32 Increased radiotracer uptake was observed following drugs that reduce DA availability, such as reserpine33 or γ-vinyl-γ-aminobutyric acid (γ-vinyl-GABA).34 These interactions were also reported in humans: decreased specific binding of [11C]raclopride or [123I]iodobenzamide [123I]IBZM) was reported following acute administration of the DA-enhancing drugs methylphenidate,35,36 amphetamine,37,38 cocaine,39 and even cognitive challenges.40 Conversely, increased
[123I]IBZM BP was documented following DA depletion with the reversible tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (α-MPT).41 The www.selleckchem.com/products/Erlotinib-Hydrochloride.html amphetamine-induced reduction Inhibitors,research,lifescience,medical in [123-I]IBZM or [11C]raclopride BP to D2 receptors has been well validated as an indirect measure of the change in synaptic DA concentration induced by the challenge. The first step was to establish that the amphetamine-induced reduction in radiotracer BP was mediated by DA release, and not by some indirect effect, of amphetamine unrelated to DA Inhibitors,research,lifescience,medical release. The mediation of the amphetamine effect, by DA release was demonstrated by establishing that pretreatment with the tyrosine hydroxylase inhibitor α-MPT blocked the effect of amphetamine on [123I]IBZM BP.14 More recently, Villemagne et al42 showed that pretreatment with the dopamine transport (DAT)
blocker GBR 12909 (a drug that, prevents amphetamine-induced DA release) Inhibitors,research,lifescience,medical blocked the effect of amphetamine on [11C]raclopride BP. The second step was to study the relationship between the magnitude of DA release and the reduction in radiotracer BP, to assess the potential of the imaging measurement to provide a quantitative measure of DA release. This comparison was accomplished in primates by comparing amphetamine-induced DA release measured with microdialysis Inhibitors,research,lifescience,medical and reduction
of radiotracer binding measured with PET or SPECT following various doses of amphetamine.14,38 These studies Inhibitors,research,lifescience,medical demonstrated that, the reduction in radiotracer BP was linearly Tipifarnib mechanism correlated with the peak DA release measured with microdialysis. This observation validated the use of this noninvasive paradigm to measure changes in synaptic DA following amphetamine, and provided an operational calibration of the imaging signal. We also evaluated the reproducibility of the SPECT measurement of the amphetamine effect on D2 receptor BP. We observed an excellent reproducibility of the measurement, both in baboons, where the intraclass correlation coefficient (ICC) was 0.97,14 and in humans, where Batimastat the ICC was 0.89.43 Together, these results supported the feasibility of measuring amphetamine-induced DA release in humans with this noninvasive technique. Imaging amphetamine-induced DA release in schizophrenia We and others adopted this imaging technique to measure amphetamine-induced DA release in patients with schizophrenia and matched healthy controls.38,44-46 Our final sample consisted of 34 patients with schizophrenia and 36 matched healthy controls.