The hypothalamo-pituitary-adrenal (HPA) axis is involved in all aspects of
cocaine self-administration.
Corticosterone seems to be crucial for the acquisition of
drug use since
self-administration does not occur unless this stress
hormone is increased above a critical reward threshold. Increasing circulating levels of
corticosterone also augments sensitivity to low doses of
cocaine, possibly from a sensitization-associated phenomenon involving
dopamine, suggesting that exposure to stress can increase individual vulnerability to
cocaine. Drugs affecting the synthesis and/or secretion of
corticosterone decrease ongoing, low-dose
cocaine self-administration. When higher doses falling on the descending limb of the
cocaine dose-response curve are self-administered, plasma
corticosterone can still reach this reward threshold even when synthesis is inhibited and
drug intake is not affected.
Corticotropin-releasing hormone (CRH) seems to play a more prominent role in the maintenance of
cocaine self-administration and may even be involved in the incentive motivation for the
drug.
Corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished
cocaine-seeking behavior. Therefore,
cocaine self-administration may represent an attempt to seek out specific sensations, with the internal state produced being very similar to that perceived by individuals who engage in risky, thrill-seeking behavior. During abstinence, exposure to stressors or
cocaine-associated cues can stimulate the HPA axis to remind the individual about the effects of
cocaine, thus producing craving and promoting relapse. Stress reduction, either alone or in combination with
pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for
cocaine addiction.