COMPARISON OF [F-18]FALLYPRIDE AND [F-18]FPMB AS HIGH AFFINITY PET RADIOTRACERS FOR DOPAMINE D-2 RECEPTORS
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Mukherjee, J; Das, M K; Yang, Z-Y; Yasillo, N J; Kronmal, S; Brown, T; Cooper, M Author InformationVentral tegmental area (VTA) dopaminergic neurons, which are well known for their central roles in reward and motivation-related behaviors, have been shown to participate in itch processing via their projection to the nucleus accumbens (NAc). However, the functional roles of different dopamine receptor subtypes in subregions of the NAc during itch processing remain unknown. With pharmacological approaches, we found that the blockade of dopamine D1 receptors (D1R), but not dopamine D2 receptors (D2R), in the lateral shell (LaSh) of the NAc impaired pruritogen-induced scratching behavior in male mice. In contrast, pharmacological activation of D2R in both the LaSh and medial shell (MeSh) of the NAc attenuated the scratching behavior induced by pruritogens. Consistently, we found that dopamine release, as detected by a dopamine sensor, was elevated in the LaSh rather than the MeSh of the NAc at the onset of scratching behavior. Furthermore, the elevation of dopamine release in the LaSh of the NAc persisted even though itch-relieving behavior was blocked, suggesting that the dopamine signal in the NAc LaSh represents a motivational component of itch processing. Our study revealed different dynamics of dopamine release that target neurons expressing two dopamine receptors subtypes within different subregions of the NAc, and emphasized that D1R in the LaSh of the NAc is important in itch signal processing. SIGNIFICANCE STATEMENT Dopamine has been implicated in itch signal processing. However, the mechanism underlying the functional role of dopamine in itch processing remains largely unknown. Here, we examined the role of dopamine D1 receptor (D1R) and D2R in the nucleus accumbens (NAc) shell during pruritogen-induced scratching behavior. We demonstrated that D1R in the NAc lateral shell (LaSh) play an important role in motivating itch-induced scratching behavior, while activation of D2R would terminate scratching behavior. Our study revealed the diverse functional roles of dopamine signals in the NAc shell during itch processing.
Scratching
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This review depicts characteristics of nuclear neuroimaging investigations of dopamine release in response to non-pharmacological stimuli. Investigations of dopamine release in response to pharmacological challenges have focused mainly on the striatum, a region with a relatively high density of dopamine D2/D3 receptors. Non-pharmacological stimuli likely elicit dopamine release in extrastriatal regions with a relatively low density of dopamine D2/D3 receptors. Several strategies will facilitate the optimal design of investigations of dopamine release in response to non-pharmacological stimuli. (1) Employ radioligands with relatively high affinities for dopamine D2/D3 receptors in extrastriatal regions, including [11C] FLB457 and [11C] fallypride. (2) Correct images for head movement during the scanning procedure. (3) Develop protocols to incorporate the influences of regional blood flow on scans of dopamine D2/D3 receptors in the striatum and in extrastriatal regions. (4) Recruit healthy adults aged 18 to 35 years to avoid the effects of ageing. (5) Identify the phase of the menstrual cycle for women to account for the normal alterations in dopamine release in the various hormonal stages. Utilization of novel techniques to quantitate the dopamine release in the appropriate extrastriatal regions will likely result in fruitful advances in knowledge about non-pharmacological alternative interventions including acupuncture, the external Qi of Yan Xin Qigong, and other therapies of traditional Chinese medicine. Neuroimaging investigations of dopamine release following these alternative treatments will likely facilitate the appropriate application of alternative treatments to a vast spectrum of nervous and mental diseases. Since the effects of dopamine release on drug and non-drug interventions are powerful tools to assess the pathophysiology and the treatment of neuropsychiatric disorders, we provide this review of the literature to guide future research. Keywords: Alternative interventions, dopamine release, nuclear neuroimaging, positron emission tomography study, menstrual cycle, radioligands, receptor affinity, Living Human Brain, non-pharmacological, Neuroimaging, Positron emission tomography
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In vitro studies on an intact gastroduodenal preparation of the guinea-pig indicated that dopamine inhibited motor activity via a direct action on the gastrointestinal wall. Dopamine-induced relaxations were prevented by dopamine antagonists, which also exerted intrinsic stimulatory effects and improved gastroduodenal coordination. These effects were confirmed in vivo on conscious dogs. The results cannot be explained by an interaction with alpha- receptors, since alpha-adrenergic blocking concentrations of prazosin were inactive against dopamine, and dopamine-blocking concentrations of domperidone did not interfere with noradrenaline-induced relaxations. Pharmacological evidence confirmed the presence of dopamine receptors in the stomach of conscious dogs. The presence of specific dopamine receptors in the gastrointestinal tract is strongly indicated, and an important role for endogenous dopamine as an inhibitory neuromodulator of gastroduodenal motility is suggested.
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Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis- flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose- dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis- flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis- flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)
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We examined D2-dopamine receptor containing neurons in cultures of neonatal rat striatum for apoptosis following dopamine treatment. Exposure to cultures to micromolar concentrations of dopamine resulted in 60-70% killing of D2-dopamine receptor neurons within 24 hr. We also utilized a double labeling procedure to determine that treatment with dopamine induced apoptosis in D2-dopamine receptor containing neurons. These results suggest that loss of D2-dopamine receptor containing neurons during aging could be due to an apoptotic effect of dopamine.
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