Central Dopaminergic Systems Research Articles

Efecto del compuesto N-2,6-dicloro-aralquil-2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas.

Dopamine 1 is involved in neurodegenerative disorders affect-ing the central nervous system (CNS), such as Parkinson’s disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane de-rivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson’s disease, the compound N-2,6-dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The phar-macological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo-typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.

Changes of Dopamine and Tyrosine Hydroxylase Levels in the Brain of Germ-free Mice.

Dopamine (DA) is one of the most important catecholamine neurotransmitters in the central nervous system. The degeneration and deletion of dopaminergic neurons are closely linked to Parkinson's disease (PD) and other psychiatric or neurological diseases. Several studies have been suggesting that intestinal microorganisms are associated with the occurrence of central nervous diseases, including diseases that are closely related to dopaminergic neurons. However, the intestinal microorganism's regulation of dopaminergic neurons in the brain is largely unknown. This study aimed to investigate the hypothetical differences of DA and its synthase tyrosine hydroxylase (TH) expression in different parts of the brain of germ free (GF) mice. Several studies in recent years have shown that commensal intestinal microbiota promotes changes in DA receptor expression, DA levels, and affects this monoamine turnover. Germ free (GF) and specific pathogen free (SPF) C57b/L male mice were used to analyze TH mRNA and expression levels, and DA levels in the frontal cortex, hippocampus, striatum, and cerebellum, using real time PCR, western blotting, and ELISA tools. Compared with SPF mice, the TH mRNA levels were decreased in the cerebellum of GF mice, while the TH protein expression was tended to increase in the hippocampus, and conversely showed significant decrease in the striatum. The average optical density (AOD) of TH immunoreactive nerve fibers and the number of axons in striatum of mice in GF group were significantly lower than that in SPF group. Compared with SPF mice, the DA concentration in the hippocampus, striatum and frontal cortex of GF mice was decreased in GF mice. The changes of DA and its synthase TH in the brain of GF mice showed that the absence of conventional intestinal microbiota had certain regulatory effects on central dopaminergic nervous system, which is considered helpful for studying the effect of commensal intestinal flora on diseases related to impaired dopaminergic nerve system.

Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L.

Psychotropic effect of Crocus sativus L. (family Iridaceae) biologically active chemical compounds are quite well documented and they can therefore be used in addition to the conventional pharmacological treatment of depression. This systematic review on antidepressant compounds in saffron crocus and their mechanisms of action and side effects is based on publications released between 1995−2022 and data indexed in 15 databases under the following search terms: antidepressant effect, central nervous system, Crocus sativus, cognitive impairement, crocin, crocetin, depression, dopamine, dopaminergic and serotonergic systems, picrocrocin, phytotherapy, neurotransmitters, safranal, saffron, serotonin, and biologically active compounds. The comparative analysis of the publications was based on 414 original research papers. The investigated literature indicates the effectiveness and safety of aqueous and alcoholic extracts and biologically active chemical compounds (alkaloids, anthocyanins, carotenoids, flavonoid, phenolic, saponins, and terpenoids) isolated from various organs (corms, leaves, flower petal, and stigmas) in adjuvant treatment of depression and anxiety. Monoamine reuptake inhibition, N-methyl-d-aspartate (NMDA) receptor antagonism, and gamma-aminobutyric acid (GABA)-α agonism are the main proposed mechanism of the antidepressant action. The antidepressant and neuroprotective effect of extract components is associated with their anti-inflammatory and antioxidant activity. The mechanism of their action, interactions with conventional drugs and other herbal preparations and the safety of use are not fully understood; therefore, further detailed research in this field is necessary. The presented results regarding the application of C. sativus in phytotherapy are promising in terms of the use of herbal preparations to support the treatment of depression. This is particularly important given the steady increase in the incidence of this disease worldwide and social effects.

Effect of chronic stress on the relative level of dopamine receptor gene expression

Background. The regulation of the central dopaminergic system under the influence of chronic stress is disturbed, however, the dynamics of changes in the dopamine receptors expression in the periphery remains poorly understood.
 Aim. Evaluation of the different models of chronic stress influence on changes in the relative level of dopamine receptor gene expression in peripheral blood cells of rats during immobilization and intense physical activity.
 Material and methods. For 270 days on 88 Wistar rats, the study on the effect of different models of chronic stress on the change in the relative level of Drd15 genes expression was performed in four groups: the first control group; the second group was subjected to intensive physical activity in the Forced swimming with a load test (7-minute swimming with a load of 8% of body weight 2 times a week); the third group experienced daily 90-minute immobilization for 14 days; the fourth group had combined exposure of physical activity and immobilization. The relative level of dopamine receptor gene expression was determined by real-time polymerase chain reaction after 90, 180, and 270 days of the experiment in peripheral blood cells of the tail vein. The calculation of the relative level of gene expression was carried out based on the Livak method (2Ct); the assessment of the difference significance using a two-sample t-test for independent samples.
 Results. The analysis of the relative level of genes encoding D1-type dopamine receptors expression showed that a decrease in the Drd1 gene expression level after 90 days of the experiment was detected only in male rats from immobilization stress and control groups [RQ 0.35 (p=0.003) and 0.21 (p=0.002), respectively], while in males from other groups and females, the activity of this gene did not change significantly throughout the course of the experiment. The relative expression level of Drd5 gene changed only in female rats. In females subjected to intense physical activity, the level of this gene expression increased almost 4 times (RQ 3.82, p=0.005) 90 days after the start of the experiment, and in females of the control group, the transcriptional activity of the gene decreased 4 times after 180 days of the experiment (RQ 0.25, p=0.015). When assessing changes in the activity of genes encoding D2-type receptors for the Drd3 and Drd4 genes, a significant increase in the relative expression level was revealed in all experimental groups, both in males and females, on the 180th day of exposure to stress factors. At the same time, activation of both genes was occurred after 90 days in the control group only in females and persisted up to another 90 days, after which it returned to the initial level. Expression of the Drd2 gene wasn't detected in rat blood cells.
 Conclusion. The relative level of expression of D1- and D2-like receptor genes in rat peripheral blood cells depends on the type of chronic stress and has pronounced sexual dimorphism.

Central dopaminergic control of cell proliferation in the colonic epithelium

Parkinson’s disease (PD) is an age-related neurodegenerative disease, mainly characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. Several non-motor symptoms, including those associated with gastrointestinal dysfunction, precede the classical motor symptoms in PD. However, the mechanisms underlying gastrointestinal dysfunction in the prodromal phase of PD remain elusive. Here, we investigated the contribution of the central DA system to cell proliferation in the colonic epithelium. Degeneration of nigrostriatal DA pathway induced by striatal 6-hydroxydopamine (6-OHDA) injection resulted in a marked reduction in cell proliferation in the colonic epithelium as assessed by Ki-67 and bromodeoxyuridine labeling assays. RNA-sequencing analysis confirmed the suppression of cell cycle-related gene expression in the colonic epithelium of 6-OHDA-lesioned mice. Mesencephalic DA neuron degeneration also caused the gut microbiota dysbiosis. Moreover, 6-OHDA-lesioned mice showed profoundly increased vulnerability to dextran sulfate sodium-induced colitis. Together, our study uncovers a crucial role for the integrity of nigral DA neurons in the maintenance of colonic epithelial cell homeostasis. Our data also provide a new strategy for protecting intestinal homeostasis in PD.

ИНФРАДИАННАЯ РИТМИКА ДЕПРЕССИВНОПОДОБНОГО ПОВЕДЕНИЯ У КРЫС

ИНФРАДИАННАЯ РИТМИКА ДЕПРЕССИВНОПОДОБНОГО ПОВЕДЕНИЯ У КРЫС

Reduced expression of dopamine D2 receptors on astrocytes in R6/1 HD mice and HD post-mortem tissue

Dysfunction of the central dopaminergic system is thought to contribute to some of the clinical features of Huntington’s disease (HD), and dopamine (DA) receptor antagonists are commonly used to good effect in its treatment. It is well established that there is an early significant reduction in neuronal D2 receptors in HD, considered to be a compensatory response to increased dopaminergic activity. However, no studies have examined the expression of D2 receptors on astrocytes which is important given that these cells have been shown to play a role in the pathogenesis of HD, as well as express dopamine receptors and modulate DA homeostasis in the normal brain. We therefore sought to investigate the expression of D2 receptors on astrocytes in HD, and found them to be reduced in both the R6/1 HD mouse model, and in human post-mortem brain in comparison to controls, suggesting that astrocytes may be important in DA-dependent aspects of HD. Further studies are needed to determine the functional significance of this finding.

Interconnection between Adrenergic and Dopaminergic Systems in Feeding Behavior in Neonatal Chicks.

Central dopaminergic (DAergic) and adrenergic systems have a prominent role in appetite regulation; however, their interaction(s) have not been studied in neonatal layer chickens.Therefore, the current study aimed to determine the interaction of central DAergic and noradrenergic systems in food intake regulation in neonatal layer chickens. In the first experiment, chickens received the intracerebroventricular (ICV) injection of a control solution, prazosin (i.e., α1 adrenergic receptor antagonist; 10 nmol), dopamine (DA; 40 nmol), and prazosin plus DA. The second to fifth experiments were similar to the first experiment except that the birds were injected with yohimbine (i.e., α2 receptor antagonist; 13 nmol), metoprolol (i.e., β1 adrenergic receptor antagonist; 24 nmol), ICI 118,551 (i.e., β2 adrenergic receptor antagonist; 5 nmol), and SR59230R (i.e., β3 adrenergic receptor antagonist; 20 nmol) instead of prazosin. In the sixth experiment, the chickens received ICV injection with the control solution and noradrenaline (NA; 75, 150, and 300 nmol). In the seventh experiment, the birds were injected with the control solution, SCH23390 (i.e., D1 DAergic receptor antagonist; 5 nmol), NA (300 nmol), and SCH23390 plus NA In the eighth experiment, the control solution, AMI-193 (i.e., D2 DAergic receptor antagonist; 5 nmol), NA (300 nmol), and AMI-193 plus NA were injected. Then, cumulative food intake was recorded at 30, 60, and 120 min after the injection. According to the obtained results, the ICV injection of DA (40 nmol) significantly decreased food intake in comparison to that reported for the control group (p <0.05). The co-injection of yohimbine plus DA significantly amplified DA-induced hypophagia in the neonatal chickens (p <0.05). In addition, the co-administration of ICI 118,551 plus DA significantly inhibited the hypophagic effect of DA in the neonatal chickens (p <0.05). Furthermore, NA (75, 150, and 300 nmol) significantly reduced food intake in a dose-dependent manner (p <0.05). The co-injection of SCH23390 plus NA decreased the hypophagic effect of NA in the neonatal chickens, compared to that reported for the control group (p <0.05). The co-injection of AMI-193 plus NA diminished NA-induced hypophagia, compared to that reported for the control group (p <0.05). The aforementioned results suggested that there is an interconnection between central DAergic and noradrenergic systems through α2/β2 adrenergic and D1/D2 DAergic receptors in food intake regulation in neonatal chicks.

Dopamine D1 Receptor in the Nucleus Accumbens Modulates the Emergence from Propofol Anesthesia in Rat.

It has been reported that systemic activation of D1 receptors promotes emergence from isoflurane-induced unconsciousness, suggesting that the central dopaminergic system is involved in the process of recovering from general anesthesia. The nucleus accumbens (NAc) contains abundant GABAergic medium spiny neurons (MSNs) expressing the D1 receptor (D1R), which plays a key role in sleep-wake behavior. However, the role of NAc D1 receptors in the process of emergence from general anesthesia has not been identified. Here, using real-time in vivo fiber photometry, we found that neuronal activity in the NAc was markedly disinhibited during recovery from propofol anesthesia. Subsequently, microinjection of a D1R selective agonist (chloro-APB hydrobromide) into the NAc notably reduced the time to emerge from propofol anesthesia with a decrease in δ-band power and an increase in β-band power evident in the cortical electroencephalogram. These effects were prevented by pretreatment with a D1R antagonist (SCH-23390). Whole-cell patch clamp recordings were performed to further explore the cellular mechanism underlying the modulation of D1 receptors on MSNs under propofol anesthesia. Our data primarily demonstrated that propofol increased the frequency and prolonged the decay time of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature IPSCs (mIPSCs) of MSNs expressing D1 receptors. A D1R agonist attenuated the effect of propofol on the frequency of sIPSCs and mIPSCs, and the effects of the agonist were eliminated by preapplication of SCH-23390. Collectively, these results indicate that modulation of the D1 receptor on the activity of NAc MSNs is vital for emergence from propofol-induced unconsciousness.

Reduction in Nesfatin-1 Levels in the Cerebrospinal Fluid and Increased Nigrostriatal Degeneration Following Ventricular Administration of Anti-nesfatin-1 Antibody in Mice.

Nesfatin-1 is one of several brain-gut peptides that have a close relationship with the central dopaminergic system. Our previous studies have shown that nesfatin-1 is capable of protecting nigral dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. A recent study also revealed a reduced blood level of nesfatin-1 in patients with Parkinson’s disease (PD). The current study was designed to investigate whether reduced nesfatin-1 in cerebrospinal fluid (CSF) induces nigrostriatal system degeneration. An intra-cerebroventricular (ICV) injection technique was used to administer anti-nesfatin-1 antibody directly into the lateral ventricle of the brain. Enzyme-linked immunosorbent assay (ELISA) results showed that ICV injection of anti-nesfatin-1 antibody into the lateral ventricle of the brain once daily for 2 weeks caused a significant reduction in nesfatin-1 levels in the CSF (93.1%). Treatment with anti-nesfatin-1 antibody resulted in a substantial loss (23%) of TH-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc), as shown by immunofluorescence staining, a depletion in dopamine and its metabolites in the striatum detected by high-performance liquid chromatography (HPLC), and obvious nuclear shrinkage and mitochondrial lesions in dopaminergic neurons in the SNpc detected by transmission electron microscopy (TEM). Furthermore, the results from our Western blot and ELISA experiments demonstrated that anti-nesfatin-1 antibody injection induced an upregulation of caspase-3 activation, increased the expression of p-ERK, and elevated brain-derived neurotrophic factor (BDNF) levels in the SNpc. Taken together, these observations suggest that reduced nesfatin-1 in the brain may induce nigrostriatal dopaminergic system degeneration; this effect may be mediated via mitochondrial dysfunction-related apoptosis. Our data support a role of nesfatin-1 in maintaining the normal physiological function of the nigrostriatal dopaminergic system.

Restoration of Noradrenergic Function in Parkinson's Disease Model Mice.

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

Painful stimulation increases spontaneous blink rate in healthy subjects

Spontaneous blink rate is considered a biomarker of central dopaminergic activity. Recent evidence suggests that the central dopaminergic system plays a role in nociception. In the present study, we aimed to investigate whether pain modulates spontaneous blink rate in healthy subjects. We enrolled 15 participants. Spontaneous blink rate was quantified with an optoelectronic system before and after: (1) a painful laser stimulation, and (2) an acoustic startling stimulation. In control experiments, we investigated whether laser stimulation effects depended on stimulation intensity and whether laser stimulation induced any changes in the blink reflex recovery cycle. Finally, we investigated any relationship between spontaneous blink rate modification and pain modulation effect during the cold pressor test. Laser, but not acoustic, stimulation increased spontaneous blink rate. This effect was independent of stimulation intensity and negatively correlated with pain perception. No changes in trigeminal-facial reflex circuit excitability were elicited by laser stimulation. The cold pressor test also induced an increased spontaneous blink rate. Our study provides evidence on the role of dopamine in nociception and suggests that dopaminergic activity may be involved in pain modulation. These findings lay the groundwork for further investigations in patients with pathological conditions characterized by dopaminergic deficit and pain.

The Effect of Escitalopram on Central Serotonergic and Dopaminergic Systems in Patients with Cervical Dystonia, and Its Relationship with Clinical Treatment Effects: A Double-Blind Placebo-Controlled Trial.

Purpose: The pathophysiology of cervical dystonia (CD) is thought to be related to changes in dopamine and serotonin levels in the brain. We performed a double-blind trial with escitalopram (selective serotonin reuptake inhibitor; SSRI) in patients with CD. Here, we report on changes in dopamine D2/3 receptor (D2/3R), dopamine transporter (DAT) and serotonin transporter (SERT) binding potential (BPND) after a six-week treatment course with escitalopram or placebo. Methods: CD patients had [123I]FP-CIT SPECT (I-123 fluoropropyl carbomethoxy-3 beta-(4-iodophenyltropane) single-photon emission computed tomography) scans, to quantify extrastriatal SERT and striatal DAT, and [123I]IBZM SPECT (I-123 iodobenzamide SPECT) scans to quantify striatal D2/3R BPND before and after six weeks of treatment with either escitalopram or placebo. Treatment effect was evaluated with the Clinical Global Impression scale for dystonia, jerks and psychiatric symptoms, both by physicians and patients. Results: In both patients treated with escitalopram and placebo there were no significant differences after treatment in SERT, DAT or D2/3R BPND. Comparing scans after treatment with escitalopram (n = 8) to placebo (n = 8) showed a trend (p = 0.13) towards lower extrastriatal SERT BPND in the SSRI group (median SERT occupancy of 64.6%). After treatment with escitalopram, patients who reported a positive effect on dystonia or psychiatric symptoms had significantly higher SERT occupancy compared to patients who did not experience an effect. Conclusion: Higher extrastriatal SERT occupancy after treatment with escitalopram is associated with a trend towards a positive subjective effect on dystonia and psychiatric symptoms in CD patients.

Dopaminergic system and its relationship with the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid systems (review)

This article reviews literature data on the activity of the central and peripheral dopaminergic systems, as well as its relationship with the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid systems. Studies have shown that dopamine levels vary depending on the territory of residence, while the data on the age dynamics of the plasma dopamine level contradict each other, which does not allow an unambiguous conclusion about a decrease or increase in its level with age. Most studies focus on the functions of dopamine in the central nervous system. Symptoms of several brain diseases, including schizophrenia, Parkinson’s disease, attention deficit and hyperactivity disorders and depression, are alleviated by the pharmacological modulation of dopamine transmission. However, there is evidence of a functional role of peripheral dopamine. While dopamine of the central dopaminergic system inhibits the secretion of thyrotropin, dopamine synthesized by sympathoadrenal nerve cells, heparinocytes, and thyroid parafollicular cells on the periphery stimulates the formation and release of iodothyronines. The neuroprotective effects of sex steroids determine the prevalence of studies of their role in preservation and maintaining the activity of the dopaminergic system. The dopaminergic system also affects the levels of sex hormones, enhancing aromatase activity, inhibiting the synthesis or secretion of prolactin, regulating the levels of gonadotropins and steroidogenesis in Leydig cells. The peripheral and central dopamine systems are sensitive to environmental influences, which indicate the relationship between the peripheral and central links.

Neuroanatomy and function of human sexual behavior: A neglected or unknown issue?

IntroductionSexual desire, arousal, and orgasm are mediated by complex, yet still not fully understood, interactions of the somatic and autonomic nervous systems operating at the central and peripheral levels. Disruption of endocrine, neural, or vascular response, caused by aging, medical illness, neurological diseases, surgery, or drugs, can lead to sexual dysfunctions, thus significantly affecting patients' quality of life.PurposeThis narrative review aims at characterizing the involvement of the central nervous system in human sexual behavior.MethodsA literature search was conducted using PubMed in its entirety up to June 2018, analyzing the studies dealing with the neurobiological and neurophysiological basis of human sexuality.ResultsSexual behavior is regulated by both subcortical structures, such as the hypothalamus, brainstem, and spinal cord, and several cortical brain areas acting as an orchestra to finely adjust this primitive, complex, and versatile behavior. At the central level, dopaminergic and serotonergic systems appear to play a significant role in various factors of sexual response, although adrenergic, cholinergic, and other neuropeptide transmitter systems may contribute as well.ConclusionsProviding healthcare professionals with information concerning sexual behavior may overcome useless and sometimes dangerous barriers and improve patient management, since sexual well‐being is considered one of the most important aspects of one's quality of life.

Changes in Oxidative Stress Index and Lipid Peroxidation Product in the Brain of Rats with Lesion of Central Dopaminergic System after Propofol Administration*

Propofol is a commonly used intravenous anesthetic agent with antioxidant properties. However, the effect of propofol on oxidative stress index (OSI) and lipid peroxidation in Parkinson’s disease is still unknown. The present study aimed to evaluate the effect of propofol on OSI and malondialdehyde (MDA) level in the selected brain regions of the rats with Parkinson’s disease (PD). 32 male Wistar rats were divided into four groups: I- control group, II- group with PD, III-control group with propofol, IV-PD group with propofol. 60mg/kg of propofol was given to the 8-weeks-old rats intraperitoneally, and the selected parts of the rats’ brains (frontal cortex, striatum, thalamus and hippocampus) were isolated after decapitation. The concentration of MDA, which is a marker of lipid peroxidation, and OSI were measured. In group IV compared to group II, was observed a significant MDA level decrease in the cortex (39%, p <0.001), striatum (28%, p <0.001), hippocampus (21%, p <0.05) and thalamus (20%, p <0.05), together with a decreased OSI level in the thalamus (71%, p <0,001), cortex (70%, p <0.05), striatum (65%, p <0.001), and hippocampus (57%, p <0.05). In group III compared to group I was observed decrease in MDA level in the cortex (40%, p <0.001). Propofol inhibits oxidative stress in all the evaluated structures of the rat brain with Parkinson’s disease. There are significant differences in the response of brain tissues to administered propofol between rats with PD and healthy ones.

Quinoline analogs of 2-aminoindane as potential central dopaminergic agents

Neurodegenerative disorders such as Parkinson and Huntington Chorea are related with damage to the central dopaminergic system. On the purpose to find new drugs able to re-establish the imbalance on the dopaminergic neurotransmission in the central nervous system and counteract some of the neurodegenerative sicknesses, we have designed, synthesized, pharmacologically evaluated, and studied through molecular modeling,2-aminoindane-quinoline analog derivatives (1–5). Pharmacological studies made on the central nervous system through ICV (intracerebroventricular) and IS (intrastriatal), of compounds (1–5) showed agonistic activity by the activation of dopaminergic mechanisms on the central nervous system. The corresponding molecular modeling study permitted us not only to explain the differential behavior of studied compounds, but also to understand whichmolecular interactions are responsible to stabilize the different complexes formed between those compounds and the D2 receptor. These results validate our medicinal chemical approach in different aspects: the receptor model used, the responsible fragment inserted within the structure of the compounds capable of interacting with the receptor, the complementary functional groups that facilitate the expected response and the pharmacological administration routes. All these aspects are important for the design of this type of compounds as potential anti-Parkinson and/or anti-Huntington agents.

Interaction of the dopaminergic and Nociceptin/Orphanin FQ on central feed intake regulation in chicken

ABSTRACT 1. The aim of the current study was to determine the effects of the central dopaminergic system on N/OFQ-induced feed intake in 3-h feed-deprived neonatal broilers. 2. In experiment 1, chicken received intracerebroventricular (ICV) injections of a control solution, SCH 23 390 (D1 receptors antagonist, 5 nmol), N/OFQ (16 nmol) or their combination (SCH23 390 + N/OFQ). In experiment 2, a control solution, AMI-193 (D2 receptors antagonist, 5 nmol), N/OFQ (16 nmol) or their combination (AMI-193 + N/OFQ) were ICV injected into chickens. In experiment 3, birds received ICV injections of a control solution, NGB2904 (D3 receptors antagonist, 6.4 nmol), N/OFQ (16 nmol) and co-injection of NGB2904 + N/OFQ. In experiment 4, ICV injections of the control solution, L-741,742 (D4 receptors antagonist, 6 nmol), N/OFQ (16 nmol) or their combination (L-741,742 + N/OFQ) were applied to broilers. In experiment 5, birds were ICV injected with control solution, L-DOPA (dopamine precursor, 125 nmol), N/OFQ (16 nmol) and L-DOPA + N/OFQ. Cumulative feed intake was recorded until 120 min after injection. 3. According to the results, ICV injection of N/OFQ significantly increased feed intake (P < 0.05). Co-injection of N/OFQ and D1 receptor antagonist (SCH 23390) amplified hyperphagic effect of N/OFQ (P < 0.05). The N/OFQ-induced feed intake was increased by the D2 receptor antagonist (P < 0.05). The hyperphagic effect of N/PFQ was weakened by co-injection of L-DOPA + N/OFQ (P < 0.05). 4. These results suggested that an interaction exists between dopamine and N/OFQ via D1 and D2 receptors on central feed intake in neonatal broiler chickens.

Dietary essential oil from navel orange alleviates depression in reserpine‐treated mice by monoamine neurotransmitters

AbstractThis study was intended to examine the effects of navel orange (Citrus sinensis (L.) Osbeck) essential oil (OEO) on depression in the reserpine‐treated mice. And the chemical composition of OEO was analysed by gas chromatography (GC) analysis. The results indicated that the major compounds of OEO were terpenes. And OEO treatment produced an antidepressant‐like effect in mice, as indicated by the increased locomotor activity in the open field test (OFT) and attenuated dyslipidemia, but it had no effect on duration of immobility in the forced swim test (FST). Dietary OEO counteracted the reserpine‐induced hypothermia and palpebral ptosis. Moreover, OEO treatment increased the levels of serotonin (5‐HT) and dopamine (DA) in the mice brain. These antidepressant‐like effects of OEO are essentially similar to the effects of the antidepressant fluoxetine. And the action of OEO may be mediated by the central serotonergic and dopaminergic systems.

A Novel Animal Model Prepared by Blocking (FOXRED1 gene) for neuro-toxicological studies of Leigh Syndrome

Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantianigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for neuro-toxicological studies of Leigh syndrome due to defective mitochondrial complex I (CI), which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.