The primary regulators of ACTH secretion, and thus cortisol, are the CRF neurons in the paraventricular nucleus of the hypothalamus, and these neurons are under opioid inhibitory tone. This study observed that naloxone-induced cortisol secretion correlated with [11C]CFN BPND measured in hypothalamus as well as with several mesostriatal brain regions of healthy subjects. Higher [11C]CFN BPND was associated with lower cortisol responses to opioid receptor blockade. Higher [11C]CFN BPND indicates either decreased endogenous beta-endorphin occupancy or increased mu opioid receptor number/affinity compared to lower [11C]CFN BPND; the scanning technique cannot distinguish among these possibilities. However, the negative correlation makes the most sense if subjects with higher binding potential in this study have lower endogenous beta-endorphin occupancy and thus place less inhibitory tone on the HPA axis. Under this assumption there would be lower levels of cortisol induced by opioid blockade in subjects with high MOR BP (e.g., low opioid inhibitory tone) compared to subjects with low MOR BP (e.g., high opioid inhibitory tone).
We identified significant correlations between [11
and naloxone-induced cortisol responses not only in the hypothalamus but also with ventral and dorsal striatum. The correlation of cortisol with [11
in the ventral striatum is particularly important since opioids modulate dopaminergic transmission in the nucleus accumbens, and thus influence reinforcement/reward to both internal and external stimuli (Wise, 2008
). This system is crucial in understanding the neurobiology of alcohol dependence and other drug dependencies (Barson et al, 2010
). It may also be dysfunctional in eating disorders, gambling and other “impulse” disorders (Berridge et al, 2010
We have previously shown that cortisol response following mental stress as well as amphetamine administration correlates with mesolimbic dopamine release and positive hedonic responses to amphetamine (Wand et al, 2007
; Oswald et al, 2005
). Preclinical studies have shown that glucocorticoids can amplify the dopaminergic signal in the nucleus accumbens (Marinelli and Piazza, 2002
). The interaction of cortisol and the endogenous opioid system observed in this study may point to a mechanism whereby cortisol can alter mesolimbic dopamine release through individual differences in opioid activity induced by genetic and/or environmental determinants (Wand, 2008
When adjusted for sex and smoking status, there was a trend for a correlation of naloxone-induced cortisol AUC and [11
in the hippocampus. This structure is an important region modulating cortisol dynamics though positive and negative feedback loops (Herman et al, 2005
). Recent studies have also shown involvement of the opioidergic systems in both the dorsal and ventral hippocampus in modulating anxiety-like behaviors and stress (Solati et al, 2010
; Zarrindast et al, 2008
It is not clear why ACTH AUC was not associated with [11
since it is ACTH that stimulates cortisol release. One possible explanation is that cortisol negative feedback truncates the ACTH response to naloxone, and therefore a full ACTH response cannot be realized. This explanation is supported by the more rapid return of ACTH than cortisol to baseline level s (see ). Another possibility relates to the short half-life of ACTH in plasma. There may not have been frequent enough blood samplings to capture the true area under the ACTH curve. Failure of naloxone-induced cortisol to predict [11
in all brain regions indicates that the technique is useful for only a subset of brain regions. Future studies should better define the brain regions where this technique will be informative and also the mechanism that allows its predictive ability. It should also be mentioned that the naloxone challenge may only be useful for characterizing mu opioid receptor availability when it is executed as a cumulative dosing procedure (Mangold et al, 2000
) since cortisol responses to individual doses of naloxone did not consistently correlate with [11
across brain regions. This may be the result of the marked individual differences in the amount of naloxone needed to obtain peak cortisol response. Last, the most robust correlations were observed when adjusting for sex and smoking, two factors with known effects on the HPA axis.
In summary, cortisol responses obtained using our cumulative naloxone challenge procedure were associated with [11C]CFN BPND in healthy subjects in several important brain regions involved in alcohol and drug reward, substance use disorders and other psychiatric and impulse control disorders. Future studies will examine for additional utility of the technique by performing similar correlations in populations with neuropsychiatric disorders.