In Vitro and In Vivo Evaluation of N -{2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-[ 11 C]methoxybenzamide, a Positron Emission Tomography (PET) Radioligand for Dopamine D 4 Receptors, in Rodents (original) (raw)
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Brain dopamine D(4) receptors: basic and clinical status
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 1999
Since their discovery in 1991, an extraordinary amount of information has accumulated about the neurobiology and pharmacology of D(4) receptors in the mammalian central nervous system, making it timely to review salient aspects of this rapidly evolving research story and its relevance to clinical neuroscience. Recent progress in the molecular, genetic, anatomical, and functional characterization of D(4) receptors in the animal and human brain is yielding insights into their neurochemical and physiological roles in brain function. The temporal patterns of postnatal D(4) receptor development appear to differ in specific regions of mammalian forebrain. Postmortem neuropathological and clinical genetic studies have generally been disappointing regarding possible relationships of D(4) receptors to the pathophysiology or treatment of schizophrenia, however, they suggest relationships to other neuropsychiatric conditions, including attention deficit hyperactivity disorder, mood disorders, ...
Dopamine D4 receptors: significance for molecular psychiatry at the millennium
Molecular Psychiatry, 1999
Extraordinary progress has been made in the molecular, genetic, anatomical, and pharmacological characterization of dopamine D 4 receptors in animal and human brain. Clarification of the neurochemical and physiological roles of these cerebral receptors is emerging. Postmortem neuropathological studies have inconsistently linked D 4 receptors to psychotic disorders, and genetic studies have failed to sustain conclusive associations between D 4 receptors and schizophrenia. However, associations are emerging between D 4 receptors and other neuropsychiatric disorders, including attention deficit hyperactivity disorder, mood disorders, and Parkinson's disease, as well as specific personality traits such as novelty-seeking. Selective D 4 agonists and antagonists have been developed as useful experimental probes. D 4 antagonists, so far, have proved ineffective in treatment of schizophrenia, but testing in a broader range of disorders may yield clinically useful drugs. D 4 receptors appear to have broad implications for the pathophysiology of neuropsychiatric illnesses and their improved treatment.
Autoradiographic Localization of the Putative D4 Dopamine Receptor in Rat Brain
Neurochem Res, 1997
The putative dopamine D4 receptor protein in rat brain was labelled and quantified autoradiographically using two selective benzamides: [ 3 H]YM-09151-2 which labels D2, D3 and D4 dopamine receptors and [ 3 H]Raclopride which labels D2 and D3. The difference in densities of both ligands at saturable concentrations, show a regional distribution for the putative D4 receptor in the following rank order: hippocampus > caudate putamen > olfactory tubercle = substancia nigra > nucleus accumbens core > cerebral cortex > cerebellum. A calculated value of 0.34 pmol/mg protein was attributable to D4 receptor maximum capacity in caudate putamen and was obtained after subtracting the Bmax of the ligands. Our results show that the distribution of D4 receptor only partially overlaps with the D4 mRNA localization reported earlier and is not only associated to limbic structures but to motor areas as well.
Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies
Molecular Brain Research, 1997
The distribution of the dopaminergic D3 receptor in rat brain was studied employing site directed poiyclonal antibodies. Antisera were raised in rabbits to two oligopeptides corresponding to amino acids 160-172 of the second extracellular loop (PI) and ammo acids 260-273 of the third intracellular loop fP1) of the D4 receptor sequence. Affinity-purified antibodies (anti-P1 and anti-P?) specifically recognized two major bands of 42-35 and 95 kDa in Western blots of denatured preparations of various rat brain areas. Immunocytochemistry studies showed that D4 receptor is widely distributed in rat central nervous sylstem /CNS) showing higher labelling in the hippocampus (CAI, CA& CA3 and dentate gyms) frontal cortex, entorhinal cortex. caudate putamen, nucleus accumbens, olfactory tubercle, cerebellum, supraoptic nucleus and sustanr.i:; nigra pars compacta. In addition, anti-PI decreased the binding of the antagonist ['H]YM-09151-2 selective for D 2, D3 and D4 receptor:, but did not modify the binding of ['Hlraclopride an antagonist selective for DZ and Q3. in striatal synaptosomes. Anti-P? did not modify the binding of these ligands. These results confirm the selectivity of the antibodies towards the D-t receptor and suggest that the bindin, ~7 site for the antagonists might be located at or close to the secoud extracellular loop of the protein sequence. D4 receptor protein is mainly eaprcssed in plasma membranes and in the peripheral cytoplasm of neurons and is more widely distributed than was originally proposed based on mRNA localization. since it is present both in hmbic. diencephalic and motor areas of rat brain. * Corresponding author. Instituto de Quimica y Fisicoquimica Biologicas (IJBA-CONICET), Fact&ad de Farmacia y Bioquimica, Junin 956, I 113 Buenos Aires, Argentina. Fax: + 54 t I ) 962-5457.
The dopamine D4 receptor: one decade of research
European Journal of Pharmacology, 2000
Dopamine is an important neurotransmitter involved in motor control, endocrine function, reward, cognition and emotion. Dopamine receptors belong to the superfamily of G protein-coupled receptors and play a crucial role in mediating the diverse effects of dopamine in Ž. the central nervous system CNS. The dopaminergic system is implicated in disorders such as Parkinson's disease and addiction, and is the major target for antipsychotic medication in the treatment of schizophrenia. Molecular cloning studies a decade ago revealed the existence of five different dopamine receptor subtypes in mammalian species. While the presence of the abundantly expressed dopamine D and D receptors was predicted from biochemical and pharmacological work, the cloning of the less abundant dopamine D , D and 1 2 3 4 D receptors was not anticipated. The identification of these novel dopamine receptor family members posed a challenge with respect to 5 determining their precise physiological roles and identifying their potential as therapeutic targets for dopamine-related disorders. This review is focused on the accomplishments of one decade of research on the dopamine D receptor. New insights into the biochemistry of 4 the dopamine D receptor include the discovery that this G protein-coupled receptor can directly interact with SH3 domains. At the 4 physiological level, converging evidence from transgenic mouse work and human genetic studies suggests that this receptor has a role in exploratory behavior and as a genetic susceptibility factor for attention deficit hyperactivity disorder.
Targeted D4 Dopamine Receptors: Implications for Drug Discovery and Therapeutic Development
Current Drug Targets, 2013
A wealth of preclinical and clinical literature has established functional associations of CNS dopamine (DA) and its multiple G protein-coupled receptor (GPCR) types in the integration of key neurological processes linked to complex behavioral activities. Conversely, an equivalent vast literature supports the role of aberrant CNS DA expression and DA receptor signaling in the etiology and persistence of major psychiatric illnesses and has established selective targeting of DA-ergic systems as a cornerstone of pharmacotherapeutic intervention and current neuroleptic drug development. The present short review focuses on potential functional/behavioral alterations linked to polymorphisms in the primary DNA sequence of the DA receptor type 4 (DRD4) gene in reference to major psychiatric illnesses. The potential clinical relevance of major polymorphisms of the DRD4 gene are discussed within the context of practical aspects of typical and atypical neuroleptic drug usage within afflicted populations of psychiatric patients. It is anticipated that additional complementary molecular, biochemical, and behavioral studies of DRD4 gene polymorphisms will provide essential information for selective targeting of heterogeneous populations of CNS D4 receptors and advance drug discovery and therapeutic development efforts for highly efficacious treatment of psychiatric illnesses.
Identification of brain neurons expressing the dopamine D4 receptor gene using BAC transgenic mice
European Journal of Neuroscience, 2006
The dopamine D4 receptor (D4R) has received considerable interest because of its higher affinity for atypical antipsychotics, the extremely polymorphic nature of the human gene and the genetic association with attention deficit and hyperactivity disorder (ADHD). Several efforts have been undertaken to determine the D4R expression pattern in the brain using immunohistochemistry, binding autoradiography and in situ hybridization, but the overall published results present large discrepancies. Here, we have explored an alternative genetic approach by studying bacterial artificial chromosome (BAC) transgenic mice that express enhanced green fluorescent protein (EGFP) under the transcriptional control of the mouse dopamine D4 receptor gene (Drd4). Immunohistochemical analysis performed in brain sections of Drd4-EGFP transgenic mice using an anti-EGFP polyclonal antibody showed that transgenic expression was predominant in deep layer neurons of the prefrontal cortex, particularly in the orbital, prelimbic, cingulate and rostral agranular portions. In addition, discrete groups of Drd4-EGFP labelled neurons were observed in the anterior olfactory nucleus, ventral pallidum, and lateral parabrachial nucleus. EGFP was not detected in the striatum, hippocampus or midbrain as described using other techniques. Given the fine specificity of EGFP expression in BAC transgenic mice and the high sensitivity of the EGFP antibody used in this study, our results indicate that Drd4 expression in the adult mouse brain is limited to a more restricted number of areas than previously reported. Its leading expression in the prefrontal cortex supports the importance of the D4R in complex behaviours depending on cortical dopamine (DA) transmission and its possible role in the etiopathophysiology of ADHD.
Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor
FEBS letters, 1995
The murine D 4 dopamine receptor was isolated from a murine genomic DNA library. The receptor's entire coding region was contained within a 6 kb EcoRI genomic fragment, indicating that the murine D4 receptor gene is significantly smaller than the corresponding D2 and D3 receptor genes, the coding regions of which each stretch over 30 kb. The murine 1)4 rt~eptor gene has three introns and four exons, in common with the rat and human D4 receptor genes. RT-PCR on mRNA from different brain regions shows that the ])4 receptor mRNA is expressed in various areas of the brain, with some differences from the rat and human receptor homologues.
Neuroscience, 2008
The role of the dopamine D 4 receptor in cognitive processes and its association with several neuropsychiatric disorders have been related to its preferential localization in the cerebral cortex. In the present work we have studied in detail the regional and cellular localization of the dopamine D 4 receptor immunoreactivity (IR) in the rat cerebral cortex and its relationship to the dopaminergic and noradrenergic nerve terminal networks, since both dopamine and noradrenaline have a high affinity for this receptor. High levels of D 4 IR were found in motor, somatosensory, visual, auditory, temporal association, cingulate, retrosplenial and granular insular cortices, whereas agranular insular, piriform, perirhinal and entorhinal cortices showed low levels. D 4 IR was present in both pyramidal and non-pyramidal like neurons, with the receptor being mainly concentrated to layers II/III. Layer I was observed to be exclusively enriched in D 4 IR branches of apical dendrites. Finally, mismatches were observed between D 4 IR and tyrosine hydroxylase and dopamine -hydroxylase IR nerve terminal plexuses, indicating that these receptors may be activated at least in part by dopamine and noradrenaline operating as volume transmission signals. The present findings support a major role of the dopamine D 4 receptor in mediating the transmission of cortical dopamine and noradrenaline nerve terminal plexuses.
The dopamine D-4 receptor, the ultimate disordered protein
2010
The human D4 dopamine receptor is a synaptic neurotransmitter receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its structure makes it a very unusual and interesting G protein-coupled receptor (GPCR) as it has several polymorphic variants of its gene in the region encoding the third intracellular loop (IL3). This region contains from two to seven or more similar 48 base pair repeats. These repeats cause this protein to have a very high disorder index and this, in turn, makes it very interactive with other proteins. Among GPCRs in general, the unusually proline-rich IL3 is unique to the D4 receptor (D4R). We believe that, as in the D2R, this region of the receptor plays a role in it's interaction with other receptors.