INCREASED DENSITY OF GUANINE-NUCLEOTIDE - BINDING-PROTEINS IN THE POSTMORTEM BRAINS OF HEROIN-ADDICTS

Objective: To directly evaluate the guanine nucleotide-binding (G) pro tein subunits alpha, beta, and gamma, which are involved in the signal transduction of opioid receptors, in the postmortem brains of heroin addicts who had died of an opiate overdose. Methods: Specimens of the frontal cortex (Brodmann's area 9) were collected from 11 heroin addic ts and 10 control subjects without a history of drug abuse. The bioche mical status of human brain G protein subunits during opiate dependenc e was studied by means of immunoblotting techniques. Solubilized G pro teins were separated by gel electrophoresis, transferred to pyroxylin membranes (western blotting) labeled with specific antiserum samples, and quantitated by image analysis after enhanced chemoluminescence. Re sults: In the frontal cortex, relevant increases in the immunoreactivi ties of G alpha i(1/2) (19% +/- 4%, P<.005), G alpha o (29% +/- 7%, P< .005), and G alpha s (26% +/- 5%, P<.005) but not of G alpha i(3) were found in heroin addicts compared with age- and sex-matched controls. Moreover, the amount of G protein beta-subunit immunoreactivity was al so consistently increased (27% +/- 8%, P<.01) compared with controls i n the same brain region. These G protein changes in the brains of huma n opiate addicts paralleled (with the exception of G alpha s) those ob tained in the brains of morphine hydrochloride-dependent rats. The inc rease in G alpha s immunoreactivity that was observed in the rat brain only after the short-term morphine administration (24% +/- 3%, P<.005 ) suggests that the increase in G alpha s immunoreactivity in the brai ns of human addicts could be the cellular response to a deadly overdos e of heroin. Conclusions: Alterations in the density of specific Gi an d Go protein subunits that are coupled to mu-opioid and other opioid r eceptors may be of clinical relevance in opiate tolerance, dependence, and abstinence syndrome.