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Diversos psicotomiméticos actúan a través de una vía de señalización común
Per Svenningsson1, Eleni T Tzavara, Robert Carruthers
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
Science (New York, N.Y.)
|November 25, 2003
Resumen
Los comportamientos similares a la esquizofrenia inducidos por varios medicamentos están mediados por una vía común que involucra a DARPP-32. Las alteraciones genéticas o moleculares en DARPP-32 redujeron significativamente estos cambios de comportamiento inducidos por fármacos en ratones.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Farmacología Farmacología.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Distintas clases de fármacos, incluidos los agentes dopaminérgicos, serotoninérgicos y glutamatérgicos, pueden inducir estados psicotomiméticos que se asemejan a los síntomas de la esquizofrenia en modelos animales.
- La identificación de un mecanismo molecular común subyacente a estos estados inducidos por drogas es crucial para comprender la fisiopatología de la esquizofrenia.
Objetivo del estudio:
- Investigar una vía de señalización compartida responsable de mediar los efectos psicotomiméticos de la D-anfetamina, el LSD y el PCP.
- Determinar el papel de la fosfoproteína regulada por dopamina y adenosina 3',5'-monofosfato (cAMP) de 32 kilodaltones (DARPP-32) en estos comportamientos inducidos por las drogas.
Principales métodos:
- Utilizó ratones genéticamente modificados que carecían de DARPP-32 o que poseían mutaciones puntuales en sus sitios de fosforilación.
- Se administró D-anfetamina, LSD y PCP para evaluar sus efectos sobre el bloqueo sensorimotor y los movimientos repetitivos.
- Examinó el estado de fosforilación de DARPP-32 y su impacto en los efectores aguas abajo como la proteína fosfatasa-1, GSK-3, CREB y c-Fos.
Principales resultados:
- DARPP-32 se somete a fosforilación / desfosforilación en tres sitios clave, lo que lleva a una inhibición sinérgica de la proteína fosfatasa-1.
- La deleción o mutación genética de DARPP-32 atenuó significativamente los efectos conductuales de la D-anfetamina, el LSD y el PCP.
- Estos hallazgos sugieren que DARPP-32 es un mediador crítico de las conductas psicotomiméticas inducidas por drogas.
Conclusiones:
- Una vía de señalización común converge en DARPP-32 para mediar los efectos conductuales de diversas drogas psicotomiméticas.
- DARPP-32 representa un objetivo terapéutico potencial para las condiciones asociadas con síntomas similares a la esquizofrenia.
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