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A complex system of neural pathways, collectively known as the microbiota–gut–brain (MGB) axis, interconnects the gut microbiota, the gastrointestinal system, and the brain along with its periphery. Previous studies have demonstrated that modulation of the MGB axis can influence stress-related behaviors such as anxiety. This connection becomes apparent in scenarios like agonistic behavior in laying hens, which is characterized by aggressive head and feather pecks, that can ultimately result in cannibalism and death. The objective was to examine the effects of a dietary synbiotic on agonistic behavior, plasma and brain monoamines, stress parameters, and cecal microbiota counts via modulation of the MGB axis. A total of 396 W36 Hy-Line laying hens were provided at random with a control (CON: basal diet) or treatment (SYN: basal diet supplemented with synbiotic) diet from 50 to 60 weeks old (nine pens/treatment, 22 birds/pen). Blood samples and video recordings (three consecutive days/week) were taken at 50 and 60 weeks. At 60 weeks, three hens/pen were euthanized for brain and cecal microbiota collection. Threatening, fighting, head, body, and feather pecking all occurred less frequently at 60 weeks in the SYN group (p < 0.05). Plasma corticosterone, adrenocorticotropic hormone, dopamine, and serotonin were significantly lower while tryptophan and 5-hydroxyindoleacetic acid were significantly higher in birds from the SYN group (p < 0.05). Significant differences in serotonin, 5-hydroxyindoleacetic acid, dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid were observed in the hypothalamus, hippocampus, and amygdala of the brain. Serotonin and dopamine turnover rates were significantly different in all three regions of the brain (p < 0.05). Cecal counts of Lactobacillus and Bifidobacterium were significantly higher in the SYN group (p < 0.05). Synbiotic supplementation resulted in many significant differences, indicating activation of the serotonergic systems and modulation of both the MGB axis and HPA axis with positive effects on welfare and stress. [ABSTRACT FROM AUTHOR]

Pheochromocytoma and Paraganglioma (PCPG) are rare and potentially lethal neuroendocrine tumors. PCPG that predominantly or exclusively produce and secrete DA is rarely seen, and it has been known that exclusively dopamine-secreting PCPG is related to advanced malignant features and metastases. Up to the present, little has been known about the role of dopamine neurotransmission and the dopaminergic system in the initiation and progression of PCPG. The genes with significant expression differences between normal tissue and pheochromocytoma and paraganglioma, survival and correlation analysis, CpG islands prediction, and miRNA-target enrichment analysis were performed by several bioinformatics tools. In the present study, it was determined that the COMT gene was significantly less expressed in PCPG than in normal tissue and the COMT gene showed a remarkable relationship between differential expression with shorter overall survival among the individuals with PCPG (HR=1, p=0.011). MAOA and COMT gene pair was significantly correlated with PCPG (p=0.012; R=0.19), and hsa-miR-5000-5p regulates the expression of both COMT and MAOA genes (p=0.00215, FDR=0.127). Our findings suppose that COMT may potentially be implicated in tumor suppressive mechanism. The expression values of COMT and MAOA genes, and hsa-miR-5000-5p may have the potential to be used in the genetic evaluation of the pathogenesis and prognosis of PCPG. Further in vitro and in vivo studies are required to clarify the molecular mechanism of the dopaminergic system in the pathogenesis and prognosis of PCPG. [ABSTRACT FROM AUTHOR]

Introduction: Post-traumatic stress disorder (PTSD) is the most prevalent neuropsychiatric disorder developed by vulnerable individuals exposed to life-threatening events. Fear extinction deficits results from decreased medial prefrontal (mPFC) activity and are a key feature of PTSD. Also, it has been shown that brain dopamine receptors are involved in fear extinction that drives learning and memory. Furthermore, dopaminergic (DAergic) dysfunction is implicated in the pathophysiology of PTSD and, as a consequence, drugs targeting the central DAergic system could have a therapeutic value for the management of this disorder. Methods and Materials: We conducted a thorough and methodical search for pertinent references using different databases, including Pubmed, Embase, MEDLINE, Scopus, Web of Science Core Collection, and Google Scholar by using combinations of keywords such as "PTSD," " dopaminergic System," "Extinction," "Facilitation," "Therapeutic methods," "Pharmacological,”. The keywords were searched in the "title/abstract" field of these databases. The resulting articles were then carefully selected for their relevance to the topic at hand. Results: Findings revealed that individuals with PTSD display fear extinction deficits raises the possibility that corticolimbic circuitry and related dopaminergic system may mediate fear memory extinction via underlying mechanisms. Also, dopaminergic mechanisms relevant for the pathogenesis of PTSD, as well as potential dopaminergic-based pharmacotherapies are discussed in the context of addressing the unmet medical need for new and effective drugs for the treatment of PTSD. Conclusion: Due to dopaminergic mechanisms' involvement in fear extinction, potential dopaminergic-based pharmacotherapies could be a promising strategy in PTSD treatment via addressing the unmet medical need for new and effective drugs for the treatment of PTSD. [ABSTRACT FROM AUTHOR]

Oleoylethanolamide is a well-recognized anorectic compound which also has noteworthy effects on food-reward, influencing the acetylcholine (ACh)/dopamine (DA) balance in the cholinergic system. After its administration, oleoylethanolamide is quickly degraded into oleic acid and ethanolamine. The effect of oleic acid on the gut-brain axis has been extensively investigated, whereas ethanolamine has received scarce attention. However, there is scattered evidence from old and recent research that has underlined the influence of ethanolamine on the cholinergic system. In the present article, we propose a model by which the released ethanolamine contributes to the overall balance between DA and ACh after oleoylethanolamide administration. [ABSTRACT FROM AUTHOR]

Highlights • Early life stress (ELS) is a risk factor for psychopathologies with dopamine dysfunction. • Over 90 publications have causally investigated the link between ELS and dopamine dysfunction in rodents. • We performed a meta-analysis to quantify the effects of ELS on biochemical indicators of the dopaminergic system. • Our results identify only a few yet robust alterations on biochemical indicators of the dopaminergic system following ELS. • We created MaDEapp, a tool to perform tailor-made meta-analysis on the topic. Abstract Adverse early life events are a well-established risk factor for the precipitation of behavioral disorders characterized by anomalies in the dopaminergic system, such as schizophrenia and addiction. The correlation between early life conditions and the dopaminergic system has been causally investigated in more than 90 rodent publications. Here, we tested the validity of the hypothesis that early life stress (ELS) alters dopamine signaling by performing an extensive 3-level mixed effect meta-analysis. We included several ELS models and biochemical indicators of the dopaminergic system in a variety of brain areas, for a total of 1009 comparisons. Contrary to our expectations, only a few comparisons displayed a significant effect. Specifically, the striatal area was the most vulnerable, displaying decreased dopamine precursor and increased metabolites after ELS. To make all data openly accessible, we created MaDEapp (https://osf.io/w25m4/), a tool to explore data of the meta-analysis with the intent to guide future (pre)clinical research and allow power calculations. All in all, ELS induces a few yet robust changes on biochemical indicators of the dopaminergic system. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates that exposure to selenium (Se) can cause neurotoxicity, and this can occur because of its interference with several neurotransmitter systems in humans and animals. Dopamine is a critical modulator of a variety of brain functions and a prime target for environmental neurotoxicants. However, effects of environmentally relevant concentrations of Se on dopaminergic system and its neurobehavioral effects are still largely unknown. For this purpose, we exposed zebrafish, a model organism, to different concentrations of dietary l -selenomethionine (control, 3.5, 11.1, 27.4, and 63.4 μg Se/g dry weight) for a period of 60 days. Cognitive performance of fish was evaluated using a plus maze associative learning paradigm. Oxidative stress, as the main driver of Se neurotoxicity, was assessed by measuring the ratio of reduced to oxidized glutathione (GSH:GSSG), lipid peroxidation (LPO) levels, and mRNA expression of several antioxidant enzymes in the zebrafish brain. Dopamine levels in the brain and the expression of genes involved in dopamine synthesis, storage, reuptake, metabolism, and receptor activation were examined. Moreover, transcription of several synaptic plasticity-related immediate-early and late response genes was determined. Overall, fish fed with the two highest concentrations of dietary Se displayed impaired associative learning. Se exposure also induced oxidative stress in the zebrafish brain, as indicated by a reduction in GSH:GSSG ratio, increased LPO levels, and up-regulation of antioxidant genes in fish treated with the two highest concentrations of Se. An increase in brain dopamine levels associated with altered expression of dopaminergic cell markers was evident in different treatment groups. Moreover, Se exposure led to the down-regulation of immediate-early and late response genes in fish that exhibiting learning impairment. Taken together, the results of this study imply that the induction of oxidative stress and dysregulation of dopaminergic neurotransmission may underlie Se-induced impairment of associative learning in zebrafish. [ABSTRACT FROM AUTHOR]

Pups have greater incentive value than males for rats during the postpartum estrus (PPE); a period when females are both maternally and sexually motivated. Mesolimbic dopaminergic system has been proposed as a general motivational circuit; however in the literature it has been more related to the control of the motivational aspects of maternal than sexual motivation of females. Therefore, we aimed to assess the effect of antagonizing dopaminergic neurotransmission of PPE females on their preference for pups over a male. To achieve this objective we tested PPE rats in a Y-maze with three-choice chambers (one containing eight pups, the other a male and the last one no stimulus) after the systemic administration of the dopaminergic antagonist haloperidol (0.0; 0.025 or 0.05 mg/kg). Furthermore, to determine if this dopaminergic antagonist differentially affects maternal and sexual motivations when pups and male are not competing, we evaluated the effect of haloperidol in the preference of females for pups vs. a non-receptive female and for a male vs. a non-receptive female. In the preference test for pups vs. male, both doses of haloperidol decreased the time that females spent in pups' chamber while increased the time that they spent in male's chamber, resulting in a lack of preference between both incentives. Besides, haloperidol reduced the effort -attempts to get access to the stimuli- made by the females to obtain the pups. Conversely, 0.05 mg/kg of haloperidol did not affect the preference for both incentives when they were confronted to a non-receptive female. Together, these results indicate that the dopaminergic activity mediates pups' preference over male during the PPE and point toward a more relevant role of this system in females' behavioral output when incentives are competing. [ABSTRACT FROM AUTHOR]

The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system. [ABSTRACT FROM AUTHOR]

Summary: Aims: Finasteride inhibits the conversion of testosterone to dihydrotestosterone. Because androgen regulates dopaminergic system in the brain, it could be hypothesized that finasteride may inhibit dopaminergic system. The present study therefore investigates the effects of finasteride in adolescent and early developmental rats on dopaminergic system, including contents of dopamine and its metabolites (dihydroxy phenyl acetic acid and homovanillic acid) and tyrosine hydroxylase expressions both at gene and protein levels. Meanwhile, open‐field behaviors of the rats are examined because of the regulatory effect of dopaminergic system on the behaviors. Methods: Open‐field behaviors were evaluated by exploratory and motor behaviors. Dopamine and its metabolites were assayed by liquid chromatography‐mass spectrometry. Tyrosine hydroxylase mRNA and protein expressions were determined by real‐time qRT‐PCR and western blot, respectively. Results: It was found that in adolescent male rats, administration of finasteride at doses of 25 and 50 mg/kg for 14 days dose dependently inhibited open‐field behaviors, reduced contents of dopamine and its metabolites in frontal cortex, hippocampus, caudate putamen, nucleus accumbens, and down‐regulated tyrosine hydroxylase mRNA and protein expressions in substantia nigra and ventral tegmental area. However, there was no significant change of these parameters in early developmental rats after finasteride treatment. Conclusion: These results suggest that finasteride inhibits dopaminergic system and open‐field behaviors in adolescent male rats by inhibiting the conversion of testosterone to dihydrotestosterone, and imply finasteride as a potential therapeutic option for neuropsychiatric disorders associated with hyperactivities of dopaminergic system and androgen. [ABSTRACT FROM AUTHOR]

Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic parameters evaluated, despite having modified some oxidative parameters. This study showed for the first time that a short post-weaning social isolation was able to induce long-term changes in the striatal dopaminergic system and increased the response to psychostimulants. These results emphasize the importance of stressful experiences during a short period of development on programming susceptibility to psychostimulants later in life. [ABSTRACT FROM AUTHOR]

Previously, we proposed that the mean diffusivity (MD), a measure of diffusion tensor imaging (DTI) in areas of the dopaminergic system (MDDS), is associated with motivation. In this study, we tested if and how the motivational state is associated with MD in comparison with other mood states. We also tested the associations of these mood states with multiple cognitive functions. We examined these issues in 766 right-handed healthy young adults. We employed analyses of MD and a psychological measure of the profile of mood states (POMS) as well as multiple cognitive functions. We detected associations between the higher Vigor subscale of POMS and lower MD in the right globus pallidum, right putamen to right posterior insula, right caudate body, and right thalamus, and these associations were highly specific to the Vigor subscale. Similarly, the association of the motivational state with creativity measured by divergent thinking (CMDT) was rather specific and prominent compared with that of the other mood states and cognitive functions. In conclusion, when affective states are finely divided, only the motivational state is associated with MD in the areas related to the dopaminergic system, and psychological mechanisms that had been associated with dopaminergic system (CMDT). These results suggest that these mechanisms specifically contribute to the motivational state and not to the other states, such as depression and anxiety. [ABSTRACT FROM AUTHOR]

Epilepsy is accompanied with a strong change in neuronal activity not only in excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission, but also in neuromodulatory agents. Dopaminergic system, as an important neuromodulatory system of the brain, has significant effect on neuronal excitability. In addition, this system undergoes many changes in epileptic brain. Understanding the effects of dopaminergic system in neuronal activities in epileptic brain and knowing the seizure-induced changes in dopaminergic system can shed light into finding the mechanisms involved in epileptogenesis and can help us in finding new treatments for epilepsy. In this review we briefly introduce dopaminergic system and its changes in brain areas which have role in epilepsy. Then, we will focus on the evidences showing the relationship between epilepsy and dopaminergic system. [ABSTRACT FROM AUTHOR]

Circadian disturbances related to Parkinson's disease are reviewed, and possible pathogenetic mechanisms are discussed. The role of dopaminergic system degeneration in the development of circadian dysfunction is emphasized. The accumulation of α-synuclein in the suprachiasmatic nucleus is considered as a possible mechanism of circadian dysfunction unrelated to dopamine deficiency. Data on the disbalance of dopamine and melatonin levels in Parkinson's disease patients and its role in disturbances of circadian rhythms of physiological processes are analyzed. [ABSTRACT FROM AUTHOR]

Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15 mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D 1 receptor agonist and quinpirol D 2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15 mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4 µg/mouse) and quinpirol (0.3, 1 and 3 µg/mouse). Pre-training administration of SCH 23390, D 1 receptor antagonist (0.75 and 1 μg/mouse, intra-mPFC), and sulpiride D 2 receptor antagonist (3 μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition. [ABSTRACT FROM AUTHOR]

Cognitive and sensorimotor processes are both needed for successful planning of footsteps during complex gait situations, but the interaction between these factors during motor planning, as well as their response to dopaminergic treatment is poorly understood in Parkinson’s disease (PD). In the current study, we evaluated walking and gaze behaviors of individuals with PD while planning an approach toward an obstacle to be stepped over. The obstacle clearance task was completed both ON and OFF dopaminergic medication by individuals with Parkinson’s disease ( n = 20) and compared to healthy age-matched control participants ( n = 19), as well as with and without an auditory digit monitoring dual task. In this novel protocol of synchronized gaze and gait data collection, each trial was split into an early and late phase prior to the obstacle, providing a unique opportunity to examine dopamine-dependent planning deficits in PD. Interestingly, only patients in the OFF medication state showed greater deceleration in the late phase (i.e., just before the obstacle) ( F (1,37) = 45.42, p < 0.001), as well as an increase in step time variability (also in this late phase) with the additional demands of a dual task ( F (2,74) = 3.49, p = 0.035). Only gait deceleration between approaching phases improved with dopaminergic treatment ( F (1,18) = 59.20; p < 0.001). Although groups showed different walking behaviors, gaze behaviors were the same for all participants, in that they planned for the obstacle more so in the early phase ( p < 0.05), and fixations were reduced across participants with the presence of the dual task ( p < 0.001). Surprisingly, the gaze behavior of the PD OFF group showed no interactions with phase or condition suggesting that the deceleration and increased variability when approaching an obstacle is the result of a greater demand for online sensory feedback that cannot be compensated for with visual strategies. We conclude that dopamine influences planning by limiting sensorimotor processing capacity, especially in the presence of increased cognitive demand in PD. [ABSTRACT FROM AUTHOR]

Albiflorin (AF), separated from the root of Paeonia lactiflora Pall, possesses neuro-protective and anti-inflammatory activities. Based on previous results, our present research aims to investigate the antidepressant-like activity of AF in chronic unpredictable mild stress (CUMS)-induced rat model of depression. Eight weeks of CUMS process successfully established depression-like rat model, as evidenced by the enhanced immobility time in forced swimming test and the reduced sucrose preference, which were reversed to near normal by AF (20 mg/kg and 40 mg/kg) and fluoxetine (3 mg/kg; positive drug) treated. Compared to non-treated depression-like rats, the increased levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HTAA) in serum and hypothalamus, and the reduced expressions of 5-HT 1A receptor and 5-HT 2A receptor in hypothalamus were observed after AF and fluoxetine oral administration indicating that AF-mediated antidepressant-like effect may be related to the normalization of serotonergic system. Additionally, four-week AF treated rats significantly showed improvement in the reduced dopamine and noradrenalin concentration in serum and hypothalamus as observed on depression-like rats. Altered levels of tyrosine hydroxylase, dopamine D 2 receptor and dopamine transporter in hypothalamus reverted to the normal level after treatment with both AF and fluoxetine. All these data demonstrate that not only serotonergic system, but also dopaminergic system is involved in AF-mediated antidepressant-like effect in CUMS-induced rat model of depression. [ABSTRACT FROM AUTHOR]

Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour (“escape jumping”). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine. [ABSTRACT FROM AUTHOR]

Post-weaning social isolation rearing (SI) in rodents elicits various behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors. In order to obtain a better understanding of SI-induced behavioral abnormalities, we herein investigated the effects of SI on social affiliation and conditioned fear memory as well as the neuronal mechanism(s) underlying these effects. Four-week-old male mice were group-housed (GH) or socially isolated for 2–4 weeks before the experiments. The social affiliation test and fear memory conditioning were conducted at the age of 6 and 7 weeks, respectively. SI mice were systemically administered saline or test drugs 30 min before the social affiliation test and fear memory conditioning. Contextual and auditory fear memories were elucidated 1 and 4 days after fear conditioning. Social affiliation and contextual and auditory fear memories were weaker in SI mice than in GH mice. Methylphenidate (MPH), an inhibitor for dopamine transporters, ameliorated the SI-induced social affiliation deficit and the effect was attenuated by SCH23390, a D 1 receptor antagonist, but not by sulpiride, a D 2 receptor antagonist. On the other hand, tacrine, an acetylcholinesterase inhibitor, had no effect on this deficit. In contrast, tacrine improved SI-induced deficits in fear memories in a manner that was reversed by the muscarinic receptor antagonist scopolamine, while MPH had no effect on memory deficits. Neurochemical studies revealed that SI down-regulated the expression levels of the phosphorylated forms of neuro-signaling proteins, calmodulin-dependent kinase II (p-CaMKII), and cyclic AMP-responsive element binding protein (p-CREB), as well as early growth response protein-1 (Egr-1) in the hippocampus. The administration of MPH or tacrine before fear conditioning had no effect on the levels of the phosphorylated forms of the neuro-signaling proteins elucidated following completion of the auditory fear memory test; however, when analyzed 30 min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively. [ABSTRACT FROM AUTHOR]

Extracellular purines have multiple functional roles in development, plastic remodelling, and regeneration of the CNS by stimulating certain P2X/Y receptor (R) subtypes. In the present study we elucidated the involvement of P2YRs in neuronal fibre outgrowth in the developing nervous system. We particularly focused on the P2Y 1 R subtype and the dopaminergic system, respectively. For this purpose, we used organotypic slice co-cultures consisting of the ventral tegmental area/substantia nigra (VTA/SN) and the prefrontal cortex (PFC). After detecting the presence of the P2Y 1 R in VTA/SN, PFC, and on outgrowing fibres in the border region (e.g. on glial processes) connecting both brain slices, we could show that pharmacological modulation of the receptor influenced neuronal fibre outgrowth. Biocytin-tracing and tyrosine hydroxylase-immunolabelling together with quantitative image analysis revealed a significant increase in fibre growth in the border region of the co-cultures after treatment with ADPβS (P2Y 1,12,13 R agonist). The observed stimulatory potential of ADPβS was inhibited by pre-treatment with the P2X/YR antagonist PPADS. In P2Y 1 R knockout (P2Y 1 R −/− ) mice, the ADPβS-induced stimulatory effect was absent, while growth was significantly enhanced in the co-cultures of the respective wild-type. This observation was confirmed in entorhino-hippocampal co-cultures, an example of a different projection system, expressing the P2Y 1 R. Using wortmannin and PD98059 we further showed that PI3K/Akt and MAPK/ERK cascades are involved in the mechanism underlying ADPβS-induced fibre growth. In conclusion, the data of this study clearly indicate that activation of the P2Y 1 R stimulates fibre growth and thereby emphasises the general role of this particular receptor subtype during development and regeneration. [ABSTRACT FROM AUTHOR]

Dopaminergic system of the brain is believed to be strongly involved in normal and pathological behavioral phenotypes of attention. In metacontrast masking studies attentional effects on metacontrast are predominantly expressed when time intervals between a target stimulus and a masking stimulus are longer rather than shorter. Taken together, this predicts that variability in common genes known to be involved in dopaminergic function could interact with target/mask intervals in determining the effects of metacontrast masking. We tested this by genotyping participants of the masking experiment for the COMT Val158Met, DAT 1 3′UTR 40 bp VNTR, and DRD 4 exon 3 48 bp VNTR variability. We found that Val homozygotes and subjects with long repeat variants of the DRD 4 gene showed relatively higher level of correct target perception with a longer target/mask time interval than with a shorter time interval while DAT 1 variability did not have any effects. Implications of this result for the development of psychophysical testing based methods of screening for vulnerability/resilience in relation to the pathology of the dopaminergic systems related attentional dysfunction are considered. [ABSTRACT FROM AUTHOR]

The effects of amphetamine and haloperidol on spike activity levels, the ability to acquire a conditioned defensive reflex to time, and the state of components of the dopaminergic system in neurons in the sensorimotor cortex and caudate nucleus in rabbits were studied. Chronic administration of amphetamine increased the level of neuron spike activity and the ability to acquire and reproduce conditioned reflexes in the sensorimotor cortex, and decreased these parameters in the caudate nucleus. Biochemical studies demonstrated hyperactivation of the dopaminergic system in the caudate nucleus, as compared with the sensorimotor cortex. On the background of chronic amphetamine, haloperidol induced effects in both locations which were close to those of single doses to intact animals. The neuroleptic led to suppression of neuron activity and a decrease in the number of conditioned reactive neurons in the sensorimotor cortex, in contrast to neurons in the caudate nucleus. Short-term exposure to haloperidol produced changes in biochemical parameters towards normalization of neurotransmitter metabolism. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and opioid systems was investigated. It was evaluated if the administration of PCS triggers toxic effect. Treatment with PCS (10mg/kg) reduced writhing induced by acetic acid and its effect lasts up to 48h after treatment. The compound caused an inhibition in neurogenic and inflammatory phases of nociception and in paw edema induced by formalin. The licking behavior triggered by glutamate was reduced by PCS. In the tail-immersion test, PCS elicited an increase in delta latency response. Pretreatment with caffeine (3mg/kg, intraperitoneally [i.p.]) and SCH58261 (3mg/kg, i.p.), antagonist at adenosinergic receptors, SCH23390 (0.05mg/kg, i.p.) and sulpiride (5mg/kg, i.p.), antagonist at dopaminergic receptors, caused a reduction in the antinociceptive action of PCS in the glutamate test. By contrast, pretreatment with WAY100635 (0.7mg/kg, i.p.), ketanserin (0.3mg/kg, i.p.), ondasentron (0.5mg/kg, i.p.), l-arginine (600mg/kg, i.p.) and naloxone (1mg/kg, subcutaneous [s.c.]) did not abolish the antinociceptive effect caused by PCS (10mg/kg, i.g.) administration. The animals treated with PCS did not show alterations in locomotor and exploratory activities, in biochemical parameters evaluated, food and water consumption, as well as in the body weight. These results clearly showed the antinociceptive action of PCS in different animal models without causing acute toxic effects in mice. Adenosinergic and dopaminergic systems seem to be related to the mechanisms by which PCS elicits antinociception. [Copyright &y& Elsevier]

Highlights: [•] Clinical and basic studies strongly implicate dopamine (DA) in autism pathogenesis. [•] Here we analyze bionetworks of DA-related proteins, and assess their role in ASD. [•] Our analyses highlight several ASD-related cellular pathways modulated by central DA. [•] They include cellular modulators of DA metabolism/signaling and cytoskeletal proteins. [•] DA-related modulators of Ca2+/other mediators’ signaling are also involved in ASD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Nucleus accumbens (NAc) and prefrontal cortex (PFC) dopaminergic and glutamatergic systems are involved in fear/anxiety-related behaviors; meanwhile NAc dopaminergic system activity is mediated by PFC via NAc glutamatergic projections. This study has investigated the involvement of NAc shell dopaminergic system in prelimbic NMDA-induced anxiolytic-like behaviors. Method: Elevated plus-maze apparatus was employed to test parameters of anxiety-like behaviors in male Wistar rats. Results: Unilateral intra-prelimbic injection of NMDA (0.9 μg/μl) but not D-AP7 (NMDA receptor antagonist; 0.25, 0.5 and 1 μg/μl) induced anxiolytic-like behaviors which was blocked by D-AP7. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1 μg/μl) and quinpirole (dopamine D2 receptor agonist; 0.125, 0.25 and 0.5 μg/μl) into the left NAc shell, did not alter anxiety-like behaviors. However, injection of SKF38393 (dopamine D1 receptor agonist; 3 μg/μl) and sulpiride (dopamine D2 receptor antagonist; 0.4 and 0.6 μg/μl) into the left NAc shell, likewise induced anxiolytic-like behaviors which were blocked by SCH23390 (0.25 μg/μl) and SKF96365 (Ca-channel blocker; 0.125 μg/μl)/SCH23390 (0.25 μg/μl), respectively. Furthermore, infusion of the subthreshold dose of SCH23390 (0.25 μg/μl) or quinpirole (0.25 μg/μl) into the left NAc shell, reduced while did not alter intra-prelimbic NMDA-induced anxiolytic-like behaviors, respectively. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1 μg/μl) or sulpiride (0.2 μg/μl), potentiated the lower dose response, while decreased the higher dose intra-left prelimbic NMDA response. Conclusion: Our results suggested a modulatory effect of the NAc shell dopaminergic system on prelimbic NMDA-induced anxiolytic-like behaviors. [Copyright &y& Elsevier]

Abstract: Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1mg/kg, p.o.) and in the FST (10mg/kg, p.o.), similar to fluoxetine (10mg/kg, p.o.), imipramine (1mg/kg, p.o.) and bupropion (10mg/kg, p.o.). The effect of ursolic acid (0.1mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05mg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist), apomorphine (0.5μg/kg, i.p., a preferential dopamine D2 receptor agonist) or bupropion (1mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D1 and D2 receptors. [Copyright &y& Elsevier]

The clinical and EEG effects of amantadine sulfate were studied in 12 patients with severe craniocerebral trauma accompanied by decreases in the level of consciousness, deficits in motor activity, increased voluntary muscle tone, and severe cognitive impairments. Neurological status, mental activity, and EEG traces were investigated before, during, and after treatment with amantadine sulfate. A relationship between changes in patient's status (levels of mental activity, motor domain) accompanying the use of amantadine sulfate with baseline EEG characteristics was found. [ABSTRACT FROM AUTHOR]

Regular consumption of psychoactive substances leads to many unfavorable sequelae, the most serious of which is the development of addictive behavior, with the compulsive desire to consume a psychoactive substance despite its serious consequences displacing all other activities. Addiction is characterized by an extremely high risk of renewed substance abuse even after prolonged periods of abstinence. It is suggested that addiction is based on the pathological usurpation of the processes of reinforcement, memory, and motivatory regulation, along with dysfunctions of the frontal areas of the cerebral cortex, which in normal conditions regulates decision-taking processes. The key role in the development of these changes belongs to the mesocortical-limbic dopaminergic system. Types of addictive behavior based on agents other than psychoactive substances are linked with similar changes in the nervous system. Addiction results from the interaction of genetic factors and environmental factors. It is characterized by phenotypic and genotypic heterogeneity and a high level of interaction between genes and the environment. Apart from genes, a wide spectrum of external conditions lead to the development of both resistance and susceptibility to disorders associated with the consumption of psychoactive substances. [ABSTRACT FROM AUTHOR]

Intraperitoneal injections of 2.5 mg/kg reserpine daily for 3 days combined with immobilization/pain stress evoked the development of ulcerous damages to the duodenum and stomach in rats. This is accompanied by increases in the content of malonic dialdehyde (MDA) and activity of superoxide dismutase (SOD) in erythrocytes, level of vitamin C in the blood plasma, and activity of SOD in a homogenate of the duodenum tissue. Injections of 0.5 mg/kg L-deprenyl (i.p.) and 50 mg/kg pentoxifylline (i.p.) provided protection effects with respect to stress-induced ulcers; the influences of these agents were mutually potentiated. [ABSTRACT FROM AUTHOR]

Abstract: We have previously shown strain and dose differences in heroin-induced behavior, reward and regional expression of somatostatin receptor mRNAs in C57BL/6J and 129P3/J mice. Using Real Time PCR we examined the effects of five doses of heroin on the levels of the transcripts of endogenous opioid peptides and their receptors and dopaminergic receptors in the mesocorticolimbic and nigrostriatal pathways in these same mice. Compared to C57BL/6J animals, 129P3/J mice had higher mRNA levels of Oprk1 in the nucleus accumbens and of Oprd1 in the nucleus accumbens and a region containing both the substantia nigra and ventral tegmental area (SN/VTA). In the cortex of 129P3/J mice, lower levels of both Oprk1 and Oprd1 mRNAs were observed. Pdyn mRNA was also lower in the caudate putamen of 129P3/J mice. Strain differences were not found in the levels of Oprm1, Penk or Pomc mRNAs in any region examined. Within strains, complex patterns of heroin dose-dependent changes in the levels of Oprm1, Oprk1 and Oprd1 mRNAs were observed in the SN/VTA. Additionally, Oprd1 mRNA was dose-dependently elevated in the hypothalamus. Also in the hypothalamus, we found higher levels of Drd1a mRNA in C57BL/6J mice than in 129P3/J animals and higher levels of DAT (Slc6a3) mRNA in the caudate putamen of C57BL/6J animals than in 129P3/J counterparts. Heroin had dose-related effects on Drd1a mRNA in the hypothalamus and on Drd2 mRNA in the caudate putamen. [Copyright &y& Elsevier]

Abstract: Research has consistently revealed that average IQ scores vary significantly across macro-level units, such as states and nations. The reason for this variation in IQ, however, has remained at the center of much controversy. One of the more provocative explanations is that IQ across macro-level units is the result of genetic differences, but empirical studies have yet to examine this possibility directly. The current study partially addresses this gap in the literature by examining whether average IQ scores across thirty-six schools are associated with differences in the allelic distributions of dopaminergic polymorphisms across schools. Analysis of data drawn from subjects (ages 12–19years) participating in the National Longitudinal Study of Adolescent Health provides support in favor of this perspective, where variation in school-level IQ scores was predicted by school-level genetic variation. This association remained statistically significant even after controlling for the effects of race. [Copyright &y& Elsevier]

Internet addiction is a clinical anomaly with strong negative consequences on social, work-related, family, financial, and economic function of a person. It is regarded as a serious public health issue. The basic idea of this paper is to, based on the currently available body of research work on this topic, point out to neurobiological pathos of Internet addiction, and its connection to the dopaminergic system. Dopamine contains all physiological functions of neurotransmitters and it is a part of chatecholamine family. Five dopaminergic receptors (D1 - D5) belong to the super family of receptors related to G-protein. Through these receptors, dopamine achieves its roles: regulation of voluntary movement, regulation of center of pleasure, hormonal regulation, and regulation of hypertension. In order to recognize an Internet user as an addict, he or she needs to comply with the criteria suggested by the American Psychiatric Association (APA). Phenomenological, neurobiological, and pharmacological data indicates similarities in pathopsychology of substance addiction and pathological gambling, which are indirectly related to the similarity with the Internet addiction. Responding to stimuli from the game, addicts have shown more brain activity in the nape region, left dorsolateral, prefrontal cortex, and left parachipocampal gyrus than in the control group. After the six-week bupropion therapy, desire to play Internet and video games, the total duration of playing, and induced brain activity in dorsolateral prefrontal cortex are lowered with the addicts. Acta Medica Medianae 2011;50(1):60-66. [ABSTRACT FROM AUTHOR]

Abstract: Although academic achievement is a heritable construct, to date research has yet to explore its molecular genetic underpinnings. Drawing on data from the National Longitudinal Study of Adolescent Health, the current longitudinal study investigated the associations between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4) and academic achievement during middle and high school (Ns ranged between 622 and 2181). Findings revealed statistically significant associations between the three dopaminergic polymorphisms and a composite genetic risk index with English, math, history, and science grades. [Copyright &y& Elsevier]

Abstract: Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In this work the mechanisms underlying its antidepressant-like effect were further studied by investigating the involvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. The effect of melatonin (1mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2mg/kg, i.p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05mg/kg, s.c., a selective dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p. administration of melatonin (0.01mg/kg) or fluoxetine (1mg/kg, a serotonin reuptake inhibitor) in combination with SFK38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility time in the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin (0.01mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5μg/kg, i.p., a dopamine D2 receptor agonist), but the pretreatment with fluoxetine (1mg/kg, i.p.) was ineffective to potentiate the effect of apomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did not affect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tail suspension test is likely mediated by an interaction with the dopaminergic system, through an activation of dopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin in depression, suggesting that it might be further investigated as an alternative for the management of depression associated with anhedonia. [Copyright &y& Elsevier]

Abstract: The prolactin release caused by salsolinol (a derivative of dopamine, DA) in rats could be prevented by its structural analogue 1-methyl-3,4-dihydroisoqinoline (1-MeDIQ). To study the participation of salsolinol in the neural stimulatory mechanism of prolactin release in lactating sheep, we tested whether 1-MeDIQ, acting at the central nervous system (CNS) level, would diminish basal prolactin release and reduce prolactin surge induced by suckling. A series of intracerebroventricular (icv) infusions of 1-MeDIQ (5×60 μg/60 μl/30 min, at 30-min intervals) were performed in nursing ewes (n =8) during the fifth week of lactation. Additionally, by combining these infusions with push–pull perfusion, we studied the concentration of dopaminergic components, i.e., salsolinol, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) within the infundibular nucleus/median eminence (IN/ME) in four of the ewes. Treatment with 1-MeDIQ significantly (P <0.001) reduced either the basal prolactin release during the non-suckling period or the suckling-induced prolactin surge. Specifically, the suppressive effect occurred gradually, affecting both the duration and amplitude of the prolactin surge. In the control ewes, the perfusate salsolinol concentration increased significantly (P <0.001) during suckling, while in the ewes treated with 1-MeDIQ only vestigial amounts of this compound were found during the non-suckling period. No DA was detected in the perfusates collected from the IN/ME of control and 1-MeDIQ-treated groups and no significant differences were found in the DOPAC concentrations between these groups. In conclusion, 1-MeDIQ is able to inhibit prolactin secretion in lactating sheep, acting at the CNS level. In addition, one of the way of 1-MeDIQ action may be directed to the local salsolinol release within the mediobasal hypothalamus. [Copyright &y& Elsevier]

Parkinson's disease (PD) is a common progressive neurodegenerative disorder, mainly classified as a movement disorder which manifests among others nonmotor symptoms such as olfactory dysfunction. The etiopathogenesis of this disease has yet to be elucidated, though it seems to be interconnected with a complex set of genetic, environmental, and immunological interactions. This review unfolds the immune alterations observed in PD patients by describing the increase in the innate immune components including complement and cytokines within their substantia nigra and cerebrospinal fluid (CSF). These alterations extended to the adaptive immune response with the elevation of T cells and autoantibodies (anti-α-synuclein and anti-GM1-ganglioside) in the peripheral blood and CSF of PD patients. Interestingly, another etiopathogenic triad has recently emerged linking PD to autoimmunity through olfactory dysfunction. Smell deficit is one of the earliest signs of PD and a unique observation suggesting olfactory declines to be a consequence of autoimmune mechanisms. Therefore, we considered several undisputed autoimmune diseases known for their olfactory consequences as template examples that may shed more light on the relationship between autoimmunity and PD. We hope that understanding the nature of this disease may lay the ground for successes in the quest to halt the progressive neurodegenerative process. [ABSTRACT FROM AUTHOR]

The aim of the present work was to study the involvement of the dopaminergic system of the telencephalic and diencephalic areas of the vertebrate brain in the organization of the sleep–waking cycle in cold-blooded and warm-blooded vertebrates. Immunohistochemical studies of tyrosine hydroxylase content, this being the key enzyme in dopamine synthesis, in the striatum, supraoptic and arcuate nuclei, and zona incerta of the hypothalamus of sturgeon and mammals (rats) of three age groups (14 and 30 days and adults), in conditions of tactile and sleep-deprivation stressors. In fish, transient stress was followed by the detection of tyrosine hydroxylase-immunoreactive cells in all parts of the brain. In prolonged stress, tyrosine hydroxylase-immunoreactive cells and fibers were not found in the forebrain, though they were well represented in the hypothalamic nuclei. In 14-day-old rat pups, 2-h sleep deprivation increased the tyrosine hydroxylase content of fibers in the caudate nucleus and cells in the zona incerta of the hypothalamus, while 30-day-old animals subjected to 6-h sleep deprivation showed increases in tyrosine hydroxylaseimmunoreactive material contents in cells in the paraventricular nucleus and decreases in the quantity in fibers. In adult rats, the arcuate nucleus and zona incerta showed decreases in the content of tyrosine hydroxylase-immunoreactive material on the background of sleep deprivation, with increases during postdeprivation sleep. These data are discussed in the light of the phylo- and ontogenetic development of the neurosecretory and neurotransmitter functions of the dopaminergic system in the evolutionarily ancient diencephalic and evolutionarily young telencephalic areas of the vertebrate brain as major systems triggering and maintaining the functional states of the body during the sleep–waking cycle. [ABSTRACT FROM AUTHOR]

Abstract: Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(−/−)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(−/−) mice. The Mdk(−/−) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(−/−) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system. [Copyright &y& Elsevier]

Abstract: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a seleno-organic compound which possesses a potent antioxidant activity and has been shown to exert neuroprotective effects in vitro and in vivo in a variety of pro-oxidative insults. The present study investigates a possible antidepressant activity of ebselen using two predictive tests for antidepressant activity in rodents: the forced swimming test and tail suspension test. Additionally, the mechanisms involved in the antidepressant-like effect of ebselen in mice were also assessed. Ebselen (10 mg/kg, s.c.) decreased the immobility time in the forced swimming test without accompanying changes in ambulation in the open-field test. In contrast, the administration of ebselen (10–30 mg/kg) did not produce any effect in the tail suspension test. The anti-immobility effect of ebselen (10 mg/kg, s.c.) was not prevented by pre-treatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a serotonin 5-HT1A receptor antagonist) or ketanserin (5 mg/kg, i.p., a serotonin 5-HT2A/2C receptor antagonist). On the other hand, the pre-treatment of mice with prazosin (1 mg/kg, i.p., an α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist) completely blocked the antidepressant-like effect of ebselen (10 mg/kg, s.c.) in the forced swimming test. It may be concluded that ebselen produces an antidepressant-like effect in the forced swimming test that seems to be dependent on its interaction with the noradrenergic and dopaminergic systems, but not with the serotonergic system. [Copyright &y& Elsevier]

Abstract: Studies have suggested a relationship between drug abuse and compulsive behaviors. The present experiments investigated the relationship between schedule-induced polydipsia (SIP) and self-administration (SA) of ethanol and sucrose. SIP served as a model of compulsive behavior, and oral self-administration on a progressive-ratio (PR) schedule of reinforcement assessed the reinforcing value of either a 10% ethanol solution or an isocaloric sucrose solution. Rats first were exposed to PR sessions in which break points were the dependent variable and then switched to SIP sessions, with number of licks as the dependent variable. Results showed a positive relationship between PR and SIP for sucrose but not for ethanol: higher and lower PRs for sucrose were associated with higher and lower SIP levels. The order of the sessions then was reversed, such that SIP sessions were run before PR sessions. An opposite relationship was observed in which high and low SIP animals exhibited low and high PR break points, respectively. The relationship between SIP and SA was dependent on the reinforcing value of the substance and on prior SIP exposure. These results may reflect a common dopaminergic substrate and suggest that prior experience in coping with stress may reduce vulnerability to substance abuse behavior. [Copyright &y& Elsevier]

The dopaminergic system has been shown to be involved in the aetiology of obsessive–compulsive disorder (OCD). Family studies suggest a higher genetic loading in patients with early onset OCD. Our investigation is the first family-based association study concerning polymorphisms in genes of the dopaminergic system in early onset OCD. We studied polymorphisms within the dopamine-4 receptor gene (DRD4), the dopamine transporter gene (DAT1) and the catecholamine- O-methyltransferase gene (COMT). Associations of alleles of DRD4 and COMT with OCD have previously been reported in adults, while a trend towards an association was found for DAT1 alleles. In our study we observed transmission disequilibrium for the 48-bp repeat polymorphism of the DRD4 gene using the ETDT ( P = 0.047) in 69 trios comprising patients with early onset OCD and both of their parents. Post hoc TDT analysis of the DRD4 showed reduced transmission of the 4-repeat allele and a slightly increased transmission rate for the 7- and the 2-repeat allele. No evidence of transmission disequilibrium was detected for alleles of the DAT1 and COMT polymorphisms. These polymorphisms do not appear to play a major role in the genetic predisposition to early onset OCD in our study group. [ABSTRACT FROM AUTHOR]

Neurodegenerative dementia is an increasingly common disorder with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) accounting for most cases. Due to the overlap in clinical symptoms, their differential diagnosis may be challenging. As clinical classification is not completely satisfying, there is a need to improve the diagnostic accuracy by complementary methods such as functional single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging. The latter may be helpful to address one distinct biological difference between DLB and AD, the severe nigrostriatal degeneration which occurs in DLB, but not to any significant extent in AD. Based on this principle, autoradiographic studies targeting presynaptic dopaminergic functions have consistently demonstrated the ability to distinguish DLB from AD in postmortem series. At the same time, several single-site and one multicentre study have independently confirmed—no matter what technique was used (SPECT or PET) and which presynaptic function was addressed (dopamine turnover, dopamine transporter, vesicular monoamine transporter)—significantly compromised scan results in DLB subjects, whereas AD patients maintained almost normal findings. Even more important, in vivo findings of presynaptic dopaminergic imaging correlated well with neuropathological findings at autopsy, suggesting a remarkable sensitivity of 88% and a specificity of 100% for the imaging procedure to distinguish between DLB and AD. Taken together, imaging of presynaptic dopaminergic terminal functions with SPECT and PET has currently the greatest evidence base to support its use, and therefore, may be highly recommended to help in the discrimination between DLB and AD. Compared to presynaptic functions, corresponding data targeting postsynaptic dopamine receptors are comparatively rare, less conclusive and suggest a very limited role for this purpose. This review discusses the findings of studies specifically dealing with imaging of the dopaminergic system in the differential diagnosis of dementia. [ABSTRACT FROM AUTHOR]

This article analyzes the simple Rescorla–Wagner learning rule from the vantage point of least squares learning theory. In particular, it suggests how measures of risk, such as prediction risk, can be used to adjust the learning constant in reinforcement learning. It argues that prediction risk is most effectively incorporated by scaling the prediction errors. This way, the learning rate needs adjusting only when the covariance between optimal predictions and past (scaled) prediction errors changes. Evidence is discussed that suggests that the dopaminergic system in the (human and nonhuman) primate brain encodes prediction risk, and that prediction errors are indeed scaled with prediction risk (adaptive encoding). [ABSTRACT FROM AUTHOR]

The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001–1 µm) induced a concentration-dependant K+-evoked [3H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 µm, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 µm) blocked the SB-357134-induced K+-stimulated [3H]ACh release, and simultaneous administration of MK-801 (1 µm) and SB-357134 (0.05 µm) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 µm, decreased dopamine release, and the increase in K+-evoked [3H]ACh release induced by 5-HT6 receptor blockade was reversed by the D1 receptor antagonist, SCH23390 (1 µm). In both the frontal cortex and striatum, bicuculline, 1 µm, showed no effect on SB-357134-evoked [3H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic, neurodegenerative disease with a 1% incidence in the population over 55 years of age. Movement impairments represent undoubtedly the hallmark of the disorder; however, extensive evidence implicates cognitive deficits as concomitant peculiar features. Brain-derived neurotrophic factor (BDNF) colocalizes with dopamine neurons in the substantia nigra, where dopaminergic cell bodies are located, and it has recently garnered attention as a molecule crucial for cognition, a function that is also compromised in PD patients. Thus, due to its colocalization with dopaminergic neurons and its role in cognition, BDNF might possess a dual role in PD, both as a neuroprotective molecule, since its inhibition leads to loss of nigral dopaminergic neurons, and as a neuromodulator, as its enhanced expression ameliorates cognitive processes. In this review, we discuss the mechanism of action of established as well as novel drugs for PD with a particular emphasis to those interfering with BDNF biosynthesis.The Pharmacogenomics Journal (2006) 6, 95–104. doi:10.1038/sj.tpj.6500360; published online 10 January 2006 [ABSTRACT FROM AUTHOR]

Organic solvents pose a considerable health risk for humans. It is due to their ability to cross biological barriers and indisputable toxicity on the one hand, and the wealth of applications and large production and consumption volumes on the other. The primary target of the toxic action of organic solvents is the nervous system. In this paper, some literature data showing that dopaminergic neurons and their projections are particularly susceptible to the toxic solvent action are presented. [ABSTRACT FROM AUTHOR]

In the present research the interaction between the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) and morphine in memory consolidation was investigated. Four sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. The drugs were administered intraperitoneally after training of the animals in the apparatus. In the first set of experiments morphine (0.3 or 0.5, but not 0.15 mg/kg) or anandamide (3 or 6 but not 1.5 mg/kg) dose-dependently impaired memory consolidation. In the second set of experiments the administration of an otherwise ineffective dose of anandamide (1.5 mg/kg) enhanced the memory impairment exerted by morphine (0.3 and 0.5 mg/kg) when the drugs were injected immediately after training. In the third set of experiments the combined treatments of anandamide (1.5 mg/kg) and morphine (0.5 mg/kg) 2 h after training were ineffective showing that the effects observed on performance following immediate posttraining administration of anandamide and morphine combinations were reflecting direct influences on memory consolidation. In the fourth set of experiments otherwise ineffective doses of the D1 DA receptor agonist SKF 38393 or the D2 DA receptor agonist LY 171555 antagonized the memory impairment produced by anandamide and morphine in combination, suggesting a possible involvement of dopaminergic mechanisms. [Copyright &y& Elsevier]

It is becoming widely accepted that the inflammatory response is involved in neurodegenerative disease. In this context, we have developed an animal model of dopaminergic system degeneration by the intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation. To address the importance of the inflammatory response in the LPS-induced degeneration of nigral dopaminergic neurones, we carried out two different kinds of studies: (i) the possible protective effect of an anti-inflammatory compound, and (ii) the effect of the intranigral injection of inflammatory cytokines (TNF-α, IL-1β and IFN-γ) on dopaminergic neurones viability. Present results show that dexamethasone, a potent anti-inflammatory drug that interferes with many of the features characterizing pro-inflammatory glial activation, prevented the loss of catecholamine content, Tyrosine hydroxylase (TH) activity and TH immunostaining induced by LPS-injection and also the bulk activation of microglia/macrophages. Surprisingly, injection of the pro-inflammatory cytokines failed to reproduce the LPS effect. Taken together, our results suggest that inflammatory response is implicated in LPS-induced neurodegeneration. This damage may be due, at least in part, to a cascade of events independent of that described for TNF-α/IL-1β/IFN-γ. [ABSTRACT FROM AUTHOR]

A brief review is provided on the role of experimental modulation of the visual system during its plastic period. The importance of several substances has been demonstrated. Potential clinical applications of available studies on the treatment of amblyopia are summarized. The role of the dopaminergic system and particularly of dopamine in amblyopia are also discussed. The results of the use of cytidine-5′-diphosphocholine (citicoline) in amblyopia are evaluated in detail. The advantages of and indications for an association of citicoline with part-time occlusion are also discussed. Finally, new administration modalities of citicoline, more detailed evaluation of its efficacy, and the use of new substances are briefly analyzed. [ABSTRACT FROM AUTHOR]