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

Abstract

Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [(11)C]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 amphetamine 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 volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative.

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

“…The lack of effect of the challenges on the nonspecific binding indicated that the change in V 3 00 was exclusively due to change in receptors availability to [ 11 C]raclopride binding. The data set also documented the (Laruelle et al, 1997;Villemagne et al, 1999). The effect of methamphetamine on [ 11 C]raclopride in vivo binding is also significantly blunted in patients with Parkinson's disease (Piccini et al, 2003).…”

Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

“…Imaging studies have corroborated the ability of oral MP to induce significant levels of DAT blockade in the striatum, with an estimated ED50 (dose required to block 50% of the DAT) of 0.25 mg/kg (Volkow et al, 1999a). Imaging studies have also shown that MP and AMP, at clinically relevant doses, can significantly increase extracellular DA (Villemagne et al, 1999;Volkow et al, 1999bVolkow et al, , 2009a. Imaging studies in non-human primates have also shown significant blockade of the NE transporter at doses that are pharmacologically equivalent to those used in humans, which is interesting in light of the data indicating that enhanced extracellular catecholamine levels in cortical regions, secondary to NE reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys (Seu et al, 2009).…”

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

“…DA releasers, such as amphetamine or methamphetamine, also bind to DAT and they enhance neurotransmitter release by reversing DA transport (Elliott and Beveridge, 2005;Sulzer et al, 2005). It has been shown that DA uptake blockers can also block reverse transport, thereby antagonizing the increase in extracellular DA induced by a DA releaser (Zetterstrom et al, 1988;Hurd and Ungerstedt, 1989;Villemagne et al, 1999;Baumann et al, 2002). Furthermore, DA uptake blockers and DA releasers exert differential effects on vesicular monoamine transporter-2 (VMAT-2) function, which seems to depend on a redistribution of VMAT-2 to different cellular compartments, and it has been suggested that the neurotoxic effects of amphetamines are related to their effects on VMAT-2 trafficking (Sandoval et al, 2003;Hanson et al, 2004).…”