Antisense Therapeutics in the Central Nervous System: The Induction of c-fos

Immediate-early genes (IEGs) are members of a class of genes that respond, in many cell types, to a variety of stimuli by rapid, but transient expression (1). Several of these IEGs code for transcription factors and include the widely studied activator protein-1 (AP-1) transcription factor complex believed to be homo- and heterodimeric assemblies of the Fos and Jun families (1–3). IEGs are induced in the central nervous system (CNS) by diverse physiological and pharmacological stimuli, many of which, when presented once or on multiple occasions, can alter the “normal” functioning of the brain in a permanent or semipermanent fashion. Examples of pharmacological stimuli that lead to long-term changes are the highly addictive psychostimulant drugs, amphetamine and cocaine These drugs produce a robust activation of IEGs (e.g., c-fos, jun -B, egr -1) in areas of the brain that are believed to be part of the neural substrates of addiction (4–8 ) In animal models of epileptogenesis or memory, such as kindling and long-term potentiation (LTP), respectively, electrical stimuli produce activation of IEGs within the brain structures thought to underlie the long-lasting changes associated with these experimental procedures (9–16 ). IEGs can also be induced by noninvasive stimuli, such as a simple light pulse given to animals in a dark room. The circadian rhythms of animals that are housed in darkened conditions can be shifted by exposing them to a light during then subjective night. Activation of IEGs in such experiments are restricted to the suprachiasmatic nucleus (SCN), which is believed to be the seat of the biological clock (17 ).