Addictions are chronic relapsing brain diseases, with behavioral manifestations. Three main factors contribute to the development
of an addiction: environment, including stress, the reinforcing effects of the drug, and genetics. In this review we will discuss the
involvement of the dysregulation of the stress responsive hypothalamic-pituitary-adrenal (HPA) axis in the acquisition of, and persistence
to drug addiction (Section B). Addictions to specific drugs such as cocaine/psychostimulants, alcohol, and mu-opioid receptor agonists
(e.g., heroin) have some common direct or downstream effects, including modulation of dopaminergic systems. Through its action on the
dopaminergic signaling pathways, cocaine affects the HPA axis, and brain nuclei responsible for movements, and rewarding effects. Several
neurobiological systems have been implicated with cocaine addiction, including dopamine, serotonin and glutamate systems, opioid
receptor and opioid neuropeptide gene systems, stress-responsive systems including CRF, vasopressin and orexin. The use of animal
models (Sections C and D) has been essential for studying the individual vulnerabilities to the effects of drugs of abuse and the neural
pathways and neurotransmitters affected by these drugs. Basic clinical research has revealed important relationship between cocaine use,
HPA axis responsiveness, and gender (Section E). Finally, we will discuss gene polymorphisms that are associated with drug use (Section
Results from animal models and basic clinical research have shown important interactions between the dopaminergic and the opioid systems.
Hence, compounds modulating the opioid system may be beneficial in treating cocaine addiction.