Not all stress is equal: CREB is not necessary for restraint stress reinstatement of cocaine-conditioned reward

Abstract

Stress elicits relapse to cocaine seeking in humans and in animal models. Cyclic AMP response element binding protein (CREB) is required for swim stress-induced reinstatement of cocaine conditioned place preference. However, the role of CREB in other stress-induced reinstatement models has not been examined. To determine whether CREB is required across different stressors we examined the ability of restraint to elicit reinstatement of cocaine-conditioned place preference in wild-type and CREBαΔ mutant mice. In contrast to previously published differences in swim stress-induced reinstatement, both wild-type and CREBαΔ mutant mice demonstrated restraint stress elicited reinstatement of cocaine-conditioned reward. While CREB is necessary for swim stress-elicited zif268 expression within the nucleus accubmens (NAc) shell and prelimbic cortex (PrL), restraint-stress-elicited comparable increases in zif268 expression within these regions in both wild-type and CREBαΔ mutant mice. Our findings suggest that not all stressors engage the same circuits or molecular mechanisms to elicit reinstatement behavior.

Figure 1. Reinstatement of cocaine conditioned reward following restraint stress

Both wildtype and mutant mice paired with cocaine showed a significant place preference to the cocaine-paired side on test day. CREBαΔ mutant mice exhibited a higher preference than wildtype animals. Following extinction training this preference was no longer present in either group. On reinstatement test day, a 15-minute restraint stress elicited a significant preference for the drug-paired side in cocaine-treated mice regardless of genotype. *Indicates significant differences from saline controls; #Indicates differences between wildtype and CREBαΔ mice.

Figure 2. Zif268 immunoreactivity following restraint stress

Example photomicrographs demonstrating that wildtype mice exhibit an increase in zif268 expression within the NAc shell (a, b, d), prelimbic cortex (f, g, i), and infralimbic cortex (k, l, n) following both restraint and forced swim stress. While, CREBαΔ mutant mice show equal levels of expression following restraint (c, h, m), they exhibit lower levels of expression within the NAc shell (e) and prelimbic cortex (j) following swim stress.

Figure 3. CREB mutant mice exhibit decreased zif268 protein expression in response to swim stress but not to restraint stress

Wildtype and CREBαΔ mutant mice mice exhibit an increase in zif268 protein following restraint stress in the prelimbic (a; PrL), infralimbic (b; IL), Nucleus accumbens (NAc) shell (c) and core (d), lateral septum (e; LS) and the central amygdala (f; CeA). In contrast, while wildtype mice exhibit a swim stress-induced (FST) increase in zif268 in all the regions mentioned above, CREBαΔ mutant mice do not exhibit increases within the PrL and the NAc shell. *Indicates significant differences from non-stressed (NS) controls; #Indicates differences between wildtype and CREBαΔ mice.