GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [C-11]raclopride continuous infusion PET scans

Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exch ange mechanism. Preclinical research supports the hypothesis that elevation s of mesolimbic DA mediate the addictive and reinforcing effects of methamp hetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high a ffinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine- induced increases in mesolimbic DA, The present study determined the abilit y of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [C-11]raclopride continuous infusion positron emission tomograp hy (PET) scans in two Papio anubis baboons. [C-11]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs . time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamin e i.v, bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V-3") The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the vol ume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiment s suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the D A hypothesis is correct, a potential treatment agent for cocaine and metham phetamine abuse, Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR1290 9 such as a decanoate derivative. Synapse 33:268-273, 1999. (C) 1999 Wiley- Liss, Inc.