Neuronal adaptations, neuroendocrine and immune correlates of heroin self-administration.
Opioid receptor-mediated action in the central nervous system (CNS) has been consistently shown to trigger changes in the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) and suppress a variety of parameters of immune function in investigator-delivered paradigms. Overwhelming evidence supports the concept that the CNS undergoes numerous and complex neuronal adaptive changes in addicts, and in animal models of heroin addiction as a result of the training of drug stimuli to serve as reinforcers, altering the function of individual neurons and the larger neural circuits within which the neurons operate. Taken together, these advances suggest that since plastic neuronal changes occur in drug addiction and related animal model paradigms, profiles of neuroendocrine and immune function would differ in a rat model of heroin self-administration compared to passive infusion of drug. Self-administration of heroin induces neuronal circuitry adaptations in specific brain regions that may be related to alterations in neuroendocrine and T lymphocyte function also observed. Animals self-administering (SA) heroin exhibit increased mu-opioid receptor agonist ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO))-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding in the anterior hypothalamus (50% and 33%) and rostral medial thalamus (33% and 36%) compared with control animals receiving identical non-contingent injections of yoked-heroin (YH) or yoked-saline (YS), respectively. No changes in agonist-stimulated G-protein sensitization were observed in 14 other brain regions studied. No changes in mu-opioid receptor density, ((3)H-DAMGO binding) were seen in all brain regions examined. The neuronal changes in SA animals were correlated with elevated adrenocorticotrophic hormone (ACTH) (64% and 104%) and glucocorticoid production (198% and 79%) compared with YH and YS groups, respectively. Neuroendocrine adaptive changes in SA animals were associated with thymic hypoplasia. Splenic T lymphocytes from animals that had self-administered heroin showed a profoundly reduced ability to proliferate in response to concanavalin A (50% and 48% compared with YH and YS controls, respectively; Fig. 1A), or a monoclonal antibody (R73) to the CD3/T-cell receptor complex (anti-TCR) plus IL-2 (55% and 59% compared with YH and YS controls, respectively; Fig. 1B). Self-administration of heroin selectively alters T lymphocyte function, as no effects on natural killer cell activity or macrophage functions were observed. These findings may have relevance to the acquisition and documented increased incidence of infectious diseases, including HIV, in heroin addicts, due to a pre-existing T-cell immunodeficient state.
Weber
R J
RJ
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA. rick@uic.edu
Gomez-Flores
R
R
Smith
J E
JE
Martin
T J
TJ
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003602:Cytotoxicity, Immunologic; D003932:Heroin / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D011916:Rats, Inbred F344; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012646:Self Administration; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D017450:Receptors, Opioid, mu; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003932:Heroin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone