br Application of D receptor
Application of D1-receptor PET in psychiatric disorders
Discussion Compared to other markers of the DA system, only a limited number of studies have investigated D1-R in psychiatric disorders. In schizophrenia, which is the most studied condition with a total of 83 identified unique patients, results have been somewhat discrepant. Although studies were not designed to specifically investigate the effect of antipsychotic medication, the data strongly suggests that antipsychotic drugs cause a decrease in D1-R, an observation which is in line with non-human experimental data [73,74]. When taking this confounder into account, the overall evidence is arguably in favour of higher levels of D1-R in frontal cortical regions in patients suffering from psychosis symptoms. Differences in quantification methods and small sample sizes limit the conclusions that can be drawn, but if replicated, the results may indicate a specific role of D1-R in psychosis, alternatively they may reflect an upregulation in response to a reduction in cortical DA release [86,87]. For affective disorders, a lower striatal D1-R levels is suggested in depression, as well as reductions in cortical D1-R in bipolar patients. However, the total sample size for these conditions is considerably smaller than for schizophrenia and the results should be viewed as preliminary. Similarly, the higher D1-R levels shown in frontal 360A for chronic ketamine users is in need for replication. A number of factors have to be considered when interpreting the data. With existing PET radioligands, it is not possible to obtain a fully unbiased measure of cortical D1-R. 5HT2a-R receptor binding may account for around 25% of the cortical binding for both [11C]SCH 23390 and [11C]NCC 112 [23,52], which reflects that 5HT2a-R shows about two-fold density compared to D1 in cortical regions in nonhuman primates  and has shown to be abundant also in human cortex . 5HT2a-R has shown to be implicated in both schizophrenia and depression based on genetic associations and gene expression data [, , ], and both established and more recently developed antipsychotics show an affinity for 5HT2a [93,94]. In schizophrenia, the follow-up study by Okubo et al. showed trend-level lower 5HT2 binding as measured using PET and [11C]NMSP in neuroleptic-treated patients, which could have contributed to the observed decreases in [11C]SCH 23390 binding, whereas no difference was found in drug-naïve patients [64,63]. Subsequently, lower binding of the 5HT2-R radioligand [18F]altanserin was shown in a sample of 30 drug-naïve patients compared to control subjects . Hence, it cannot be excluded that differences in 5HT2a-R density may have influenced the results for cortical regions in schizophrenia. In contrast, striatal 5HT2a-R density is 2–3 fold lower than striatal D1-R [40,96] and blocking of 5HT2a-R did not affect binding of either [11C]SCH 23390 or [11C]NCC 112 in striatal regions , confirming that the influence of 5HT2a-R in this region should be negligible. For D2/D3-R antagonist radioligands such as [11C]raclopride, sensitivity of binding to endogenous DA levels is well-documented [97,98]. For D1-R radioligands, ex vivo studies in rodents have shown no effect on [11C]SCH 23390 binding by amphetamine-induced DA release or DA depletion  whereas other studies found an increase in [11C]NNC 112 binding, and a paradoxical decrease of [11C]SCH 23390 binding in response to DA depletion [100,101]. In non-human primate in vivo studies neither [11C]SCH 23390 nor [11C]NNC 112 binding was shown to be affected by acute increases or decreases in endogenous DA caused by amphetamine and reserpine respectively [102,103]. Similar results of no change in response to amphetamine was observed for [11C]NNC 756 in baboons . Dopamine depletion in human subjects using alpha-methyl-para-tyrosine did not change [11C]SCH 23390 binding, despite a clear increase in D2/D3-R binding as measured using [11C]raclopride . For the D2/D3-R, agonist radioligands have shown increased sensitivity to endogenous DA levels compared to antagonist radioligands . One potential explanation is that D2/D3-R may exist in an active (G-protein-coupled state) and an inactive state, and that agonist radioligands only bind to the active state resulting in a larger degree of displacement by endogenous ligands. With regard to the D1-R, the agonist radioligand [11C]N-methyl-NNC 01–0259 failed to show any differences in response to amphetamine-induced DA release . Taken together, the available evidence does not support endogenous DA as a confounding factor in D1-R PET studies. Possible explanations for this lack of sensitivity to endogenous DA is the lower affinity for DA , a large degree of extra-synaptic receptor location [106,107] or that only a small fraction of dopamine D1-like receptors exist in the high-affinity state .