It has been reported that IFNalpha is able to modulate a number of central nervous system (CNS) functions and related behaviors, in particular those related to morphine withdrawal in rats. IFNalpha has also been reported to cause antinociception when administered intracerebrally, cause excitation of neurons in culture and directly effects the activity of temperature and glucose sensitive neurons. Some of the effects of IFNalpha are reversible by naloxone, an opioid antagonist. Interferon alpha (IFNalpha), when used therapeutically as an antiviral or anticancer agent causes a variety of neurologic and psychiatric side effects. In human clinical trials IFNalpha has been reported to elicit behavioral patterns and psychiatric complications similar to those observed in AIDS related dementia (HIV-1 associated cognitive/motor complex). Symptoms include depression, paranoia, suicidal tendencies, etc. In the case of IFNalpha therapeutic use, the symptoms disappear when treatment is discontinued. The possible cause of AIDS dementia by inappropriate modulation of CNS immune system products or receptors is further suggested by the following: (1) an unusual acid labile form of IFN is observed in high levels in AIDS patients, (2) there may be regions of structural homology between IFNalpha and HIV protein, pl7, and (3) although the ability of leukocytes to produce IFNalpha decreases with severity of HIV-1 symptoms, IFNalpha in serum is elevated in early and mid stages of HIV-1 progression. Both IFNalpha and gamma activate the tryptophan degradation pathway which produces the neurotoxin, quinolinic acid. The principle cells involved in producing quinolinic acid, the glia, are sensitive to opioids and have opioid receptors. Thus, it is possible that the action of IFNalpha in these dementias may be mediated through receptors sensitive to certain opioids. Data from rat brain membrane binding studies by our laboratory and others are consistent with the hypothesis that some of the CNS effects of IFNalpha directly involve opioid receptors. This project is aimed at systematically (1) characterizing the binding of IFNalpha to rat brain membranes, and (2) the effect of opioid ligands on IFNalpha binding to rat brain membranes. Membrane binding studies using nonlabelled opioid ligands to inhibit radiolabelled IFNalpha binding or, conversely, using IFNalpha to inhibit receptor class specific opioid radioligand binding, will identify the receptor class of IFNalpha interactions. These studies will be done in vitro using membrane fractions from rat brain, incubations with labelled ligands, e.g., 3H-opioid ligands or 125I-labelled IFNalpha, and scintillation counting. From these studies it will be possible to determine the degree of specificity of IFNalpha-opioid receptor interactions to allow design of studies to further explore the biological relevance of these interactions.
