Corticosterone levels and stress-induced reinstatement

One possible explanation for attenuation of stress-induced reinstatement of Fix-C
CPP is that pre-treatment with MK-801, 7-NI or antalarmin may have suppressed HPA
activity and thereby prevented activation of the stress response. This explanation is
unlikely since we found that none of the abovementioned pharmacological modulators
attenuated swim-induced increases in corticosterone levels indicating an activation of the
HPA axis comparable to vehicle-treated animals (Fig. 4.6). The fact that antalarmin did
not block corticosterone increase is somewhat surprising considering CRH activation is
upstream of glucocorticoid release. However, conflicting lines of evidence have shown
that acute administration of antalarmin both blocks (Kreibich et al., 2009) and has no
effect (Deak et al., 1999) on plasma corticosterone levels following exposure to stressful
stimuli. The discrepancy between our work and that of Kreibich and colleagues (2009)
may result from a) differences in mouse strain used based on innate variations in response
to stress and b) plasma corticosterone assay kits which may have inherent procedural
variations for detecting corticosterone levels. Taken together, although MK-801, 7-NI
and antalarmin had no effect on HPA axis hormones they still attenuated stress-induced
reinstatement of Fix-C CPP suggesting a greater influence of these pharmacological
modulators at extrahypothalamic brain targets. Indeed, it has been shown that the activity
of CRH at extrahypothalamic targets, but not on the HPA axis, mediate stress-induced
relapse in rats (Erb et al., 1998).
In summary, we show that the pattern of cocaine administration during
conditioning engages different signaling molecules that differentially contribute to stressinduced
reinstatement of place preference. Stress-induced reinstatement of Fix-C CPP is
NMDAR-NO-CRH-R1-dependent while stress-induced reinstatement of Esc-C CPP is
likely dependent on other signaling molecules. Since drug addiction is associated with
escalation in drug use, future studies should be aimed at identifying an effective
pharmacotherapeutic that attenuates stress-induced reinstatement of Esc-C CPP as this
will be of valuable utility for the management of relapse. The behavioral differences
between Fix-C and Esc-C CPP in response to pharmacological manipulations may be
relevant to a) the severity of addiction and b) the inconsistencies in treatment outcomes in
human drug-users.

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