RESUMEN
Reasoning and problem solving deficits have been reported in schizophrenic patients. In the present study, we have tested rats in a two-lever reversal learning task in a Skinner box to model these deficits. In other studies using the Skinner box, atypical antipsychotics fully reversed phencyclidine (PCP)-induced impairments in reversal learning which is in contrast to clinical observations where antipsychotics lack the ability to fully reverse cognitive deficits in schizophrenia. Therefore, it can be argued that the outcome of these tests may lack predictive value. In the present study, after training on a spatial discrimination between two levers, rats were exposed to a reversal of the previously learned stimulus-response contingency during 5 days. We first investigated the effects of sub-chronic treatment with the non-competitive N-methyl-d-aspartate (NMDA) antagonists dizocilpine (MK-801) and PCP on reversal learning and extinction in male Sprague Dawley rats. Subsequently, we studied the effects of different PCP treatment regimes. Then, we investigated whether the atypical antipsychotics risperidone and clozapine and the 5-hydroxytryptamine6 (5-HT6) antagonist GSK-742457 could reverse the PCP-induced deficits. All drugs were administered subcutaneously (s.c.). MK-801 did not impair reversal learning, while PCP (1.0 and 2.0 mg/kg) induced a clear deficit in reversal learning. Both compounds, however, disrupted extinction at all tested doses. Risperidone and clozapine were both ineffective in significantly ameliorating the PCP-induced deficit in reversal learning which fits well with the clinical observations. The lowest dose of clozapine (1.25 mg/kg) had an intermediate effect in ameliorating the deficit in reversal learning induced by PCP (not different from control or PCP-treated rats). The lowest dose of GSK-742457 (0.63 mg/kg) fully reversed the PCP-induced deficits while the higher dose (5.0 mg/kg) had an intermediate effect.
Asunto(s)
Clozapina/farmacología , Condicionamiento Operante/efectos de los fármacos , Fenciclidina/farmacología , Quinolinas/farmacología , Aprendizaje Inverso/efectos de los fármacos , Risperidona/farmacología , Sulfonas/farmacología , Animales , Antipsicóticos/farmacología , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Extinción Psicológica/efectos de los fármacos , Discapacidades para el Aprendizaje/inducido químicamente , Masculino , Fenciclidina/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/farmacologíaRESUMEN
BACKGROUND: Promotion of cell-mediated immunity appears to be an important goal in the control of HIV infection. Topical dinitrochlorobenzene (DNCB) stimulates systemic cell-mediated immunity via the induction of cutaneous delayed-type hypersensitivity. OBJECTIVE: Our goal was to evaluate the clinical and immunologic effects of chronic DNCB application in a group of 24 HIV-infected patients. METHODS: We observed the patients for a mean of 28 months (range, 14 to 44 months). Of the 24 patients, 13 continued weekly DNCB application throughout the study (the compliant group), and 11 discontinued DNCB use after a mean of 10.9 months (the noncompliant group). RESULTS: Two of the 13 compliant patients progressed to AIDS; none of these patients died. In contrast, AIDS developed in 5 of the 11 noncompliant patients and four of these patients died. Analysis of lymphocyte subsets revealed significant increases in natural killer cells and activated/cytotoxic CD8 T-cell subsets in the compliant group. In contrast, these cellular immune-related lymphocyte subsets decreased in the noncompliant subjects. Although CD4 T-cell levels decreased in both groups, there was a significantly greater drop in the noncompliant patients. CD8+CD38+ T cells increased significantly in both groups. CONCLUSION: Chronic DNCB application appears to have a beneficial clinical and immunomodulatory effect in HIV-infected patients.
Asunto(s)
Dinitroclorobenceno/uso terapéutico , Infecciones por VIH/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Antígenos CD/análisis , Relación CD4-CD8 , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunidad Celular , Subgrupos Linfocitarios , Masculino , Cooperación del PacienteRESUMEN
Dendritic cells, the primary antigen presenting cells of the human immune system, are heavily infected with human immunodeficiency virus (HIV) in patients with the acquired immunodeficiency syndrome (AIDS). Dinitrochlorobenzene (DNCB) is a contact sensitizing agent that acts as a potent immune modulator of dendritic cells. In this pilot study, we examined the safety and efficacy of topical DNCB application in patients with early HIV disease. Topical DNCB was well tolerated by these patients, with an adverse reaction rate of 10%. CD4+ T-cell counts remained stable with repeated DNCB use. In contrast, CD8+ T-cell counts and natural killer cells increased significantly following DNCB sensitization. This increase in CD8+ T-cell and natural killer cell subsets was accompanied by a decrease in HIV replication, as measured by serum HIV RNA levels. Based on this pilot study, we conclude that topical DNCB is safe in early HIV disease and may decrease viral load via a systemic effect on dendritic cells, CD8+ T-cells and natural killer cells. These results require confirmation in larger controlled trials.