Fos Protein Expression and Cocaine-Seeking Behavior in Rats after Exposure to a Cocaine Self-Administration Environment

Abstract

To examine neuronal activation associated with incentive motivation for cocaine, cocaine-seeking behavior (operant responding without cocaine reinforcement) and Fos expression were examined in rats exposed to saline and cocaine priming injections and/or a self-administration environment. Rats were first trained to self-administer cocaine or received yoked saline administration ("control"). They then received 21 daily exposures to either the self-administration environment ("extinction") or a different environment ("no extinction") without cocaine available. Extinction training, used to decrease incentive motivation for cocaine elicited by the self-administration environment, decreased cocaine-seeking behavior elicited by both the environment and the cocaine priming injection. Exposure to the self-administration environment enhanced Fos expression in the no extinction group relative to control and extinction groups in the anterior cingulate, basolateral amygdala, hippocampal CA1 region, dentate gyrus, nucleus accumbens shell and core, and central gray area, regardless of whether or not priming injections were given. The priming injections enhanced Fos expression in the ventral tegmental area, caudate putamen, substantia nigra pars reticulata, entorhinal cortex, central amygdala, lateral amygdala, arcuate nucleus, and central gray area, regardless of group. Thus, these changes likely reflect an unconditioned effect from either cocaine or injection stress. The priming injections also enhanced Fos expression in the anterior cingulate, but only in cocaine-experienced groups, suggesting that this enhancement reflects an experience-dependent motivational effect of the priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

“…The latter finding suggests that c-Fos expression was activated by the presentation of alcohol-paired stimuli and not by the performance of operant behavior. Our observation of increased c-Fos expression in the BLA after reexposure to the alcoholpaired discrete cues is in agreement with earlier studies which showed that reexposure to cocaine-, amphetamine-, morphine-, or beer-associated context and discrete cues activated c-Fos in this brain region (Topple et al, 1998;Baker et al, 1999;Mead et al, 1999;Neisewander et al, 2000;Ciccocioppo et al, 2001;Harris and Aston-Jones, 2003). Moreover, the BLA has been shown to be involved in context-and cue-induced relapse to drug-seeking, and to control the ability of environmental stimuli to form Pavlovian associations with reinforcing stimuli (Whitelaw et al, 1996;Meil and See, 1997;Kruzich and See, 2001;Shalev et al, 2003).…”

“…It has been shown that cocaine-and alcohol-paired discrete cues did not activate c-Fos expression in the CeA (Neisewander et al, 2000;Ciccocioppo et al, 2001;Dayas et al, 2007;Zhao et al, 2006). However, in the latter studies many extinction sessions were run prior to the final reinstatement session (a factor which could account for the discrepancies between the results of those studies and our data).…”

“…It can also be speculated that c-Fos expression induced by drugrelated cues is driven by ERK-dependent phosphorylation of Elk-1 and CREB transcription factors (Sgambato et al, 1998;Vanhoutte et al, 1999;Valjent et al, 2000). c-Fos protein expression and the ERK pathway have been shown to be activated in the amygdala after reexposure to drugpaired stimuli (Neisewander et al, 2000;Lu et al, 2005), what may suggest the involvement of ERK pathway in the regulation of c-Fos expression. However, there is also evidence that cocaine-induced c-Fos expression in the amygdala may not depend on the ERK pathway (Radwanska et al, 2005).…”

“…The AP-1 transcription factor is a complex of Fos and Jun proteins, known to regulate the broad spectrum of neuronal plasticity-related genes (Kaczmarek, 1993;Rylski and Kaczmarek, 2004). It has been shown that c-Fos expression is induced in the amygdala after reexposure to drug-related stimuli (Brown et al, 1992;Neisewander et al, 2000;Ciccocioppo et al, 2001). The upstream regulators of this event are mostly unknown although possible candidates are extracellular signal-regulated kinases (ERK) which have been found to control c-fos expression in many experimental paradigms (Sgambato et al, 1998;Radwanska et al, 2005).…”

Effects of Cocaine on c-Fos and NGFI-B mRNA Expression in Transgenic Mice Underexpressing Glucocorticoid Receptors

“…The formation of Pavlovian conditioning is thus likely to have occurred by the association of neutral stimuli, such as the presence of the experimenter and the injection, and the unconditional rewarding effect of COC. Other studies have also reported a correspondence between COC-conditioned hyperactivity and enhanced Fos expression within the prefrontal cortex and the nucleus accumbens (Franklin and Druhan, 2000;Neisewander et al, 2000). Such observations may underlie the implication of those structures in the development of incentive motivation towards COC and other drugs of abuse.…”