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Abstract: Though there is evidence that sustained exposure of dopamine (DA) receptors to agonists can elicit a supersensitivity of adenylyl cyclase (AC), little is known about the pharmacological characteristics of this phenomenon, and possible interrelationships amongst DA receptor subtypes have not been examined. In cells co-transfected with D1 plus D2, or D1 plus D3, receptors, which are known to physically and functionally interact, long-term exposure to quinpirole, pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicited supersensitivity of D1 receptor-activated AC. By contrast, D2/D3 receptor agonists that also act as D1 receptor agonists, bromocriptine, lisuride, cabergoline, apomorphine and DA itself, did not elicit supersensitivity. Interestingly, AC supersensitivity was also observed in the nucleus accumbens of mice pretreated with twice-daily pramipexole and quinpirole, whereas no change was seen either with lisuride or with the DA precursor, l-DOPA. Thus, AC supersensitivity is elicited by the sustained exposure of cloned human and native mouse populations of dopaminergic receptors, to D2/D3 but not D1/D2/D3 agonists. These observations may be related to the exacerbation of gambling in Parkinson’s disease that is provoked by antiparkinson agents acting as selective D2/D3 receptor agonists, notably pramipexole. [ABSTRACT FROM AUTHOR]

• LED light at 610 nm negatively impacts the survival of dopamine neurons in culture. • 610 nm LED light damages mouse mesencephalic and hiPSC-derived dopamine neurons. • Elevated dopamine in differentiated MN9D cells increases vulnerability to light. • 610 nm LED light increases ROS production in differentiated MN9D cells. • MN9D co-treatment with H2O2 boosts light induced ROS production and cytotoxicity. Our recent study revealed that fluorescent lamp light can penetrate deep into the brain of mice and rats leading to the development of typical histological characteristics associated with Parkinson's disease such as the loss of dopamine neurons in the substantia nigra. Monochromatic LED lights were thus used in this work to deepen our knowledge on the effects of the major wavelength peaks of fluorescent light on mouse and human dopaminergic cells. In particular, we exposed immortalized dopaminergic MN9D neuronal cells, primary cultures of mouse mesencephalic dopaminergic cells and human dopaminergic neurons differentiated from induced pluripotent stem cells (hiPSC) to different LED light wavelengths. We found that chronic exposure to LED light reduced overall undifferentiated MN9D cell number, with the most significant effects observed at wavelengths of 485 nm and 610 nm. Moreover, LED light especially at 610 nm was able to negatively impact on the survival of mouse mesencephalic dopaminergic cells and of human dopaminergic neurons derived from hiPSC. Notably, differentiated MN9D dopaminergic cells, which closely resemble mature dopamine neuronal phenotype, acutely exposed for 3 h at 610 nm, showed a clear increase in ROS production and cytotoxicity compared to controls undifferentiated MN9D cells. These increases were even more pronounced by the co-treatment with the oxidative agent H 2 O 2. Collectively, these findings suggest that specific wavelengths, particularly those capable of penetrating deep into the brain, could potentially pose an environmental hazard in relation to Parkinson's disease. [ABSTRACT FROM AUTHOR]

• Artificial light could indirectly damage dopamine neurons blunting the circadian rhythms of melatonin secretion. • Artificial light could directly damage dopamine neuron by photoactivating biological relevant molecules. • Light can modify the firing rate of dopamine neurons by activating opsins expressed in the substantia nigra. • Excessive artificial light could be an adjunctive environmental risk factor for Parkinson's disease. Growing awareness of adverse impacts of artificial light on human health has led to recognize light pollution as a significant global environmental issue. Despite, a large number of studies in rodent and monkey models of Parkinson's disease have reported that near infrared light has neuroprotective effects on dopaminergic neurons, recent findings have shown that prolonged exposure of rodents and birds to fluorescent artificial light results in an increase of neuromelanin granules in substantia nigra and loss of dopaminergic neurons. The observed detrimental effect seems to be dependent on a direct effect of light on the substantia nigra rather than a secondary effect of the alterations of circadian rhythms. Moreover, inferences from animal models to human studies have shown a positive correlation between the prevalence of Parkinson's disease and light pollution. The present article discusses experimental evidence supporting a potentially deleterious impact of light on dopaminergic neurons and highlights the mechanisms whereby light might damage neuronal tissue. Moreover, it analyses epidemiological evidence that suggests light pollution to be an environmental risk factor for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abstract: G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR (“heterodimers”). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D1/D5 and D2/D3/D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D1 and adenosine A1 receptors; D2 or D3 and adenosine A2 receptors; and D2 and somatostatin SST5 receptors. Further, D1,D2 and D3 receptors physically assemble into functional D1/D2,D1/D3 and D2/D3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D3/D2 and D3/D1 heterodimers, including observations that some antiparkinsonian agents – such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole –show amplified potency at D3/D2 heterodimers versus constituent monomers, and others in contrast, such as the D3/D2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D3 and D1 receptors, long-term exposure to pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicits supersensitivity of D1 receptor-activated adenylyl cyclase, and conversely, D3/D2 receptor agonists such as apomorphine and bromocriptine (which also act as D1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson''s disease by antiparkinsonian agents is discussed. [Copyright &y& Elsevier]

Recently, employing radioligand displacement and functional coupling studies, we demonstrated that SB269,652 (N-[(1r,4r)−4-[2-(7-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]−1H-indole-2-carboxamide) interacts in an atypical manner with dopamine D 3 receptor displaying a unique profile reminiscent of a negative allosteric ligand. Here, we characterized the binding of radiolabelled [ 3 H]SB269,652 to human dopamine D 3 receptor stably expressed in Chinese Hamster Ovary cells. Under saturating conditions, SB269,652 showed a KD value of ≈ 1 nM. Consistent with high selectivity for human dopamine D 3 receptor, [ 3 H]SB269,652 binding was undetectable in cells expressing human dopamine D 1 , D 2L or D 4 receptors and absent in synaptosomes from dopamine D 3 receptor knockout vs . wild-type mice. In contrast to saturation binding experiments, the dissociation kinetics of [ 3 H]SB269,652 from human dopamine D 3 receptors initiated with an excess of unlabelled ligand were best fitted by a bi-exponential binding model. Supporting the kinetic data, competition experiments with haloperidol, S33084 (a dopamine D 3 receptor antagonist) or dopamine, were best described by a two-site model. In co-transfection experiments binding of SB269,652 to dopamine D 3 receptor was able to influence the functional coupling of dopamine D 2 receptor, supporting the notion that SB269,652 is a negative allosteric modulator across receptor dimers. However, because SB269,652 decreases the rate of [ 3 H]nemonapride dissociation, the present data suggest that SB269,652 behaves as a bitopic antagonist at unoccupied dopamine D 3 receptor, binding simultaneously to both orthosteric and allosteric sites, and as a pure negative allosteric modulator when receptors are occupied and it can solely bind to the allosteric site. [ABSTRACT FROM AUTHOR]

We investigated the effects of continuous artificial light exposure on the mouse substantia nigra (SN). A three month exposure of C57Bl/6J mice to white fluorescent light induced a 30% reduction in dopamine (DA) neurons in SN compared to controls, accompanied by a decrease of DA and its metabolites in the striatum. After six months of exposure, neurodegeneration progressed slightly, but the level of DA returned to the basal level, while the metabolites increased with respect to the control. Three month exposure to near infrared LED light (∼710 nm) did not alter DA neurons in SN, nor did it decrease DA and its metabolites in the striatum. Furthermore mesencephalic cell viability, as tested by [ 3 H]DA uptake, did not change. Finally, we observed that 710 nm LED light, locally conveyed in the rat SN, could modulate the firing activity of extracellular-recorded DA neurons. These data suggest that light can be detrimental or beneficial to DA neurons in SN, depending on the source and wavelength. [ABSTRACT FROM AUTHOR]

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D 3 versus D 2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD 3 and hD 2L receptors, (+)PHNO revealed high affinity at hD 4.4 but not hD 1 or hD 5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT 1A and h5-HT 7. (+)PHNO behaved as a full agonist at hD 4.4 and h5-HT 1A receptors with potencies comparable to its actions at hD 3 and hD 2L receptors, and with less potency at 5-HT 7 receptors. In binding assays with membranes derived from cells co-expressing hD 3 and hD 2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD 3 or hD 2L receptors, suggesting that (+)PHNO promotes formation of hD 3 -hD 2L heterodimers. Further, in cells co-expressing hD 3 and hD 2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD 2L receptors. In conclusion, (+)PHNO is a potent agonist at hD 4. 4 , h5-HT 1A and h5-HT 7 as well as hD 3 and hD 2L receptors, and it potently activates dopamine hD 3 -hD 2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders. [ABSTRACT FROM AUTHOR]