MEDIAL PREFRONTAL CORTICAL INJECTIONS OF C-FOS ANTISENSE OLIGONUCLEOTIDES TRANSIENTLY LOWER C-FOS PROTEIN AND MIMIC AMPHETAMINE WITHDRAWAL BEHAVIORS

Prefrontal cerebral cortical areas display decreased expression of sev eral transcription factor/ immediate-early genes, including c-fos, dur ing amphetamine withdrawal.(52) Antisense strategies can help to test possible roles for this prefrontal c-fos down-regulation in the behavi oural correlates of amphetamine withdrawal. Medial prefrontal cortical injections delivering 1.7 nmoles of anti c-fas oligonucleotides revea led an approximately 3 h half-life for phosphothioate and a 15 min hal f-life for phosphodiester oligonucleotides. Antisense phosphothioates complementary to the c-fos translational start site reduced levels of c-Fos protein, while exerting modest and variable effects on c-fos mes senger RNA levels. Neither missense phosphorothioate nor antisense pho sphodiester oligonucleotides significantly reduced levels of either c- fos messenger RNA or protein. Animals injected with anti c-fos phospho thioate oligonucleotides into the medial prefrontal cortex displayed m arked reductions in linear locomotor activity and repetitive movements measured in a novel environment, effects not seen when missense oligo nucleotides were used or when animals were accustomed to the activity monitor prior to antisense oligonucleotide injection. Behavioural chan ges produced by prefrontal cortical injections of c-fos antisense olig onucleotides closely mimic alterations recorded during amphetamine wit hdrawal. Prefrontal c-fos could thus conceivably play roles in the neu robiological underpinnings of psychostimulant withdrawal and of respon ses to stressors such as exposure to novel environments. (C) 1997 IBRO . Published by Elsevier Science Ltd.