RESUMEN
Neuroplasticity is a key factor in restoration of brain function following neuropathology associated with disease or drug exposure. Here we examined the potential for chronic treatment with the selective D1 receptor antagonist SCH39166 to reverse the profound and enduring cognitive impairment associated with amphetamine (AMPH) sensitization in the nonhuman primate and to stimulate re-growth of atrophied pyramidal dendrites in the dorsolateral prefrontal cortex of these animals. Four rhesus monkeys with sustained cognitive impairment (>1year following AMPH sensitization) were treated for up to 8months with SCH39166. Cognitive testing was performed before, during, and for up to 1(1/2) year following treatment. Significant improvement in working memory performance was observed only after cessation of the D1 antagonist treatment but then was sustained for the duration of the post-treatment testing period. Postmortem quantitative assessment of Golgi-impregnated pyramidal neurons in BA9 showed that apical dendritic length and trunk spine density were increased in D1 antagonist treated monkeys relative to AMPH-sensitized and AMPH-naïve monkeys. These findings, which suggest that the deleterious consequences of AMPH sensitization can be reversed by modulation of D1 receptor signaling, have implications for treating the underlying neural basis of cognitive deficits in both schizophrenia and substance abuse.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cognición/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Neuronas/efectos de los fármacos , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Dendritas/efectos de los fármacos , Dendritas/ultraestructura , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/ultraestructura , Femenino , Macaca mulatta , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal/efectos de los fármacosRESUMEN
UNLABELLED: We investigated the effects of GC-1, a TRbeta-selective thyromimetic, on bone development of hypothyroid rats. Whereas T3 reverted the IGF-I deficiency and the skeletal defects caused by hypothyroidism, GC-1 had no effect on serum IGF-I or on IGF-I protein expression in the epiphyseal growth plate of the femur, but induced selective effects on bone development. Our findings indicate that T3 exerts some essential effects on bone development that are mediated by TRbeta1. INTRODUCTION: We investigated the role of the thyroid hormone receptor beta1 (TRbeta1) on skeletal development of rats using the TRbeta-selective agonist GC-1. MATERIALS AND METHODS: Twenty-one-day-old female rats (n = 6/group) were rendered hypothyroid (Hypo) and treated for 5 weeks with 0.3 ug/100 g BW/day of T3 (1xT3), 5xT3, or equimolar doses of GC-1 (1xGC-1 and 5xGC-1). Serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF)-I concentrations were determined by radioimmunoassay (RIA). BMD and longitudinal bone growth were determined by DXA. Trabecular bone histomorphometry and epiphyseal growth plate (EGP) morphometry were performed in the distal femur. Expressions of IGF-I protein and of collagen II and X mRNA were evaluated by immunohistochemistry and in situ hybridization, respectively. To determine hormonal effects on ossification, skeletal preparations of hypothyroid-, 5xGC-1-, and 5xT3-treated neonatal rats were compared. RESULTS: Hypothyroidism impaired longitudinal body growth and BMD gain, delayed ossification, reduced the number of hypertrophic chondrocytes (HCs; 72% versus Euthyroid [Eut] rats; p < 0.001), and resulted in disorganized columns of EGP chondrocytes. Serum IGF-I was 67% reduced versus Eut rats (p < 0.001), and the expression of IGF-I protein and collagen II and X mRNA were undetectable in the EGP of Hypo rats. T3 completely or partially normalized all these parameters. In contrast, GC-1 did not influence serum concentrations or EGP expression of IGF-I, failed to reverse the disorganization of proliferating chondrocyte columns, and barely affected longitudinal growth. Nevertheless, GC-1 induced ossification, HC differentiation, and collagen II and X mRNA expression and increased EGP thickness to Eut values. GC-1-treated rats had higher BMD gain in the total tibia, total femur, and in the femoral diaphysis than Hypo animals (p < 0.05). These changes were associated with increased trabecular volume (48%, p < 0.01), mineralization apposition rate (2.3-fold, p < 0.05), mineralizing surface (4.3-fold, p < 0.01), and bone formation rate (10-fold, p < 0.01). CONCLUSIONS: Treatment of hypothyroid rats with the TRbeta-specific agonist GC-1 partially reverts the skeletal development and maturation defects resultant of hypothyroidism. This finding suggests that TRbeta1 has an important role in bone development.