forskolin-stimulated phosphorylated CREB production and the inhibitory effect was prevented by spiperone. Taken together with our previous data, the results indicate that activation of D1-dopamine receptor in bovine pinealocyte stimulates NAT activity and enhances melatonin level whereas activation of D2-dopamine receptor leads to an inhibitory effect and these stimulatory and inhibitory effects act, in part, via a cAMP-dependent transcription mechanism.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acyltransferases; Animals; Benzazepines; Cattle; Cells, Cultured; Colforsin; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Melatonin; Phosphorylation; Pineal Gland; Quinpirole; RNA, Messenger; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Spiperone; Transcription, Genetic
PubMed: 15725338
DOI: 10.1111/j.1600-079X.2004.00189.x -
Journal of Neural Transmission.... 1983Of the several dopamine-sensitive sites in the brain, the one that most correlates with psychomotor behaviour is the D2 receptor. This receptor has two states. The D2Hi...
Of the several dopamine-sensitive sites in the brain, the one that most correlates with psychomotor behaviour is the D2 receptor. This receptor has two states. The D2Hi state is characterized by its nM affinity for dopamine. The D2Lo state is typified by its microM affinity for dopamine. Neuroleptics have the same affinity (50 pM for spiperone) for both states. Guanine nucleotides convert most, if not all, of the D2Hi sites into D2Lo sites. Any D2Hi sites which are insensitive to GTP, if such exist, may be separate D4 sites. In addition to the binding of 3H-spiperone being higher in post-mortem schizophrenic brains, the proportions of the D2 receptor in the D2Hi state appear to be less in preliminary data on the schizophrenic brain.
Topics: Brain; Dopamine; Guanine Nucleotides; Humans; Receptors, Dopamine; Spiperone; Substrate Specificity; Sulpiride
PubMed: 6576113
DOI: No ID Found -
American Journal of Hypertension Jun 1990The D1 and D2 dopamine receptors have been biochemically characterized using specific probes based on the subtype selective antagonists SCH 23390 and spiperone,... (Review)
Review
The D1 and D2 dopamine receptors have been biochemically characterized using specific probes based on the subtype selective antagonists SCH 23390 and spiperone, respectively. The D2 dopamine receptor was identified from several tissues by photoaffinity labeling and was purified from bovine anterior pituitary to homogeneity using a combination of affinity, lectin and hydroxylapatite chromatography. A complementary DNA (cDNA) encoding a rat brain D2 dopamine receptor has been cloned via low stringency hybridization using a portion of the beta 2-adrenergic receptor gene as a probe. Photoaffinity crosslinking and affinity chromatography have also been used to identify and purify the rat brain D1 dopamine receptor.
Topics: Affinity Labels; Amino Acid Sequence; Animals; Benzazepines; Dopamine Antagonists; Molecular Biology; Molecular Sequence Data; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 2143386
DOI: 10.1093/ajh/3.6.29s -
Progress in Neuro-psychopharmacology &... May 2001In the absence of selective agonists and antagonists able to discriminate between individual members of the D1-like and D2-like families of dopamine receptor subtypes,... (Review)
Review
In the absence of selective agonists and antagonists able to discriminate between individual members of the D1-like and D2-like families of dopamine receptor subtypes, functional parcellation has remained problematic. 'Knockout' of these subtypes by targeted gene deletion offers a new approach to evaluating their roles in the regulation of behaviour. Like any new technique, 'knockout' has associated with it a number of methodological limitations that are now being addressed in a systematic manner. Studies on the phenotype of D1(A/1), D(1B/5), D2, D3 and D4 'knockouts' at the level of spontaneous and agonist/antagonist-induced behaviour are reviewed, in terms of methodological issues, neuronal implications and potential clinical relevance. Dopamine receptor subtype 'knockout' is a nascent technology that is now beginning to fulfil its potential. It is being complemented by more systematic phenotypic characterisation at the level of behaviour and additional, molecular biologically-based approaches.
Topics: Animals; Gene Deletion; Humans; Mice; Mice, Knockout; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4
PubMed: 11383985
DOI: 10.1016/s0278-5846(01)00152-x -
Molecules (Basel, Switzerland) Mar 2019: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of...
: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. : Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D₁-like and D₂-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. : Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D₁R-like selective ligands binding. : This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands.
Topics: Binding Sites; Drug Design; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Ligands; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Receptors, Dopamine; Reproducibility of Results; Structure-Activity Relationship
PubMed: 30934701
DOI: 10.3390/molecules24071196 -
Behavioural Brain Research Aug 2015Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3)...
Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization. In adolescent and adult male rats, we examined (1) alterations occurring in dopamine receptor-related mRNAs (DRD1, DRD2, DRD3 and D3nf) at two time points during a sensitizing regimen of nicotine and (2) whether DRD3 antagonism either during the initial treatment (induction) or at a later challenge exposure (expression) is able to block nicotine sensitization. Nicotine-induced changes were seen for DRD3 and D3nf mRNAs in the nucleus accumbens shell early in repeated exposure in both age groups. DRD3 antagonism only blocked the induction of sensitization in adolescents and did not block the expression of sensitization in either age group. Adolescents and adults showed opposite DRD1 mRNA responses to nicotine treatment, while no age- and nicotine-related changes in DRD2 mRNA were observed. These data reveal important age-dependent regulation of DRD1- and DRD3-related mRNAs during the course of nicotine exposure. Furthermore, they highlight a requirement for DRD3 signaling in the development of adolescent nicotine sensitization, suggesting it may represent an appropriate target in the prevention of nicotine dependence initiated at this age.
Topics: Animals; Biphenyl Compounds; Central Nervous System Sensitization; Corpus Striatum; Male; Motor Activity; Nicotine; Piperazines; RNA, Messenger; Rats; Rats, Long-Evans; Receptors, Dopamine; Receptors, Dopamine D3
PubMed: 25907750
DOI: 10.1016/j.bbr.2015.04.025