RESUMEN
Despite enormous progress in fundamental knowledge in neuroscience, no revolutionary therapies in psychiatry (and neurology) have emerged in the past ten years. Most drugs alleviate symptoms, rather than restoring the 'set point' of brain function from a pathological position to a more normal one. We propose a hypothesis-driven, systems-level approach to drug discovery and development that is based on pathophysiology and which uses new animal models.
Asunto(s)
Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/fisiopatología , Psicotrópicos/uso terapéutico , Animales , Humanos , Psicotrópicos/síntesis química , Psicotrópicos/farmacologíaRESUMEN
1. The electroencephalographic (EEG) effects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 - 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 - 3 mg kg(-1) s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 - 3 Hz with decreases in power at higher frequencies (9 - 30 Hz). At high doses (3 mg kg(-1) s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 - 0.1 mg kg(-1) i.p.) caused similar effects but with lesser changes in power. 2. In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 - 10 mg kg(-1) i.p.). The atypical antipsychotic clozapine (0.2 mg kg(-1) s.c.) synchronized the EEG (peak 8 Hz). The 5-HT(2A)-antagonist, M100907, specifically increased EEG power at 2 - 3 Hz at low doses (10 and 50 microg kg(-1) s.c.), whereas at higher doses (0.1 mg kg(-1) s.c.) the profile resembled that of clozapine. 3. Clozapine (0.2 mg kg(-1) s.c. ), GYKI 53655 (5 mg kg(-1) i.p.), prazosin (0.05 and 0.1 mg kg(-1) i.p.), and M100907 (0.01 and 0.05 mg kg(-1) s.c.) antagonized the decrease in power between 5 and 30 Hz caused by PCP (1 mg kg(-1) s.c.), but not the increase in power at 1 - 3 Hz in prefrontal cortex.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Maleato de Dizocilpina/farmacología , Alucinógenos/farmacología , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Clozapina/antagonistas & inhibidores , Clozapina/farmacología , Estado de Conciencia , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electroencefalografía/efectos de los fármacos , Fluorobencenos/farmacología , Masculino , Modelos Biológicos , Piperidinas/farmacología , Prazosina/farmacología , Corteza Prefrontal/fisiología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A , Receptores AMPA/antagonistas & inhibidores , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacologíaRESUMEN
Although many new potential drug targets have been discovered subsequent to the cloning of the human genome and the discovery of most of the relevant receptors, the role of these receptors in psychiatric disease is still not clear. We argue that research into the disease process leading to new animal models that can be transposed to man is critical to drug discovery, and present an example of an animal model for schizophrenia using electroencephalography.