According to their effects on postsynaptic levels of cyclic adenosine monophosphate (cAMP), dopamine receptors are grouped into two families, the D₁ receptor family (dopamine D₁ and D₅ receptors) and the D₂ receptor family (dopamine D₂, D₃ and D₄ receptors). As the main target of antipsychotic medication, dopamine D_2/3 receptors have been of particular interest for imaging studies in schizophrenia. Moreover, D_2/3 receptor imaging techniques have successfully been used to demonstrate alterations in brain dopamine transmission in addictive disorders (Volkow et al. 2009; Urban and Martinez 2012). While current evidence speaks against a relevant alteration in the quantity of D_2/3 receptors that are accessible to PET imaging in schizophrenia (Howes et al. 2012), several studies have shown a reduction of D_2/3 binding in addictive disorders (Volkow et al. 2009; Urban and Martinez 2012).

There are several studies on the influence of genetic variation on D_2/3 receptor binding in the literature (Table 6.4; for review, see Willeit and Praschak-Rieder 2010). To our knowledge, the only replicated finding as of yet is a reduction in binding of the D_2/3 radioligand [¹¹C]raclopride in carriers of the Taq1 A1 allele as compared to A2 homozygotes (Pohjalainen et al. 1998; Jonsson et al. 1999). However, a study of this polymorphism with SPECT and the radioligand [¹²³]IBZM did not show differences between the genotypic groups (Laruelle et al. 1998). Other polymorphisms in the D2 receptor gene showed in part significant effects but still warrant replication (Table 6.3). A recent study investigated a possible association between polymorphisms in the Period2 (PER2) gene and dopamine D_2/3 receptor binding as measured using [¹¹C]raclopride and PET (Shumay et al. 2012a). PER2 is part of the clock-gene family and involved in the reaction of organisms to circadian and circannual changes in lighting conditions and day length. Dopamine transmission shows circadian and seasonal changes in rodents and humans (Castaneda et al. 2004; Tsai et al. 2011; Eisenberg et al. 2010). The authors report on a newly identified VNTR polymorphism in the human PER2 gene that was associated with cocaine craving and striatal dopamine D_2/3 receptor binding. This finding is so far very exciting as it brings together several research strings on the physiology of dopamine function and its implication in addiction (see also Praschak-Rieder and Willeit 2012 for further discussion).

Another frequently studied target is the dopamine transporter (DAT), a member of the monoamine-transporter family that transports dopamine back into the presynaptic neuron immediately after its release into the extracellular space. DAT is the main target of therapeutic drugs, for example, methylphenidate, used to treat attention-deficit hyperactivity disorder (ADHD) or the antidepressant bupropion. DAT is also the main site of action of drugs of abuse such as cocaine or amphetamines. Radiolabelled DAT blockers such as [¹¹C]methylphenidate or [¹¹C]cocaine have successfully been used to quantify DAT availability in the human brain.

Several polymorphisms within the DAT gene or in its promoter region have been identified and studied for association with psychiatric disorders, and there is extensive literature on imaging the effects of some of these polymorphisms on DAT binding in the human brain (Willeit and Praschak-Rieder 2010). The most frequently imaged polymorphism is a 40-bp (base pair) VNTR (variable number of tandem repeats) polymorphism in the 3′ untranslated region of exon 15 of the DAT gene SLC6A3 (Vandenbergh et al. 1992, 2000). These studies included healthy subjects as well as patients with alcohol dependence, schizophrenia, ADHD and Parkinson’s disease (Heinz et al. 2000a; Jacobsen et al. 2000; Martinez et al. 2001; Lynch et al. 2003; Cheon et al. 2005; van Dyck et al. 2005; Krause et al. 2006; Lafuente et al. 2007; van de Giessen et al. 2009; Table 6.4). A recent methodologically sound meta-analysis (Costa et al. 2011) provides no evidence to support the hypothesis that the DAT 40-bp VNTR is significantly associated with interindividual differences in DAT availability in the striatum. A SPECT study investigating a cluster of polymorphisms flanking a recently described splice variant in the DAT gene (Talkowski et al. 2010) did not show significant differences in [¹²³I]-β-CIT binding (van de Giessen et al. 2012). In summary, the results of these studies give no clear picture on the effects of the DAT 40-bp VNTR polymorphism. However, the number of studies is relatively small, and there is significant heterogeneity between the studies.

Radiolabelled dopamine precursors able to cross the blood-brain barrier (e.g. [¹⁸F]dihydroxyphenylalanine, [¹⁸F]DOPA) are converted into the DAT substrate [¹⁸F]dopamine in dopaminergic neurons. The striatal [¹⁸F]DOPA influx constant Ki reflects presynaptic dopamine uptake, synthesis and storage capacity and is regarded as a good proxy for presynaptic dopamine metabolism in the brain (Cumming 2009). Together with so-called ‘competition’ paradigms, a research technique that allows for measuring the inhibition of radioligand binding at D_2/3 receptors by endogenous dopamine, [¹⁸F]DOPA studies have now clearly shown that presynaptic dopamine synthesis capacity (Reith et al. 1994; Hietala et al. 1995, 1999; Lindstrom et al. 1999; Meyer-Lindenberg et al. 2002; McGowan et al. 2004; Kumakura et al. 2007; Bose et al. 2008; Nozaki et al. 2009), baseline synaptic dopamine levels (Abi-Dargham et al. 2000, 2009; Kegeles et al. 2010) and pharmacologically induced dopamine release (Laruelle et al. 1996; Breier et al. 1997; Abi-Dargham et al. 1998, 2009) are increased in schizophrenia (for review, see Howes et al. 2012).

Imaging measures of the hyper-dopaminergic state in schizophrenia can as well be conceptualized as an endophenotype of the disorder. Indeed, there are a number of studies on the genetic background of in vivo imaging measures of presynaptic dopamine function (Table 6.5). These studies investigated the influence of polymorphisms in the DAT gene (Martinez et al. 2001; Brody et al. 2006), in D₂ and D₃ receptor-related genes (Brody et al. 2006; Pecina et al. 2012; Savitz et al. 2013), in the gene coding for oxytocin (Love et al. 2012) and in the μ-opioid receptor gene (Domino et al. 2010) on DAT function. In these studies, dopamine release was induced either by administration of d-amphetamine, by nicotine from cigarettes or by behavioural stimuli such as stress and pain. All of the above-mentioned studies describe an association with reductions in D_2/3 radioligand binding (as an indirect measure for dopamine release) and the respective candidate genes. Although there emerges no consistent picture due to the variety of polymorphisms and the different methods used, all of these studies were able to show that results of ‘competition studies’ are in part driven by genetic variation. Some of the information collected in these studies might thus be used for refining future studies in patients with schizophrenia. Perhaps even more important, these studies were able to show that several neurochemical pathways are involved in regulating dopamine release in the living human brain. Regulatory mechanisms include feedback regulation in dopamine terminal fields (see, e.g. Savitz et al. 2013, brain opioid systems (Domino et al. 2010) and the neuropeptide oxytocin (Love et al. 2012)).

Catechol-O-methyltransferase (COMT) is an enzyme that catalyzes degradation of catecholamines (including epinephrine, norepinephrine and dopamine) in the periphery and the brain. While regulation of extracellular dopamine levels is heavily dependent on DAT function in subcortical brain areas, COMT is believed to be a key mechanism regulating dopamine activity in cortical, especially frontal cortical brain areas (Ciliax et al. 1999; Lewis et al. 2001; Matsumoto et al. 2003).

Several SNPs have been described in the COMT gene, but without doubt, the SNP causing a valine-to-methionine substitution at position 158 (COMT Val158Met) is one of the most studied polymorphisms in psychiatry and a series of other disorders. The COMT 158Val variant degrades dopamine more efficiently than the COMT 158Met variant (Lachman et al. 1996), and the polymorphism has been associated with several psychiatric and other disorders. A finding that seems to hold true is a difference in executive function mediated mainly by prefrontal cortex dopamine between carriers of the gene variants. Thus, several studies have investigated behavioural, cognitive, functional and anatomical variance associated with this gene as an endophenotype in various disorders (see, e.g. Schosser et al. 2011; Witte and Floel 2011; Ira et al. 2013).

Two studies investigated the effects of COMT Val158Met using [¹⁸F]DOPA and PET. A study (Meyer-Lindenberg et al. 2005) in healthy volunteers found increased striatal [¹⁸F]DOPA uptake in 158Val carriers when compared to 158Met homozygotes. Another study in patients with early Parkinson’s disease (Wu et al. 2012) describes higher [¹⁸F]DOPA uptake measured between 150 and 210 min after radioligand injection in 158Met homozygous patients. Besides differences between study samples (young healthy volunteers versus patients with Parkinson’s disease), the difference might be due to the fact that higher [¹⁸F]DOPA in 158VMet homozygous patients with Parkinson’s disease was measured from 150 min after tracer injection onwards. At this time, the [¹⁸F]DOPA signal is believed to reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid (Ruottinen et al. 2001; Ceravolo et al. 2002).

A study in healthy volunteers investigated the effects of COMT Val158Met on dopamine D_2/3 receptor binding using PET and the radioligands [¹¹C]raclopride and [¹¹C]FLB457 for assessing striatal and cortical D_2/3 binding, respectively. Since genotype had no effect on binding of either radioligand, the authors concluded that baseline in vivo D_2/3 receptor availability does not differ between COMT Val158Met genotypic groups. In contrast, another study using the dopamine D₁ receptor radioligand [¹¹C]NNC112 (Slifstein et al. 2008) found significantly higher cortical D₁ receptor binding in Val158 homozygotes, while no difference was found in striatum. This finding is in good agreement with the functional role of COMT Val158Met, as low dopamine levels have been found to cause upregulation of dopamine D₁ receptors in the rodent brain, while dopamine transmission in the basal ganglia is less affected due to the prominent role of DAT in these brain areas (Gogos et al. 1998; Guo et al. 2003). A recent study investigating the effects of the COMT Val158Met polymorphism on brain 5-HT_1A receptor binding found significantly higher [¹¹C]WAY100635 binding in Val158 homozygotes in orbitofrontal cortex, cingulum, insula and amygdale (Baldinger et al. 2013). Peak differences were found in the posterior cingulate cortex.