RESUMEN
INTRODUCTION: We hypothesized that perioperative fibrinogen level, platelet count, and rotational thromboelastometry (ROTEM) data values decrease in proportion to cardiopulmonary bypass (CPB) time, particularly in patients who underwent deep hypothermic circulatory arrest (DHCA). METHODS: A total of 160 patients were enrolled and divided into the following three groups depending on CPB time: <2-h, 2- 3-h, and >3-h groups. Blood samples were obtained during CPB weaning. Platelet count, ROTEM data, fibrinogen level, and antithrombin level were determined. For propensity matching, we selected 15 patients who underwent DHCA and 15 patients who did not undergo DHCA and used propensity scores to match CPB time and other characteristics. RESULTS: The <2-h, 2-3-h, and >3-h groups included 74, 63, and 23 patients, respectively. No significant differences in platelet count and fibrinogen level were observed between the groups. Antithrombin level and amplitude of clot firmness at 10 min in the EXTEM and FIBTEM tests were lowest in the >3-h group. Similarly, blood loss volume and transfusion volume were highest in the >3-h group. Significant differences in platelet count, ROTEM data, lowest esophageal and bladder temperatures, and transfusion volume were observed between patients who underwent DHCA and patients who did not undergo DHCA. CONCLUSIONS: The longer the CPB time, the greater the perioperative blood loss volume and transfusion volume, particularly if CPB time is greater than 3 hours. Sub-group analysis revealed that DHCA affects perioperative platelet count and function as well as blood loss volume.
RESUMEN
AIMS: Here we examined whether intellectual disability is independently associated with hyperglycaemia. METHODS: We recruited 233 consecutive young and middle-aged adults with intellectual disability. After exclusion of subjects on medication for metabolic diseases or with severe intellectual disability (IQ < 35), 121 subjects were divided by IQ into a group with moderate intellectual disability (35 ≤ IQ ≤ 50), a mild intellectual disability group (51 ≤ IQ ≤ 70) and a borderline group (IQ > 70). RESULTS: HbA1c level was higher in subjects with moderate intellectual disability (42 ± 9 mmol/mol; 6.0 ± 0.8%) than those in the borderline group (36 ± 4 mmol/mol; 5.5 ± 0.3%) and mild intellectual disability group (37 ± 5 mmol/mol; 5.5 ± 0.5%) groups. HbA1c level was correlated with age, BMI, blood pressure, serum triglycerides and IQ in simple linear regression analysis. Multiple regression analysis indicated that IQ, age, BMI and diastolic blood pressure were independent explanatory factors of HbA1c level. CONCLUSIONS: An unfavourable effect of intellectual disability on lifestyle and untoward effect of hyperglycaemia on cognitive function may underlie the association of low IQ with hyperglycaemia.
Asunto(s)
Hemoglobina Glucada/metabolismo , Hiperglucemia/sangre , Discapacidad Intelectual/sangre , Inteligencia , Adulto , Índice de Masa Corporal , Estudios Transversales , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Hiperglucemia/epidemiología , Hiperglucemia/etiología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/epidemiología , Pruebas de Inteligencia , Masculino , Estudios Retrospectivos , Clase SocialRESUMEN
Essentials We generated recombinant rhodocytin that could aggregate platelets via CLEC-2. Recombinant wild-type rhodocytin formed heterooctamer with four α- and ß-subunits. Asp 4 in α-subunit of rhodocytin was required for binding to CLEC-2. Inhibitory mutant of rhodocytin blocked podoplanin-dependent hematogenous metastasis. SUMMARY: Background Rhodocytin, a disulfide-linked heterodimeric C-type lectin from Calloselasma rhodostoma consisting of α-subunits and ß-subunits, induces platelet aggregation through C-type lectin-like receptor 2 (CLEC-2). CLEC-2 is a physiological binding partner of podoplanin (PDPN), which is expressed on some tumor cell types, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. Thus, modified rhodocytin may be a possible source of anti-CLEC-2 drugs for both antiplatelet and antimetastasis therapy. However, its molecular function has not been well characterized, because of the lack of recombinant rhodocytin that induces platelet aggregation. Objective To produce recombinant rhodocytin, in order to verify its function with mutagenesis, and to develop an anti-CLEC-2 drug based on the findings. Methods We used Chinese hamster ovary cells to express recombinant rhodocytin (wild-type [WT] and mutant), which was analyzed for induction/inhibition of platelet aggregation with light transmission aggregometry, the formation of multimers with blue native PAGE, and binding to CLEC-2 with flow cytometry. Finally, we investigated whether mutant rhodocytin could suppress PDPN-induced metastasis in an experimental lung metastasis mouse model. Results Functional WT] rhodocytin (αWTßWT) was obtained by coexpression of both subunits. Asp4 in α-subunits of rhodocytin was required for CLEC-2 binding. αWTßWT formed a heterooctamer similarly to native rhodocytin. Moreover, an inhibitory mutant of rhodocytin (αWTßK53A/R56A), forming a heterotetramer, bound to CLEC-2 without inducing platelet aggregation, and blocked CLEC-2-PDPN interaction-dependent platelet aggregation and experimental lung metastasis. Conclusion These findings provide molecular characterization information on rhodocytin, and suggest that mutant rhodocytin could be used as a therapeutic agent to target CLEC-2.
Asunto(s)
Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Lectinas Tipo C/antagonistas & inhibidores , Neoplasias Pulmonares/prevención & control , Glicoproteínas de Membrana/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Proteínas Recombinantes/farmacología , Venenos de Víboras/farmacología , Animales , Células CHO , Cricetulus , Femenino , Células HEK293 , Humanos , Lectinas Tipo C/química , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Multimerización de Proteína , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Venenos de Víboras/química , Venenos de Víboras/genética , Venenos de Víboras/metabolismoRESUMEN
Population-based studies have demonstrated that children with a history of febrile seizure (FS) perform better than age-matched controls at hippocampus-dependent memory tasks. Here, we report that FSs induce two distinct structural reorganizations in the hippocampus and bidirectionally modify future learning abilities in an age-dependent manner. Compared with age-matched controls, adult mice that had experienced experimental FSs induced by hyperthermia (HT) on postnatal day 14 (P14-HT) performed better in a cognitive task that requires dentate granule cells (DGCs). The enhanced memory performance correlated with an FS-induced persistent increase in the density of large mossy fiber terminals (LMTs) of the DGCs. The memory enhancement was not observed in mice that had experienced HT-induced seizures at P11 which exhibited abnormally located DGCs in addition to the increased LMT density. The ectopic DGCs of the P11-HT mice were abolished by the diuretic bumetanide, and this pharmacological treatment unveiled the masked memory enhancement. Thus, this work provides a novel basis for age-dependent structural plasticity in which FSs influence future brain function.
Asunto(s)
Fiebre/complicaciones , Memoria/fisiología , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Convulsiones/fisiopatología , Envejecimiento , Animales , Bumetanida/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/fisiopatología , Ratones , Convulsiones/etiología , Convulsiones/metabolismoRESUMEN
The effect of streptozotocin (STZ)-induced diabetes and a combination of chronic treatment with haloperidol (HPD) on dopamine (DA)D2, serotonin (5-HT) 5-HT1A and 5-HT2A receptors was investigated in rat brain. Rats were randomly assigned to one of four groups: vehicle-vehicle, STZ-vehicle, vehicle-HPD, and STZ-HPD groups. Four weeks after single administration of STZ (65 mg/kg IV) or vehicle (citrate buffer), rats received depot HPD (4 mg/kg IM) or vehicle (sesame oil) once a week for 4 weeks. Sixteen days after the last injection of HPD or vehicle, rats were sacrificed, and the density of binding sites was determined using [3H]spiperone as ligand in the striatum (D2),[3H]8-hydroxy-2-(di-n-propyl)-aminotetraline in the hippocampus (5-HT1A), and [3H]ketanserin in the frontal cortex (5-HT2A). The density of D2 receptors was significantly increased in the vehicle-HPD compared to vehicle-vehicle controls. However, striatal D2 receptor density of the STZ-HPD and the STZ-vehicle were not significantly different from the vehicle-vehicle group. A significant increase in cortical 5-HT2A receptor density was observed only in the group of STZ-vehicle. Treatment with STZ, HPD, or the combination thereof, did not affect the density of 5-HT1A receptors. The affinity constants for D2, 5-HT1A, and 5-HT2A receptors were not affected by any treatment. These results suggest that diabetic state may affect brain serotonergic activity via an increase in the density of 5-HT2A receptors. This may indicate an increased vulnerability to major depression in patients with diabetes. The lack of an effect of the combined chronic treatment with STZ and HPD on the D2 receptor density may correspond to the increased risk to develop tardive dyskinesia in patients with diabetes.
Asunto(s)
Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Encéfalo/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Ketanserina/farmacología , Masculino , Neostriado/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Espiperona/farmacología , EstreptozocinaRESUMEN
[reaction: see text] 3-Fluoro-5-methylene-2-cyclopentenone is treated with appropriate nucleophiles and Lewis acids to undergo regioselective 1,2-addition, exocyclic 1,4-addition, and endocyclic 1,4-addition, leading to 3-substituted 4-methylene-2-cyclopentenones, 5-substituted 3-fluoro-2-cyclopentenones, and 3-substituted 5-methylene-2-cyclopentenones in good yields, respectively.
Asunto(s)
Ciclopentanos/síntesis química , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , EstereoisomerismoRESUMEN
The Escherichia coli surE gene is co-transcribed with pcm, encoding the L-isoaspartyl protein repair methyltransferase, and is highly conserved among both the Eubacteria and the Archaea; however, no biochemical function has yet been identified for this gene. Isoaspartyl accumulation during stationary phase was much higher in a pcm surE double mutant than in either single mutant, suggesting that the two genes may represent two parallel pathways by which E. coli can respond to protein damage. A null mutation in surE also suppressed stress-survival defects previously observed in a pcm mutant strain, providing further evidence for an interaction between the two gene products.
Asunto(s)
Fosfatasa Ácida , Ácido Aspártico/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas de Escherichia coli , Escherichia coli/genética , Escherichia coli/metabolismo , Genes Bacterianos , Mutación , Proteína Metiltransferasas/genética , Proteína Metiltransferasas/metabolismo , Proteínas Bacterianas/química , Escherichia coli/crecimiento & desarrollo , Fenotipo , Filogenia , Proteína D-Aspartato-L-Isoaspartato MetiltransferasaRESUMEN
Medial preoptic area (MPA), supraoptic nucleus (SON), magnocellular (MaPVN) and parvocellular (PaPVN) paraventricular hypothalamic nuclei, and mesencephalic lateral tegmentum (MLT) are involved in maternal behavior, parturition and lactation. This study investigated the FosB and Fos immunoreactivity in these regions of virgin, pregnant, parturient, lactating, and lactating-arrested rats. The patterns of FosB and Fos expression were compared between the sections taken from the same animals. Quantitative immunohistochemistry revealed a significant increase in the numbers of FosB-positive neurons in the MPA, SON, MaPVN, and MLT of parturient and lactating females as compared with pregnant or virgin animals. In lactating rats, the numbers of FosB-positive neurons in the MPA, PaPVN, and MLT were increased, but the numbers in the SON and MaPVN were decreased as compared with parturient females. Many Fos-positive neurons were also seen in parturient and lactating rats, and the patterns of Fos expression in each region were quite similar to those of FosB. Moreover, double-labeling immunohistochemistry revealed that: (1) many FosB-positive nuclei were observed in oxytocin and vasopressin neurons of the SON and PVN in parturient rats; (2) within FosB-positive neurons, 89.5% in the MPA, 86.8% in the MLT of parturient rats, and 92% in the MPA and 90.8% in the MLT of lactating animals were also Fos-positive. Only a small number of FosB and Fos-positive neurons were seen in females that were killed in the early stage of parturition. Removal of the litters immediately after parturition completely eliminated FosB and Fos expression in each region in the dams. Taken together, the present results suggest that FosB expression is co-involved with Fos in the neural activation during parturition and lactation in rats.
Asunto(s)
Tronco Encefálico/metabolismo , Genes fos/genética , Hipotálamo/metabolismo , Área Preóptica/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Femenino , Genes Inmediatos-Precoces , Trabajo de Parto , Lactancia , Embarazo , Proteínas Proto-Oncogénicas c-fos/genética , Ratas , Ratas WistarRESUMEN
Chronic administration of haloperidol (2 mg/kg x 21 days) in drinking water decreased basal dopamine (DA) release and metabolism in rat striatum and nucleus accumbens in awake, freely moving rats. In contrast with previous in vivo voltammetric studies in chloral hydrate-anesthetized rats, DA release and metabolism decreased in both regions following administration of (-)apomorphine (50 micrograms/kg, i.v.). These results demonstrate that stimulation of pre- or postsynaptic DA receptors by apomorphine in rats chronically treated with haloperidol further diminishes the release of DA and decreases DA metabolism. These results are difficult to reconcile with current concepts of neuroleptic-induced depolarization inactivation which predict increased release of DA following DA agonist administration.
Asunto(s)
Apomorfina/farmacología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Haloperidol/farmacología , Núcleo Accumbens/metabolismo , Núcleos Septales/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Masculino , Ratas , Ratas EndogámicasRESUMEN
The effect of chronic administration of antipsychotic drugs (21 days in drinking water followed by 3 days drug washout) on the D-amphetamine (1.0 mg/kg, s.c.)-induced increase in dopamine (DA) release in the striatum and the nucleus accumbens of awake, freely-moving rats was investigated with microdialysis. Chronic administration of haloperidol, a typical antipsychotic, (0.5 mg/kg/day), decreased basal extracellular DA release in the striatum and the nucleus accumbens but did not affect D-amphetamine-induced DA release in either region. In marked contrast, chronic administration of three atypical antipsychotic drugs: amperozide (2 mg/kg/day), clozapine (10 mg/kg/day) and melperone (2 mg/kg/day) increased basal extracellular DA and enhanced D-amphetamine-induced DA release in the striatum. In the nucleus accumbens, basal extracellular DA was decreased by chronic amperozide, unchanged by chronic clozapine and increased by chronic melperone. Most significantly, D-amphetamine-induced DA release was inhibited by chronic amperozide or clozapine, but unaffected by chronic melperone in this region. These results suggest that atypical antipsychotic drugs can alter DA release in a region specific manner. In particular, attenuation of amphetamine-like stimulation of DA release with reduced basal DA release in the nucleus accumbens could contribute to the antipsychotic action of amperozide which has a very weak affinity for D2 DA receptors.
Asunto(s)
Antipsicóticos/farmacología , Cuerpo Estriado/efectos de los fármacos , Dextroanfetamina/farmacología , Dopamina/metabolismo , Haloperidol/farmacología , Núcleo Accumbens/efectos de los fármacos , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Antipsicóticos/administración & dosificación , Cuerpo Estriado/metabolismo , Diálisis , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Serotonin (5-HT)(1A) receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT(1A) receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohe xanecarboxamide trihydrochloride (WAY100635), a selective 5-HT(1A) receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT(2A)/D(2) receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0. 03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01-1.0 mg/kg), potent D(2) receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1-0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT(2A) receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT(1A) receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT(2A) receptors. The significance of these results for EPS and antipsychotic action is discussed.
Asunto(s)
Antipsicóticos/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Piperazinas/farmacología , Receptores de Serotonina/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Clozapina/farmacología , Cuerpo Estriado/metabolismo , Fluorobencenos/farmacología , Haloperidol/farmacología , Masculino , Microdiálisis , Núcleo Accumbens/metabolismo , Piperidinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptores de Serotonina 5-HT1 , Risperidona/farmacología , Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , TritioRESUMEN
The effects of (+-)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following D-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (-)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 micrograms/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.
Asunto(s)
Anfetamina/farmacología , Anfetaminas/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Análisis de Varianza , Animales , Apomorfina/antagonistas & inhibidores , Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Sinergismo Farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/agonistasRESUMEN
Serotonin (5-hydroxytryptamine, 5-HT)(1A) receptor agonism and 5-HT(2A) receptor antagonism are components in the action of some of the recently developed antipsychotic drugs, e.g., clozapine and ziprasidone. However, studies of the role of 5-HT(1A) receptor agonism in the ability of these drugs to modulate dopamine (DA) release in the nucleus accumbens (NAC), which may be relevant to antipsychotic action, are lacking. Thus, we examined the effect of clinically available agents, ipsapirone, a 5-HT(1A) receptor partial agonist, and the mixed 5-HT(1A/1B)/beta receptor antagonist S(-)-pindolol, on DA release in the NAC compared to the striatum (STR). Ipsapirone produced a biphasic effect; low dose (0.1 mg/kg) decreased, high dose (3 mg/kg) increased and intermediate doses (0.1 and 1 mg/kg) did not change DA release in the NAC, respectively. However, ipsapirone, at all doses (0.3, 1, 3, but not 0.1 mg/kg) increased striatal DA release. S(-)-pindolol (3, 10, but not 1 mg/kg) produced a comparable increase in DA release in the NAC and STR. These results suggest that the ability of lower dose of ipsapirone to decrease DA release in the NAC is more likely to be due to 5-HT(1A) receptor agonism. On the other hand, the effect of higher dose of ipsapirone on striatal DA release may be due to 5-HT(1A) receptor antagonism, as is the case with S(-)-pindolol. The mechanism and clinical significance of these results for developing antipsychotic drugs is discussed.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Pindolol/farmacología , Pirimidinas/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Valores de ReferenciaRESUMEN
(+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 1.25, 2.5 and 5 mg/kg), a serotonin (5-HT)2A/2C agonist, produced an inverted U-shaped increase in DA release in rat medial prefrontal cortex (mPFC) with a significant effect only at 2.5 mg/kg. This effect was completely abolished by M100907 (0.1 mg/kg), a 5-HT2A antagonist, and WAY100635 (0.2 mg/kg), a 5-HT1A antagonist, neither of which when given alone affected dopamine release. DOI (2.5 mg/kg), but not the 5-HT2C agonist Ro 60-0175 (3 mg/kg), attenuated clozapine (20 mg/kg)-induced mPFC dopamine release. These results suggest that 5-HT2A receptor stimulation increases basal cortical dopamine release via 5-HT1A receptor stimulation, and inhibits clozapine-induced cortical dopamine release by diminishing 5-HT2A receptor blockade.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/antagonistas & inhibidores , Dopamina/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Depresión Química , Fluorobencenos/farmacología , Indofenol/análogos & derivados , Indofenol/farmacología , Microdiálisis , Piperazinas/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2C , Receptores de Serotonina 5-HT1 , Tasa de Secreción/efectos de los fármacos , Antagonistas de la Serotonina/farmacologíaRESUMEN
R(+)-8-OH-DPAT (0.05, but not 0.025, 0.1, 1 mg/kg), a 5-HT(1A) receptor agonist, decreased l-3,4-dihydroxyphenylalanine (DOPA) accumulation in rat striatum following NSD-1015, an l-aromatic amino acid decarboxylase inhibitor. Amphetamine (1 mg/kg) increased striatal DOPA accumulation, an effect attenuated by R(+)-8-OH-DPAT (0.05 mg/kg). However, both amphetamine (1 mg/kg) and R(+)-8-OH-DPAT (0.05 mg/kg) decreased cortical DOPA accumulation; there were no additional decreases from their combination. Neither amphetamine (1 mg/kg), R(+)-8-OH-DPAT (0.05 mg/kg), or the combination, significantly affected DOPA accumulation in the nucleus accumbens. The significance of and possible mechanisms for these findings are discussed.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Anfetamina/antagonistas & inhibidores , Cuerpo Estriado/efectos de los fármacos , Dopamina/biosíntesis , Receptores de Serotonina/efectos de los fármacos , Anfetamina/administración & dosificación , Análisis de Varianza , Animales , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inyecciones Subcutáneas , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/administración & dosificaciónRESUMEN
Pretreatment with R(+)-8-OH-DPAT, a selective serotonin (5-HT)1A receptor agonist (50 micrograms/kg, s.c.), inhibited D-amphetamine sulfate (1.0 mg/kg, s.c.)-induced increases in extracellular levels of both 5-HT and dopamine (DA) in rat medial prefrontal cortex, as determined by in vivo microdialysis. The inhibitory effect of R(+)-8-OH-DPAT was completely reversed by the selective 5-HT1A receptor antagonist WAY 100,635 (100 micrograms/kg s.c.) administered 5 min prior to R(+)-8-OH-DPAT. These results suggest that stimulation of 5-HT1A receptors may inhibit amphetamine-induced release of 5-HT and DA in the medial prefrontal cortex.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetamina/antagonistas & inhibidores , Ansiolíticos/farmacología , Agonistas de Dopamina/farmacología , Corteza Prefrontal/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Dopamina/metabolismo , Evaluación Preclínica de Medicamentos , Masculino , Microdiálisis , Piperazinas/farmacología , Corteza Prefrontal/metabolismo , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
The effects of chronic treatment with clozapine and haloperidol on basal dopamine release and metabolism were studied in the striatum and the nucleus accumbens of awake, freely moving rats using in vivo microdialysis. Chronic haloperidol (2 mg/kg X 21 days) but not chronic clozapine (20 mg/kg X 21 days) decreased basal dopamine release and metabolism in both the striatum and the nucleus accumbens. These results differ significantly from those previously reported with in vivo voltammetry. Possible explanations are discussed.
Asunto(s)
Clozapina/farmacología , Cuerpo Estriado/metabolismo , Dibenzazepinas/farmacología , Dopamina/metabolismo , Haloperidol/farmacología , Núcleo Accumbens/metabolismo , Núcleos Septales/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Diálisis , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Endogámicas , Técnicas EstereotáxicasRESUMEN
The effect of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, fluoxetine (10 mg/kg s.c.), two tricyclic antidepressants, clomipramine (10 mg/kg s.c.) and imipramine (10 mg/kg s.c.), and vehicle on extracellular dopamine levels was studied in rat nucleus accumbens and striatum by in vivo microdialysis. Fluoxetine produced significant decreases in extracellular dopamine levels in both the nucleus accumbens and striatum (mean maximum percentage decrease: 58% and 57% of pre-drug baseline, respectively). In contrast, imipramine and clomipramine significantly increased extracellular dopamine in the striatum (148% and 150%, respectively) compared to the effect of vehicle alone (118%). These results suggest that the selective serotonin reuptake inhibitor, fluoxetine, and the tricyclic antidepressants, clomipramine and imipramine, affect dopaminergic activity in diverse ways and in a region-specific manner. Thus, the antidepressant effect of these drugs is unlikely to be related to their acute effects on dopaminergic neurotransmission. The differential effects of the selective serotonin reuptake inhibitor and tricyclic antidepressants on extracellular dopamine could account for other differences in their clinical and side effect profiles. Further studies of the chronic effects of the selective serotonin reuptake inhibitor and the tricyclic antidepressants on dopaminergic activity are required to elucidate the role of dopamine in the antidepressant effect.
Asunto(s)
Antidepresivos/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Fluoxetina/farmacología , Núcleo Accumbens/efectos de los fármacos , Animales , Clomipramina/farmacología , Imipramina/farmacología , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factores de TiempoRESUMEN
The anticonvulsant mood stabilizers valproic acid (250, 500 but not 50 mg/kg) and carbamazepine (6, 12.5 but not 3 mg/kg) were found to increase extracellular dopamine levels in rat medial prefrontal cortex, but not nucleus accumbens. Increased prefrontal dopamine was completely abolished by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexa necarboxamide (WAY100635, 0.05 mg/kg). Anticonvulsants and clozapine may share a common mood stabilizing mechanism since clozapine is reported to have mood stabilizing effects and increase prefrontal dopamine by 5-HT1A receptor activation.
Asunto(s)
Anticonvulsivantes/farmacología , Carbamazepina/farmacología , Dopamina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Receptores de Serotonina/metabolismo , Ácido Valproico/farmacología , Animales , Relación Dosis-Respuesta a Droga , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Piperazinas/farmacología , Corteza Prefrontal/metabolismo , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacologíaRESUMEN
The effect of chronic treatment with the tricyclic antidepressant drug, imipramine (10 mg/kg per day), the selective serotonin (5-HT) reuptake inhibitor, fluoxetine hydrochloride (10 mg/kg per day), and vehicle, in drinking water for 24-28 days followed by 3-5 days withdrawal, on extracellular dopamine levels was studied in rat nucleus accumbens by in vivo microdialysis. Basal extracellular dopamine levels in the nucleus accumbens were increased after chronic imipramine (12.7 +/- 1.5 fmol/20 microl per 30 min, P = 0.019), and moderately decreased after chronic fluoxetine (6.5 +/- 0.6, P = 0.047), as compared to the vehicle controls (9.1 +/- 0.7), determined by one-way analysis of variance (ANOVA). Repeated measure ANOVA indicated that the D-amphetamine sulfate (0.5 mg/kg, s.c.)-induced increase in extracellular dopamine levels in the nucleus accumbens was potentiated after chronic imipramine (P = 0.002), but unchanged after chronic fluoxetine (P = 0.83). The difference in the effect of amphetamine could be influenced by the significant differences in basal levels. However, these results were also confirmed by analysis of the net area under the curve (net-AUC) for a 180-min period (six samples): for chronic imipramine (337 +/- 45 fmol/180 min, P = 0.005) and chronic fluoxetine (249 +/- 38, P = 0.57), as compared to the vehicle controls (178 +/- 29), determined by one-way ANOVA. We suggest that the effect of treatment with these agents on mesolimbic dopamine is unlikely to be involved in their shared antidepressant action, but may be relevant to other aspects of the therapeutic profile of these two drugs, e.g. the switch into mania which is more common after treatment with imipramine than fluoxetine and exacerbation of positive symptoms in patients with schizophrenia or schizoaffective disorder.