RESUMEN
Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.
Asunto(s)
Esquizofrenia , Ratas , Animales , Esquizofrenia/genética , Ratas Brattleboro , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/genética , Apomorfina/farmacología , Dopamina , Modelos Animales de EnfermedadRESUMEN
We performed a complex functional study of the effects of prostaglandin synthesis blockage with diclofenac on manifestation of the hydroosmotic effect of vasopressin V2-receptor agonist desmopressin in the kidneys of Wistar rats with normal synthesis of endogenous vasopressin and homozygous Brattleboro rats with hereditary impaired synthesis of neurohypophyseal hormone vasopressin. Blockage of prostaglandin synthesis led to more pronounced increase in urine osmolality in Brattleboro rats than in Wistar rats due to elevation of not only urine but also sodium gradient at the expense of elimination of the inhibitory effect of prostaglandins on sodium reabsorption and membrane permeability for urine. During combined treatment, the effects of the hormone predominated: the increase in urine osmolality in Wistar and Brattleboro rats did not differ from that after desmopressin administration.
Asunto(s)
Fármacos Antidiuréticos/farmacología , Diabetes Insípida Nefrogénica/tratamiento farmacológico , Diclofenaco/farmacología , Antagonistas de Prostaglandina/farmacología , Prostaglandinas/biosíntesis , Vasopresinas/farmacología , Animales , Desamino Arginina Vasopresina/farmacología , Diabetes Insípida Nefrogénica/patología , Diabetes Insípida Nefrogénica/orina , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Corteza Renal/patología , Médula Renal/efectos de los fármacos , Médula Renal/metabolismo , Médula Renal/patología , Concentración Osmolar , Ratas , Ratas Brattleboro , Ratas Wistar , Sodio/orina , Vasopresinas/deficienciaRESUMEN
Vasopressin (AVP) regulates the body salt-water balance. Brattleboro rats carry an AVP gene mutation resulting in a recessive form of central diabetes insipidus, being ideal for AVP deficiency studies. Herein, we studied the water permeability of the apical and basolateral sides of outer medullary collecting duct (OMCD) principal cells in response to dDAVP (a V2 receptor agonist) administration in Wistar and Brattleboro rats. Biophysical measurements of the water permeability (Pf ) of isolated OMCD principal cells were performed with the calcein quenching method with/without dDAVP (10-8 mol/L). mRNA transcripts and protein levels of AQP2, AQP3 and AQP4 were assessed by RT-PCR and western blot respectively. dDAVP increased the apical and basolateral Pf of OMCD principal cells in Wistar rats, while in Brattleboro rats this effect was present basolaterally. Long-term dDAVP administration in both strains resulted in a significant increase in mRNA expression of all assessed AQP's while only the protein levels of AQP2 and AQP3 were significantly increased. Short-term (20 minutes) dDAVP treatment of isolated OMCD fragments resulted in significantly increased plasma membrane expression of AQP2 in Wistar rats and of AQP2 and AQP3 in Brattleboro rats. In summary, dDAVP induces different expression of AQP2, AQP3 and AQP4 in Wistar and Brattleboro rats during short- and long-term treatment. In Wistar rats dDAVP mainly increased AQP2 expression while in Brattleboro rats it increased functional water permeability mainly by AQP3 expression.
Asunto(s)
Médula Renal/citología , Médula Renal/metabolismo , Túbulos Renales Colectores/citología , Túbulos Renales Colectores/metabolismo , Agua/metabolismo , Animales , Acuaporinas/biosíntesis , Desamino Arginina Vasopresina/farmacología , Médula Renal/efectos de los fármacos , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales Colectores/efectos de los fármacos , Concentración Osmolar , Permeabilidad/efectos de los fármacos , Ratas , Ratas Brattleboro , Ratas Wistar , Agua/administración & dosificaciónRESUMEN
Hyperviscosity syndrome was described in Brattleboro rats. The aim of this study was to investigate the possibility of Brattleboro rats using, as a test system for the study of agents with hemorheological activity. Under conditions of this model of high blood viscosity syndrome in Brattleboro rats, Lychnis chalcedonica L. extract (150 mg/kg) administered intragastrically for 10 days exhibited hemorheological activity by modulating macro- (plasma viscosity, fibrinogen concentration) and microrheological (erythrocyte aggregation and deformability parameters. Hence, Brattleboro rats are an adequate model of hyperviscosity syndrome that can be used for search and testing of substances with hemorheological activity.
Asunto(s)
Viscosidad Sanguínea/efectos de los fármacos , Deformación Eritrocítica/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Fármacos Hematológicos/farmacología , Extractos Vegetales/farmacología , Animales , Agregación Eritrocitaria/efectos de los fármacos , Eritrocitos/metabolismo , Eritrocitos/patología , Fibrinógeno/metabolismo , Hematócrito , Masculino , Ratas , Ratas Brattleboro , Ratas Wistar , Silene , Especificidad de la Especie , SíndromeRESUMEN
Caveolin (Cav)1 is expressed in the basolateral membrane domain of renal collecting duct (CD) principal cells (PCs), where it is associated with caveolae. To reveal any potential involvement of Cav1 in vasopressin signaling, we used specific monoclonal and polyclonal antibodies to examine its localization in CD PCs of Brattleboro (BB) rats treated with vasopressin (DDAVP). Compared with controls, immunofluorescence revealed a time-dependent increase in Cav1 expression in the apical membrane domain of PCs, where it overlapped with aquaporin-2 (AQP2). After 24 h of DDAVP treatment, Cav1 was visible as an increased number of small apical spots. The staining gradually became more extensive, and, after 2 wk of DDAVP, it occupied the majority of the apical membrane domain of many PCs. Cav1 also assumed an apical localization in PCs of DDAVP-treated Sprague-Dawley and Long-Evans rats. Similarly, Cav2 appeared at the apical pole of PCs after DDAVP treatment of BB, Sprague-Dawley, and Long-Evans rats. Immunogold electron microscopy confirmed bipolar Cav1 membrane expression in DDAVP-treated BB rats, whereas caveolae were only detected on the basolateral membrane. Immunoblot analysis of BB rat whole kidney homogenates revealed no significant increase in Cav1 levels in DDAVP-treated rats, suggesting that DDAVP induces Cav1 relocalization or modifies its targeting. We conclude that Cav1 and Cav2 trafficking and membrane localization are dramatically altered by the action of DDAVP. Importantly, the absence of apical caveolae indicates that while Cavs may have an as yet undetermined role in vasopressin-regulated signaling processes, this is probably unrelated to AQP2 internalization by caveolae.