dopaminergic

Previous studies have suggested that caffeine reduces the risk of L-DOPA-induced dyskinesia. However, caffeine is also known to promote dopamine signaling, which seemingly contradicts this observed effect. To this end, the study aimed to clarify the mechanism of caffeine neuroprotection when excess dopamine is present. Transgenic (UA57) overproducing dopamine was exposed to caffeine for 7 days and monitored by observing GFP-tagged dopaminergic (DA) neurons via fluorescence microscopy. Caffeine (10 mM) prevented neuronal cell loss in 96% of DA neurons, with a mean GFP intensity that is 40% higher than control (0.1% DMSO). To confirm if cAMP plays a role in the observed neuroprotection by caffeine, cAMP levels were elevated via forskolin (10 μM), an adenylyl cyclase activator. Forskolin (10 μM) exposure did not confer neuroprotection and was similar to control (0.1% DMSO) at the 7th day, suggesting that cAMP is not the sole secondary messenger utilized. Rotigotine (160 μM), a dopamine...

Parkinson's disease is a complex disorder characterized by degeneration of dopaminergic neurons in the substantia nigra in the brain. Stem cell transplantation is aimed at replacing dopaminergic neurons because the most successful drug therapies affect these neurons and their synaptic targets. We show here that neural progenitors can be grown from the olfactory organ of humans, including those with Parkinson's disease. These neural progenitors proliferated and generated dopaminergic cells in vitro. They also generated dopaminergic cells when transplanted into the brain and reduced the behavioral asymmetry induced by ablation of the dopaminergic neurons in the rat model of Parkinson's disease. Our results indicate that Parkinson's patients could provide their own source of neuronal progenitors for cell transplantation therapies and for direct investigation of the biology and treatments of Parkinson's disease.Disclosure of potential conflicts of interest is fo...

The one-pot N-demethylation and acid-catalyzed rearrangement of morphinan-N-oxides offers a new, shorter and more efficient route to neuropharmacologically important N-substituted aporphines. An improved procedure is described for the preparation of the starting alkaloid N-oxides using Na2WO4 as catalyst. The transetherification during the rearrangement of codeinone into 2-O-alkyl-norapocodeines is documented.

ABSTRACT A series of 2-amino-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes were synthesized and tested for affinity for dopaminergic and α-adrenergic receptor subtypes via radioligand binding assays. The unsubstituted analogue 2a showed weak affinity for both D1 and α2-adrenoceptors. This compound exhibited subtype selectivity in both dopaminergic and α adrenergic systems. Analogue 5 showed affinity only for the D1-receptor. Most other analogues showed no affinity for either receptor at concentrations up to 10 μM. Functional studies showed compound 2a to be an α-adrenoceptor antagonist, and confirmed its α2-adrenoceptor selectivity predicted by the radioligand binding assay.

Catecholamine absorbing proteins (CATNAPs) are localized in the brain and thus far have no known biochemical and pharmacological characteristics consistent with other receptor proteins or metabolic enzymes in the central nervous system. The oxidative metabolism of catecholamines in the brain, especially the catabolism of dopamine and its conjugation with metabolic brain proteins, results in the production of highly toxic free radicals. Since such processes are implicated in the pathophysiology of various neurodegenerative diseases, including parkinsonism, and since CATNAPs bind catecholamines with high affinity, there is a need to further investigate if these novel proteins could play a protective role against these harmful catecholamine metabolites. In this study, we demonstrate the purification, pharmacological characterization and modulation of CATNAPs, as the first steps necessary to elucidate the function of these proteins in the brain. First, CATNAPs were identified from tissues using [3H]N-n-propylnorapomorphine (a specific dopamine receptor agonist) and [125I]6-hydroxy-5-iodo[N(N-2,4-dinitro-phenyl)- aminopropyl]1,2,3,4-tetrahydronaphthalene ([125I]DATN; a highly specific ligand synthesized in our laboratory). Three proteins, with molecular masses of 47, 40 and 26 kDa, were identified and purified, which allowed for the subsequent production of antibodies against each of these CATNAPs. The effects of in vivo chronic administration of several dopaminergic agents on CATNAPs were also examined by Western immunoblotting. L-3,4-Dihydroxyphenylalanine (L-DOPA) treatment in rats resulted in the increase of all of the three proteins, as compared to controls. Treatment in rats with the dopamine depleting agent, reserpine, produced a significant decrease in all of the three CATNAPs. In addition, the effects of direct administration of apomorphine, dopamine, epinephrine, isopropylnorepinephrine, norepinephrine, N-n-propylnorapomorphine and 6-hydroxydopamine on CATNAP levels in rats were examined. Interestingly, we observed an increase (as compared to control) of the 47, 40 and 26 kDa proteins in animals treated with dopamine, norepinephrine, N-n-propylnorapomorphine and apomorphine. In contrast, animals treated with 6-hydroxydopamine showed significant decreases in the levels of all three proteins. It is evident that as the concentration of catecholamines increases, there is a corresponding increase in the levels of CATNAPs in the brain. These results clearly demonstrate the pharmacological modulation of CATNAPs by dopaminergic agents and suggest their possible role in the cytoprotection against damage caused by free radicals generated by oxidative stress.

The differences in dopamine turnover rate between the putamen and the caudate nucleus in the striatum lesioned by a neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in the common marmoset, a small New World monkey. Systemic administration of MPTP damaged equally and dose-dependently nigrostriatal dopaminergic neurons projecting both to the caudate nucleus and the putamen. The compensatory increase of dopamine turnover, however, occurred more prominently in the putamen than in the caudate. The neural connection and function of the caudate nucleus and the putamen have been differentiated anatomically or physiologically. The compensatory increase of dopamine turnover rate is another different aspect of functions between the caudate nucleus and the putamen. Dopaminergic neurons projecting to the putamen showed more prominent cell loss than those projecting to the caudate in Parkinson's disease or related disorders. The selective augmented turnover rate of lesioned dopaminergic neurons might be, at least partly, involved with selective degeneration of nigrostriatal neurons projecting to the putamen.

It has recently been revealed that spatial neglect can be modulated by motivational factors including anticipated monetary reward. A number of dopaminergic agents have been evaluated as treatments for neglect, but the results have been mixed, with no clear anatomical or cognitive predictors of dopaminergic responsiveness. Given that the effects of incentive motivation are mediated by dopaminergic pathways that are variably damaged in stroke, we tested the hypothesis that the modulatory influences of reward and dopaminergic drugs on neglect are themselves related. We employed a single-dose, double-blind, crossover design to compare the effects of Co-careldopa and placebo on a modified visual cancellation task in patients with neglect secondary to right hemisphere stroke. Whilst confirming that reward improved visual search in this group, we showed that dopaminergic stimulation only enhances visual search in the absence of reward. When patients were divided into REWARD-RESPONDERs and ...

We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.

In order to investigate factors affecting adrenal maturation leading to adrenarche, the effect of dopaminergic blockade on the morphology and function of the adrenal reticularis zone was studied in fourteen preadrenarchal dogs. Seven animals of 7 weeks of age (adrenarche at 11 weeks) were treated with domperidone (DOM) 3 times/day p.o. (3 mg/kg) at 09.00 h, 14.00 h, and 21.00 h, plus an additional injection of DOM s.c. (0.6 mg/kg) at 21.00 h for 15 days. Seven control animals received diluent. Twelve hours after the last injection, dogs received 0.25 mg ACTH i.m. and were sacrificed 60 min later. Blood was collected and adrenals removed. After histological evaluation, the percent of the reticularis, fasciculata, and glomerulosa zones with respect to the total cortex was calculated. Plasma androstenedione (A), dehydroepiandrosterone (DHA), 17-OH-progesterone (17P), and cortisol (F) levels in response to ACTH were also assessed. DOM-treated dogs show a significant development of the zona reticularis compared to control animals (19.2 +/- 0.6% vs 8.8 +/- 2.09% respectively, X +/- SE, P less than 0.01). In the same animals, the DHA response to ACTH (9.0 +/- 1.6 ng/dl) was significantly higher than in placebo-treated dogs (3.8 +/- 1.1 ng/dl, P less than 0.05) while no significant differences were found in F, A, and 17P levels between the two groups. Finally the post-ACTH A/DHA ratio of DOM-treated dogs (1.33 +/- 0.28) was significantly decreased in respect to the placebo-treated animals (5.49 +/- 2.54, P less than 0.01). These data demonstrate that the morphological and functional development of zona reticularis may be subject to dopaminergic control and this could represent an important step in the initiation of adrenarche. However, the cellular mechanism responsible remains to be clarified.

There is evidence that the dopaminergic system is involved in probabilistic reinforcement learning and reward-related decision-making. However, little is known about the effects of external dopaminergic challenges on processing of uncertainty in decision-making tasks. Therefore, the present study examined changes in fMRI activation patterns in a natural sampling paradigm. Decision making under uncertainty was examined before and after administration of a single dose of 40 mg methylphenidate as an acute dopaminergic pharmacological challenge. We found that the level of uncertainty was positively correlated with activations in the prefrontal cortex. Conversely, negative correlations with uncertainty were found in the left hippocampus, right amygdale, and right middle temporal gyrus. The drug intervention with methylphenidate revealed a differential picture. Uncertain information processing was associated with higher activation in the parietal association cortex and posterior cingulate cortex after placebo relative to methylphenidate. The methylphenidate challenge relative to placebo was associated with higher left and right parahippocampal as well as cerebellar activation under uncertainty. Apparently, the pro-dopaminergic pharmacological influence induces a relative shift towards recruitment of hippocampal areas under uncertainty, whereas under placebo conditions, higher levels of parietal cortex activations are involved in the task. The findings suggest a role of dopamine in uncertainty processing and shed light on the pharmacological mechanisms of methylphenidate.

Background Perivascular macrophages and microglia are critical to CNS function. Drugs of abuse increase extracellular dopamine in the CNS, exposing these cells to elevated levels of dopamine. In rodent macrophages and human T-cells, dopamine was shown to modulate cellular functions through activation of dopamine receptors and other dopaminergic proteins. The expression of these proteins and the effects of dopamine on human macrophage functions had not been studied. Methods To study dopaminergic gene expression, qRT-PCR was performed on mRNA from primary human monocyte derived macrophages (MDM). Expression and localization of dopaminergic proteins was examined by immunoblotting isolated plasma membrane, total membrane and cytosolic proteins from MDM. To characterize dopamine-mediated changes in cytokine production in basal and inflammatory conditions, macrophages were treated with different concentrations of dopamine in the presence or absence of LPS and cytokine production was assay...

Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease.

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social, and behavioral development. SSD is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples-Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families)-and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (p = 1.43x10(-4) ), showed the strongest associations with pho...

Substituted 1,3dioxolane and dioxane, the structures close to analgesics, anesthetics, dopaminergic.
  Dioxane and dioxolane can be physiologically active. Interesting is the search for such examples, which are not among the natural substances and pharmacological substances.
In this example, opens up a huge spectrum for research. My job is to try to write dioxane in pharmacology analgesics, anesthetics and dopaminergic. 1,3dioxolan and dioxane convenient for the synthesis and planning of catabolites. Research results from these substances can present as surprises, and the original settings and properties.
The figure shows the structure of dioxane and dioxolane analgesic, anesthetic and dopaminergic nature:

Synthetic terpenes as a universal  gabaergic, dopaminergic and light cannabinoids. 
  In contrast terpene-glutaminergic, GABA activating terpenes are not represented in nature. Glutaminergic terpenes have a more destructive effect on the Central nervous system, however, included in the composition of the essential oil of wormwood and spices of saffron - stigmas of Crocus sativus. 
Strukture of GABA and glutamic acid are close, and it would be logical to fix to try to replace glutamic features active terpenes on the GABA radicals. At least to get away from the glutamic activity, or even to replace it with GABA activity. What was done on the example of the five-membered derivative of the aglycone picrocrocin (Krokus sativus). Also given the possible recreational potential, was an attempt to make cannabinoid accents, and thus to  probably implementing triple structure recreational activity. Design of multifunctional structures allows to obtain recreational substances with a unique qualities and minimal negative qualities.
In the event the success of the approach and implementation. Like many natural multifunctional substances, such structures can have a future as a legal pharmacological and recreational drugs.
Examples of some derivatives of terpenes:
Синтетические терпены как универсальные ГАМК энергетик, допаминергик и легкие каннабиноиды.
В отличие от терпенов глутаминергической активности, ГАМК активирующие терпены не представлены в природе. Глутаминергические терпены имеют несколько разрушительное влияние на центральную нервную систему, тем не менее входят в состав эфирного масла горькой полыни и приправы шафрана из рылец крокуса шафранного.
Природа ГАМК и глутаминовой кислоты близка, и логичной была бы попытка заменить глутаминовые черты активных терпенов на ГАМК радикалы. Как минимум уйти от глутаминовой активности, или даже заменить её на ГАМК активность. Что и было сделано на примере пятичленного производного агликона пикрокроцина (крокус посевной). Также учитывая возможный рекреационный потенциал, были внесены и каннабиноидные акценты, таким образом чтобы получить структуры вероятно c тройным  рекреационным действием. Дизайн многофункциональных структур позволяет получать рекреационные вещества с уникальными показателями и минимальными негативными качествами.
При успешности подхода и реализации, подобно многим природным многофункциональным веществам, такие структуры могут иметь будущее как легальные фармакологические и рекреационные препараты.
Примеры некоторых производных терпенов:

Apart from stroke, epilepsy is the most common neurological disorder with 0.5% of prevalence. The present study was performed in order to determine the monoamine levels, (M(1)-like) muscarinic and (D(1)- and D(2)-like) dopaminergic receptor changes in frontal cortex of adult rats after pilocarpine-induced status epilepticus (SE). Male Wistar rats were treated with a single dose of pilocarpine (400 mg/kg, s.c.) and the control group received 0.9% saline (s.c.). Both groups were sacrificed 1 h after treatment. The frontal cortex was dissected for neurochemical assays. The results show a downregulation of 27% in M(1) muscarinic receptor density, but in the dissociation constant (K(d)) value remained unaltered. D(1) and D(2) dopaminergic receptor densities and their K(d) values remained unaltered. Monoamine and metabolites levels presented decreases of 44%, 27%, 30% and 42% in dopamine (DA), homovanilic acid (HVA), norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) contents, respectively. Moreover, in serotonin (5-HT) level remained unaltered and the 4-hydroxy-3-methoxy-phenylacetic acid (DOPAC) concentration was augmented by 34%. The results suggest that dopaminergic system in this area studied may not be directly involved in the seizures and status epilepticus, but different monoamines and metabolites can be modified in this cerebral area during seizure process. In conclusion, the neurochemical alterations that occur in frontal cortex of adult rats observed during the establishment of the status epilepticus induced by pilocarpine are decrease in M(1) receptor density concentration and a reduction in DA and NE levels.