This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. al., 1989a; Ross et al., 1989b; Seeman et al., 1989). Indications that this sensitivity could also be observed using positron emission tomography (PET) technology rapidly followed, when increased displacement of the D2/3 tracer (18F)-N-methylspiroperidol was observed following administration of the anticholinergic benztropine to baboons (Dewey et al., 1990). This finding was subsequently confirmed by applying the same technique to investigate amphetamine-induced DA release (Dewey et al., 1991). Landmark investigations in humans followed swiftly afterwards; data showing decreases in binding of the D2/3 receptor PET radiotracer [11C]raclopride in response to administration of amphetamine were published in 1992 (Farde et al., 1992) and similar results were subsequently obtained following administration of the DA re-uptake inhibitor methylphenidate (Volkow et al., 1994). The ability of D2/3 receptor radiotracers to index DA release is commonly described by the classical occupancy model; D2/3 receptor radiotracers compete with DA for receptor binding, thus a decrease in radiotracer binding potential (BP) is interpreted as an increase in DA release (see (Laruelle 2000a)). The amount of radiotracer present in a particular brain region of interest (ROI) can be detected using PET and SPET. The Engeletin supplier specific binding of the radiotracer to receptors is then inferred through careful modeling of radiotracer kinetics. These techniques, used in combination with administration of pharmacological compounds that target non-dopaminergic neurotransmitter systems, have allowed examination of the neuropharmacology of DA release in the Engeletin supplier human brain (Breier et al., 1998; Brody et al., 2004; Dewey et al., 1993; Vollenweider et al., 1999), Engeletin supplier and studies employing pharmacological challenges which release DA (e.g. amphetamine), reveal much about the neurochemistry of many brain disorders (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996; Laruelle et al., 1999; Piccini et al., 2003; Rosa et al., 2002; Singer et al., 2002; Volkow et al., 1997; Volkow et al., 2007). However, the ability to study DA release produced by ethologically-relevant, non-pharmacological stimuli is of greater functional relevance in terms of investigating the dopaminergic basis of human behavior and its role in disease mechanisms. The possibility that D2/3 radiotracer PET techniques might prove sensitive enough to measure the relatively smaller changes in DA release expected following non-pharmacological interventions was first proposed Engeletin supplier in 1995 following detailed review of dopaminergic neurophysiology and integration of these parameters into simulations (Fischer et al., 1995; Morris et al., 1995). Encouraged by the positive results of these simulations, we performed our initial study of DA release during videogame playing and Kv2.1 (phospho-Ser805) antibody observed significant decreases in [11C]raclopride BP (Koepp et al., 1998). Since the publication of our original finding (Koepp et al., 1998), there have been a large number of studies in this field, employing a Engeletin supplier number of different approaches, and there is no clear consensus as to the best method. The aim of this paper is to systematically review the molecular imaging studies of DA release in man and to critically appraise the methodological approaches used. In addition, we re-analyze our original data to evaluate and illustrate the degree to which certain methodological factors may alter findings. We conclude by reviewing the findings of molecular imaging studies of non-pharmacologically-evoked changes in DA release in man, and summarize what these studies have told us about the role of DA in aspects of human behavior. As studies in experimental animals have since significantly increased our understanding of dopaminergic neurophysiology, we begin this review by describing components of this system relevant to measuring non-pharmacologically-induced changes in DA release using D2/3 receptor radiotracers and PET methodology. We then present the findings of our.