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Biomedical subjects

Jorge Diaz

Publications and source records attributed to Jorge Diaz.

13 recordsLinked to original sources
PubMed2005

A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning.

Environmental stimuli associated with a single cocaine exposure acquire long-lasting motivational properties that are able to induce relapse. We measured Brain-derived neurotrophic factor (BDNF) and dopamine D3 receptor (Drd3) expressions in rat brain regions that have been involved in drug-conditioning. Acute cocaine produced a transient increase in BDNF mRNA in the prefrontal cortex, associated with a long-lasting increase in drd3 mRNA, and a delayed and long-lasting increase in Drd3 protein in the nucleus accumbens. Methamphetamine and morphine, two drugs known to easily induce drug-conditioning, also markedly elevated BDNF mRNA. Nicotine had more limited effects. Abused drugs increase acutely BDNF expression, which leads to subsequent long-lasting elevation of Drd3 in the nucleus accumbens that may facilitate responding to drug-associated stimuli.

Animals↗
PubMed2005

Wenckebach's periods or alternating Wenckebach's periods during 4:1 atrioventricular block?

This article deals with the tracings of a patient having episodes of atrial flutter with 4:1 atrioventricular (AV) block increasing to 8:1 AV block. This phenomenon was attributed to the coexistence of 3-level block due to transverse dissociation with 2:1 AV block in the most proximal level, or first level as well as in the second level coexisting with a Wenckebach's period in the most distal, or third level. It is suggested that perhaps the term Wenckebach's periods during progression of 4:1 AV block best describes this arrhythmia so as to maintain the term alternating Wenckebach's periods only to those occurring when 2:1 block increases to higher degrees of AV block.

Aged↗
PubMed2004

Neuroadaptations to hyperdopaminergia in dopamine D3 receptor-deficient mice.

The dopamine D3 receptor (D3R) has been implicated in schizophrenia, drug addiction, depression and Parkinson's disease. The D3R is localized post-synaptically on nucleus accumbens neurons, but is also an autoreceptor on dopaminergic neurons in the mesencephalon. Its functional role as autoreceptor is highly debated, but supported by the elevated basal extracellular dopamine levels found in D3R-deficient mice. To investigate the functional role of the D3R in vivo, we used mice with a targeted disruption of the D3R gene. We found a higher basal level of grooming in D3R-deficient mice, compared to their wild-type littermates. This behavior, which is under the control of D1R stimulation, may be related to an increased dopaminergic tone, since no changes in the gene expression of dopamine D1 and D2 receptors were noticed in the striatum of these mice. D3R-deficient mice displayed other neuroadaptive changes, including decreased tyrosine hydroxylase, increased dopamine transporter mRNAs and increased dopamine reuptake in striatum. The level of tyrosine hydroxylase protein was unchanged in the striatum, as preprodynorphin and preproenkephalin gene expressions. All the changes identified in D3R-deficient mice cannot explain hyperdopaminergia, but, on the contrary, tend to attenuate this phenotype. These results support a distinct role for D2R and D3R as autoreceptors: the D2R is the release-regulating and firing rate-regulating autoreceptor, whereas the D3R may control basal dopamine levels in the striatum, by an unknown mechanism, which does not involve regulation of dopamine transporters or tyrosine hydroxylase. This hyperdopaminergia phenotype of D3R-deficient mice may explain their hyperactivity to drug-paired environmental cues.

Animals↗
PubMed2004

Role of DRD3 in morphine-induced conditioned place preference using drd3-knockout mice.

The dopamine D3 receptor (DRD3) mediates expression of conditioned effects of psychostimulants, but conflicting results have been obtained with opiates. In a conditioned place preference (CPP) procedure, morphine increased the time spent in a compartment previously paired with drug injection. CPP was obtained at morphine doses of 16 and 32 mg/kg in wild-type (drd3+/+) mice and 8, 16 and 32 mg/kg in DRD3-knockout (drd3-/-) mice. BP897, a DRD3-selective partial agonist, inhibited the expression of morphine-CPP in drd3+/+, but not drd3-/- mice. BP 897 reduced brain regional activation, measured by c-fos imaging after the CPP test session, in the somatosensory cortex of drd3+/+, but not drd3-/- mice. These results confirm the role of DRD3 in the expression of conditioned effects of morphine and the participation of the somatosensory cortex in these effects.

Animals↗
PubMed2004

GIPC recruits GAIP (RGS19) to attenuate dopamine D2 receptor signaling.

Pleiotropic G proteins are essential for the action of hormones and neurotransmitters and are activated by stimulation of G protein-coupled receptors (GPCR), which initiates heterotrimer dissociation of the G protein, exchange of GDP for GTP on its Galpha subunit and activation of effector proteins. Regulator of G protein signaling (RGS) proteins regulate this cascade and can be recruited to the membrane upon GPCR activation. Direct functional interaction between RGS and GPCR has been hypothesized. We show that recruitment of GAIP (RGS19) by the dopamine D2 receptor (D2R), a GPCR, required the scaffold protein GIPC (GAIP-interacting protein, C terminus) and that all three were coexpressed in neurons and neuroendocrine cells. Dynamic translocation of GAIP to the plasma membrane and coassembly in a protein complex in which GIPC was a required component was dictated by D2R activation and physical interactions. In addition, two different D2R-mediated responses were regulated by the GTPase activity of GAIP at the level of the G protein coupling in a GIPC-dependent manner. Since GIPC exclusively interacted with GAIP and selectively with subsets of GPCR, this mechanism may serve to sort GPCR signaling in cells that usually express a large repertoire of GPCRs, G proteins, and RGS.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Subapical localization of the dopamine D3 receptor in proximal tubules of the rat kidney.

The dopamine D3 receptor (D3R), intensively studied in neuroscience, also plays an important role in the regulation of renal and cardiovascular function. In contrast to functional findings, less information is available on its localization in the kidney. Neither RT-PCR studies nor radioligand binding assays are suitable to selectively determine the distribution of renal D3R at the level of cellular or even subcellular structures. We studied the renal D3R distribution in Sprague-Dawley rats by a polyclonal antiserum directed against an epitope in the third intracytoplasmic loop. D3R immunoreactivity was detected by indirect immunofluorescence and confocal laser scanning microscopy. D3R staining was confined to the renal cortex and occurred in proximal convoluted tubules near or in direct connection with the urinary pole of the glomeruli. The fluorescent spots were restricted to the subapical portion of the proximal tubular cells. Double staining with the F-actin marker phalloidin revealed a localization of the D3R below the brush border region. However, staining by anti-beta1/beta2-adaptins, recognizing clathrin-coated compartments, did not correspond to the distribution of the D3R signal. This is the first description of a D3R accumulation in a cytoplasmic pool in the kidney, probably corresponding to a recycling mechanism or storage compartment.

Animals↗
PubMed2003

Interactions of GIPC with dopamine D2, D3 but not D4 receptors define a novel mode of regulation of G protein-coupled receptors.

The C-terminus domain of G protein-coupled receptors confers a functional cytoplasmic interface involved in protein association. By screening a rat brain cDNA library using the yeast two-hybrid system with the C-terminus domain of the dopamine D(3) receptor (D(3)R) as bait, we characterized a new interaction with the PDZ domain-containing protein, GIPC (GAIP interacting protein, C terminus). This interaction was specific for the dopamine D(2) receptor (D(2)R) and D(3)R, but not for the dopamine D(4) receptor (D(4)R) subtype. Pull-down and affinity chromatography assays confirmed this interaction with recombinant and endogenous proteins. Both GIPC mRNA and protein are widely expressed in rat brain and together with the D(3)R in neurons of the islands of Calleja at plasma membranes and in vesicles. GIPC reduced D(3)R signaling, cointernalized with D(2)R and D(3)R, and sequestered receptors in sorting vesicles to prevent their lysosomal degradation. Through its dimerization, GIPC acts as a selective scaffold protein to assist receptor functions. Our results suggest a novel function for GIPC in the maintenance, trafficking, and signaling of GPCRs.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease.

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to nerve growth factor, which are responsible for neuron proliferation, survival and differentiation. A more diverse role for BDNF as a neuronal extracellular transmitter has, nevertheless, been proposed. Here we show that BDNF synthesized by dopamine neurons is responsible for the appearance of the dopamine D3 receptor during development and maintains its expression in adults. Moreover, BDNF triggers behavioral sensitization to levodopa in hemiparkinsonian rats. In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which develop levodopa-induced dyskinesia, we show an overexpression of this receptor. Administration of a dopamine D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, while leaving unaffected the therapeutic effect of levodopa. These results suggest that the dopamine D3 receptor participates in both dyskinesia and the therapeutic action of levodopa and that partial agonists may normalize dopamine D3 receptor function and correct side-effects of levodopa therapy in PD patients.

Animals↗
PubMed2003

CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors.

To identify proteins interacting with the C-terminal cytoplasmic tail of the dopamine D(3) receptor (D(3)R), we used the two-hybrid system to screen a rat brain cDNA library. We isolated three partial cDNAs encoding, respectively, for the MUPP1 multi-PDZ protein, for the N-terminal region of radixin, for GIPC and for a 160-amino acid open reading frame sharing high homology with the human CLIC6, also identified as parchorin in rabbit. In the two-hybrid system, CLIC6 was also able to interact with the D(2)R and D(4)R. The interaction between D(3)R and CLIC6 was confirmed by the use of a GST-D(3)R C-terminus fusion protein and COS cell extracts transiently expressing epitope-tagged CLIC6. In adult rat brain, CLIC6 mRNA expression was restricted to the choroid plexus, the striatal proliferative subventricular zone and the cerebellum where it is co-expressed with the D(3)R in the Purkinje cells of the lobules IX and X. CLIC6 mRNA was also detected in the pituitary in the posterior lobe and in cells co-expressing the D(2)R at the border between the intermediate and anterior lobes. In transfected HEK293 cells, D(3)R and CLIC6 co-localized at the plasma-membrane. No effect of CLIC6 transfection was observed on either intracellular chloride concentration or D(3)R/D(2)R-mediated response. In two-hybrid system, CLIC6 also interacted with MUPP1 and radixin but not GIPC, suggesting it could take part in a complex with D(2)-like receptors, not only by direct interaction with their C-termini, but also through interactions with scaffolding proteins.

Amino Acid Sequence↗
PubMed2003

Increased dopamine D3 receptor expression accompanying behavioral sensitization to nicotine in rats.

Behavioral sensitization to nicotine, which appears following repeated nicotine administration, has been suggested to take part in the development of smoking habit in humans. The mesolimbic dopaminergic system plays a role in this process and a hypersensitivity of postsynaptic neurons of the nucleus accumbens as been proposed as a mechanism, but changes in dopamine D(1) or D(2) receptors have not been demonstrated to date. A challenge administration of nicotine (0.5 mg/kg s.c.) produced a strong increase in locomotor activity in rats repeatedly pretreated with nicotine (0.5 mg/kg s.c.), but not saline, once a day for 5 days. This behavioral sensitization was accompanied by an increase in D(3) receptor binding and mRNA in the shell of nucleus accumbens. D(3) receptor expression was unchanged in the core of nucleus accumbens and dorsal striatum, as it was in the shell of nucleus accumbens after an acute administration of nicotine to naive rats. In contrast, no changes were noticed in D(1) and D(2) receptor expressions in any brain region examined after chronic or acute treatment with nicotine. In addition, nicotine challenge decreased preprodynorphin and preprotachykinin mRNA levels in naive rats, but only preprotachykinin mRNA levels in rats pretreated with nicotine. These biochemical changes resemble those occurring during behavioral sensitization to levodopa of dopamine-denervated rats, which had been causally related to the induction of D(3) receptor expression. We propose that a similar mechanism is responsible for behavioral sensitization to nicotine.

Animals↗
PubMed2002

Role of the dopamine D3 receptor in reactivity to cocaine-associated cues in mice.

Environmental stimuli previously associated with drug effects can acquire secondary reinforcing properties, able to maintain drug-seeking behaviour or induce relapse. We have used a classical Pavlovian conditioning procedure to assess the role of the dopamine D3 receptor (D3R) in the expression of drug-conditioned responses. Mice repeatedly receiving cocaine in a particular environment distinct from home-cages displayed hyperlocomotion after subsequent exposure to the drug-paired environment. Cocaine-conditioned hyperactivity was inhibited by BP 897 or SB-277011-A, D3R-selective partial agonist and antagonist, respectively. D3R gene-targeted mice showed a trend towards an increase in cocaine cue-conditioned hyperactivity. BP 897 had no effect on reactivity to neutral or aversive cues. Cocaine-conditioned mice had increased levels of D3R mRNA and binding in the nucleus accumbens (NAc), and transcripts of brain-derived neurotrophic factor (BDNF), a factor controlling D3R expression, in the ventral tegmental area (VTA). Cocaine had no effects on D3R or BDNF genes when administered in home-cages. Cocaine cue-conditioned c-fos expression was found in cortical areas, notably in the somatosensory cortex, where it was inhibited by BP 897, and in several regions belonging or linked to the limbic system. In conditioned mice, BP 897 inhibited c-fos expression in VTA and activated it in amygdala. These results demonstrate a modulation of reactivity to cocaine cues by the D3R, the expression of which is elevated in the NAc by the repeated association of drug effects with a particular context, through a BDNF-dependent mechanism. D3R-selective partial agonist or antagonist inhibit cocaine cue-conditioned activity possibly by normalizing exacerbated D3R function in the NAc, but our results also point to a possible participation of a pathway involving the VTA, amygdala and somatosensory cortex.

Animals↗
PubMedDate not supplied

Brain-derived neurotrophic factor controls dopamine D3 receptor expression: implications for neurodevelopmental psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to nerve growth factor, which are responsible for neuron proliferation, survival and differentiation. A more diverse role for BDNF as a neuronal extracellular transmitter has, nevertheless, been proposed. The dopamine D(3) receptor has been implicated in neuropsychiatric disorders including schizophrenia, drug addiction, depression and Parkinson's disease. Its expression during development and in adulthood is highly dependent on dopaminergic innervation. Here we show that BDNF synthesized by dopamine neurons is responsible for the appearance of the D(3) receptor during development and maintains D(3) receptor expression in adults. Moreover, BDNF triggers D(3) receptor overexpression and behavioral sensitization to levodopa in denervated animals. These results suggest that BDNF, by controlling the expression of specific genes such as the D(3) receptor gene, may be an important factor in neurodevelopmental psychiatric diseases.

Journal Article↗