GABAergic mechanisms of heroin-induced brain activation assessed with functional MRI.
Heroin has been hypothesized to activate opiate receptors and inhibit gamma-aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells. Since the distal sites and consequences of this disinhibition are not well understood on a systems level, heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A significant blood oxygen level-dependent (BOLD) signal increase was seen in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex following acute heroin administration. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that the heroin-induced negative and positive BOLD changes are due to direct inhibitory and indirect disinhibitory mechanisms of GABAergic activities. Administration of GVG altered these mechanisms and further suggested that involvement of the opiate's pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release.
Xi
Zheng-Xiong
ZX
Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Wu
Gaohong
G
Stein
Elliot A
EA
Li
Shi-Jiang
SJ
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003932:Heroin / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000187:drug effects*
D000701:Analgesics, Opioid; D005680:gamma-Aminobutyric Acid; D003932:Heroin