In vitro characterisation of the high affinity D2/D3 dopamine agonist (+)PhNO

Parker, Christine A.; Clarke, Kirsten; Gee, Antony D.; Rabiner, Eugenii A.

doi:10.1016/j.neuroimage.2006.04.019

Cited by 9 publications

(8 citation statements)

References 4 publications

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“…However, Narendran et al [2006] [Malmberg et al, 1994;Seeman, 2001]; therefore, it is a radioligand for brain imaging with and equal preference for D 2 / D 3 . On the other hand, while Freedman et al [1994] and Parker et al [2006] found that (+)-PHNO has more than ten-fold higher affinity for D 3 than of D 2 , recent data by Seeman et al [2005a] ]. This possibility is also supported by studies done in rodents that show that […”

Section: Bp Maps Comparisonmentioning

confidence: 99%

Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Graff‐Guerrero¹,

Willeit²,

Ginovart³

et al. 2007

Human Brain Mapping

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The D(2) receptors exist in either the high- or low-affinity state with respect to agonists, and while agonists bind preferentially to the high-affinity state, antagonists do not distinguish between the two states. [(11)C]-(+)-PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]-(+)-PHNO and [(11)C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)-receptors. However, [(11)C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [(11)C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]-(+)-PHNO (1.8 vs. 3.3). Moreover [(11)C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]-(+)-PHNO in the globus pallidus and ventral-striatum could be the presence of a greater proportion of high- vs. low-affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D(3)-over-D(2) with [(11)C]-(+)-PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease.

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Section: Bp Maps Comparisonmentioning

confidence: 99%

Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Graff‐Guerrero¹,

Willeit²,

Ginovart³

et al. 2007

Human Brain Mapping

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“…Interestingly, an imaging study comparing DA increases using BP ND and 4-propyl-9-hydroxynaphthoxazine ([ 11 C]PHNO) (radiotracer with >20-fold higher affinity for D3 over D2 receptors, and presumably more sensitive to competition with endogenous DA) (63,64) in response to a stressor in individuals at high risk for schizophrenia showed that those who abused marijuana had a blunted response, consistent with decreased DA signaling (22). Because the study used cognitive stress as a challenge, it was not confounded by potential group differences in stimulant-induced changes in cerebellar radiotracer delivery.…”

Section: Mp-induced Changes In DVmentioning

confidence: 99%

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Volkow

Wang

Telang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

188

147

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Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [ 11 C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [ 11 C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BP ND )] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BP ND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.nucleus accumbens | amotivation | cannabinoid 1 receptors | brain imaging | midbrain D espite the high prevalence of marijuana consumption, the effects of marijuana abuse in the human brain are not well understood. Marijuana, like other drugs of abuse, stimulates brain dopamine (DA) signaling in the nucleus accumbens (1, 2), which is a mechanism believed to underlie the rewarding effects of drugs (3-5) and to trigger the neuroadaptations that result in addiction (reviewed in ref. 6). Indeed, in humans, imaging studies have shown that drugs of abuse increase DA release in striatum (including the nucleus accumbens), and these increases have been associated with the subjective experience of reward (7-9). However, for marijuana, the results have been inconsistent: One study reported striatal DA increases during intoxication (10); two studies showed no effects (11, 12); and one study reported DA increases in individuals with a psychotic disorder and in their relatives, but not in controls (13). Imaging studies of the brain DA system in marijuana abusers have also shown different findings from those reported for other types of substance abusers. Specifically, substance abusers (cocaine, methamphetamine, alcohol, heroin, and nicotine), but not marijuana abusers (14-16), show reduced baseline availability ...

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“…The selectivity of (1)-PHNO and raclopride at D2 vs. D3 has been discussed (Freeman et al, 1993;Graff-Guerrero et al, 2009a;Narendran et al, 2006;Parker et al, 2006;Rabiner et al, 2007;Seeman et al, 1993 andSokoloff et al, 1990). Raclopride does not show differentiation of D2 from D3 due to its similar binding affinities for those two receptors (Sokoloff et al, 1990).…”

Section: Agonist Radioligands In D2 Bindingmentioning

confidence: 99%

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [³H]‐MNPA, [³H]‐(+)‐PHNO, and [³H]‐raclopride

Teng

Zysk

Dorff

et al. 2010

Synapse

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Positron emission tomography (PET) antagonist ligands such as [(11)C]-raclopride are commonly used to study dopamine D2 receptor (D2) binding of antipsychotics. It has been suggested that agonist radioligands bind preferentially to the high-affinity state of D2 receptor and may provide a more relevant means of assessing D2 occupancy. The main objective of this study was to determine if D2 receptor occupancy (RO) could be differentiated with agonist and antagonist radioligands in vivo. Agonist radioligands [(3)H]-MNPA and [(3)H]-(+)-PHNO were synthesized and compared to antagonist [(3)H]-raclopride in the in vitro binding and in vivo occupancy studies. In vivo, unanesthetized rats were pretreated with quinpirole (full agonist), aripiprazole (partial agonist), or haloperidol (antagonist) prior to administration of the agonist or antagonist radioligand. All three pretreatment compounds showed equivalent dose-dependent D2 receptor occupancy in the rat striatum with each radioligand. The in vivo receptor occupancy results suggested that the binding of quinpirole, aripiprazole, and haloperidol to the high or low affinity state of the D2 receptor could not be differentiated using radiolabeled agonists or antagonists, presumably due to a predominance of high affinity states of the D2 receptor in vivo. This hypothesis was supported in part by the in vitro binding results. Our in vitro results show that [(3)H]-MNPA binds to D2S transfected CHO cell membranes at a single high affinity site. Displacement of [(3)H]-(+)-PHNO binding by quinpirole and elimination of most [(3)H]-(+)-PHNO binding by the guanine nucleotide GppNHp in striatal membranes suggest that the majority of D2 in striatal tissue is G-protein coupled. Together, these findings suggest that D2 agonist radioligands produce in vivo receptor occupancy comparable to [(3)H]-raclopride.

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In vitro characterisation of the high affinity D2/D3 dopamine agonist (+)PhNO

Cited by 9 publications

References 4 publications

Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [³H]‐MNPA, [³H]‐(+)‐PHNO, and [³H]‐raclopride

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In vitro characterisation of the high affinity D2/D3 dopamine agonist (+)PhNO

Cited by 9 publications

References 4 publications

Brain region binding of the D2/3 agonist [11C]‐(+)‐PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

Brain region binding of the D2/3 agonist [11C]‐(+)‐PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [3H]‐MNPA, [3H]‐(+)‐PHNO, and [3H]‐raclopride

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Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

D2 receptor occupancy in conscious rat brain is not significantly distinguished with [³H]‐MNPA, [³H]‐(+)‐PHNO, and [³H]‐raclopride