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.

Fig. 1.

Effect of extinction training on cocaine-seeking behavior. Cocaine-seeking behavior is illustrated as nonreinforced lever presses (±SEM) during the first 90 min on extinction training days and on the test day. *p < 0.05, represents a difference from other groups tested; Fisher's LSD test. +p < 0.05, represents a difference from the cocaine–extinction group tested on day 1; t test.

Fig. 2.

Effect of saline and cocaine priming injections on reinstatement of cocaine-seeking behavior in animals tested in all three phases. Cocaine-seeking behavior is illustrated as nonreinforced lever presses (±SEM) across 30 min intervals. *p< 0.05, represents a difference from all other groups; Fisher's LSD test. +p < 0.05, represents a difference from controls; Fisher's LSD test. †p < 0.05, represents a difference from previous 30 min interval; ANOVA main effect.

Fig. 3.

Schematic representation of regions analyzed.Numbers at the top left of each section represent the distance (in millimeters) from bregma.Numbers in the sections represent the regions (area in square millimeters) analyzed as follows: 1, dorsal caudate putamen, 0.135; 2, anterior cingulate, 0.135;3, NAc core, 0.135; 4, NAc shell, 0.1;5, ventral pallidum, 0.09; 6, lateral septal nucleus, 0.09; 7, motor cortex, 0.125;8, lateral amygdala, 0.09; 9, central amygdala, 0.134; 10, basolateral amygdala, 0.134;11, cortical amygdala, 0.09; 12, medial amygdala, 0.09; 13, lateral hypothalamus, 0.09; 14, arcuate nucleus, 0.05; 15, dentate gyrus, 0.1;16, central gray area, 0.07; 17, hippocampal CA3 region, 0.1; 18, hippocampal CA1 region,19, entorhinal cortex, 0.125; 20, ventral subiculum, 0.1; 21, substantia nigra pars compacta, 0.6;22, substantia nigra pars reticulata, 0.07;23, VTA, 0.07. Drawings were adapted from the Paxinos and Watson atlas (1986).

Fig. 4.

Fos-positive nuclei/0.1 mm²(±SEM) in brain regions that exhibited enhanced Fos protein expression by the priming injections. The data are collapsed across conditioning groups. *p < 0.05, represents a difference from the respective group receiving exposure to the environment only; Fisher's LSD test. Cpu, Caudate putamen;EC, entorhinal cortex; CeA, central amygdala; LA, lateral amygdala; Arc, arcuate nucleus; CG, central gray area.

Fig. 5.

Fos-positive nuclei/0.1 mm²(±SEM) in the substantia nigra pars reticulata demonstrating enhanced Fos protein expression in rats with a history of cocaine self-administration. The data are collapsed across groups receiving exposure to the environment versus the environment and priming injections. *p < 0.05, represents a difference from controls; Fisher's LSD test.

Fig. 6.

Fos-positive nuclei/0.1 mm²(±SEM) in brain regions that exhibited a pattern of changes consistent with conditioned Fos protein expression by the self-administration environment. The data are collapsed across groups receiving exposure to the environment versus the environment and priming injections, except in the central gray area, which illustrates the groups receiving exposure to the environment only. *p < 0.05, represents a difference from all other groups; Fisher's LSD test.

Fig. 7.

Fos-positive nuclei/0.1 mm²(±SEM) in the anterior cingulate. *p < 0.05, represents a significant difference from other groups shown; Fisher's LSD test.