The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease.

Purpose: Comparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)-induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice. Methods: After DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated. Results: The mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive: 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.7- and 2.1-fold, P < 0.001). Interestingly, DR1 and DR2 immunostaining patterns stained independently in DE-induced LGs. CD3+ and CD19+ cell infiltration was significantly increased by DR2i (P < 0.001) but not by DR1i. Furthermore, IFN-γ, IL-17, and TNF-α were significantly upregulated by DR2i compared with the blow-only condition. The severity of corneal erosion and inflammation was also aggravated by DR2i. Conclusions: Upregulation of DR1 and DR2 was observed in DE-induced mouse LGs. As the inflammatory conditions are aggravated by the inhibition of DRs, especially DR2, their activity may be an important factor preserving ocular surface homeostasis.

Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice.

Methamphetamine (Meth) abuse is a common HIV comorbidity. Males and females differ in their patterns of Meth use, associated behaviors, and responses, but the underlying mechanisms and impact of HIV infection are unclear. Transgenic mice with inducible HIV-1 Tat protein in the brain (iTat) replicate many neurological aspects of HIV infection in humans. We previously showed that Tat induction enhances the Meth sensitization response associated with perturbation of the dopaminergic system, in male iTat mice. Here, we used the iTat mouse model to investigate sex differences in individual and interactive effects of Tat and Meth challenge on locomotor sensitization, brain expression of dopamine receptors (DRDs) and regulatory adenosine receptors (ADORAs). Because Meth administration increases the production of reactive oxygen species (ROS), we also determined whether the effects of Meth could be rescued by concomitant treatment with the ROS scavenger N-acetyl cysteine (NAC). After Meth sensitization and a 7-day abstinence period, groups of Tat+ and Tat-male and female mice were challenged with Meth in combination with NAC. We confirmed that Tat expression and Meth challenge suppressed DRD mRNA and protein in males and females' brains, and showed that females were particularly susceptible to the effects of Meth on D1-like and D2-like DRD subtypes and ADORAs. The expression of these markers differed strikingly between males and females, and between females in different phases of the estrous cycle, in a Tat -dependent manner. NAC attenuated Meth-induced locomotor sensitization and preserved DRD expression in all groups except for Tat + females. These data identify complex interactions between sex, Meth use, and HIV infection on addiction responses, with potential implications for the treatment of male and female Meth users in the context of HIV, especially those with cognitive disorders.

Restriction and hyperlipidic diets during pregnancy, lactation and adult life modified the expression of dopaminergic system related genes both in female mice and their adult offspring.

The neurocircuitry underlying hunger, satiety, motivation to eat and food reward is complex, however a lot of mechanisms are still unknown. Two main cerebral areas are responsible for controlling feeding through hunger and food reward: the hypothalamus (HPT) and the ventral tegmental area (VTA), respectively. The dopaminergic system modulates both these areas and is essential to control food ingestion. Therefore, we aim to evaluate the effects of restrictive and hyperlipidic diets during pregnancy, lactation and during adult life of the offspring, on the expression of dopaminergic system genes in VTA and HPT of mice dams and their adult male offspring. We also measured diets' effect in locomotor activity in the open field (OF) test. Female mice were divided into control (CONT), restriction (RD) and hyperlipidic (HD) dietary groups, and mated with isogenic male mice. On the 9th postpartum day (PPD), dams were tested in the OF, and on the 22nd PPD cerebral areas were collected. After weaning, the offspring also were divided into one of three diet groups, independently of the diets provided to their dams. In the 80th PPD, the offspring was tested in the OF, and at 100th PPD, VTA and HPT were collected. Gene expression was analyzed by quantitative reverse transcription real-time polymerase chain reaction. The correlation between gene expression and locomotor activity was also assessed. In dams' VTA, both diets upregulated the expression of Th, Slc6a3/Dat1, Drd1 and Drd2 genes. In opposition, in the offspring the maternal diet was associated with a reduction in Th and Ddc gene expression. In the HPT, mice dams that received restriction or hyperlipidic diets had increased Th mRNA levels, but reduced the expression of Drd4 gene. The offspring diet had no effect on the expression of the studied genes in their adult lives. Both diets increased mice dam's locomotion in the OF, however none of them altered the offspring locomotor activity. We detected a positive correlation between the duration of total locomotion in the OF and Slc6a3/Dat1 gene expression in VTA of mice dams. In the HPT, a negative correlation of locomotion and Drd4 mRNA levels, and a positive correlation with Th gene expression was observed. Our results show that restriction and hyperlipidic diets alter mice dams' locomotor activity in the OF and modify the expression of dopaminergic system genes in VTA and HPT of mice dams and in VTA of the offspring.

Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems.

Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.

Serotonin and Dopamine Receptor Expression in Solid Tumours Including Rare Cancers.

In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target.

The serotonin or dopamine by cyclic adenosine monophosphate-protein kinase A pathway involved in the agonistic behaviour of Chinese mitten crab, Eriocheir sinensis.

Agonistic behaviour is common in an encounter between two crustaceans. It often causes limb disability and consumes a lot of energy, which is harmful for the growth and survival of commercially important crustaceans. In the present study, we mainly focused on the agonistic behaviour of the Chinese mitten crab, Eriocheir sinensis, which is an important species of the aquaculture industry in China. We recorded agnostic behaviour with a high-definition camera and preliminarily evaluated the role of serotonin (5-HT) or dopamine (DA)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway and eyestalk in the behaviour. The results showed that agonistic behaviour in E. sinensis consisted of three stages: approach, contact and fight. We found that the number of fights and cumulative time of fight were significantly higher in the male vs. male group than in the female vs. female and female vs. male groups (P < 0.05). After 1 h of agonistic behaviour, 5-HT concentration showed a significant increase and DA concentration showed a significant decrease when compared with the control group (no encounter; P < 0.05). 5-HT1B and 5-HT2B mRNA levels showed a significant increase in the eyestalk (P < 0.05). 5-HT7 mRNA levels showed significant downregulation in the thoracic ganglia and DA1A mRNA levels showed upregulation in the intestine (P < 0.05). DA2 mRNA levels showed a significant decrease in the eyestalk (P < 0.05). These changes were accompanied by a significant increase in cAMP level and significant decrease in PKA level in the haemolymph (P < 0.05). In addition, a significant decrease in glucose levels was detected after the agonistic behaviour. Crustacean hyperglycemic hormone (CHH) mRNA levels showed significant upregulation in the eyestalk and significant downregulation in the intestine (P < 0.05). The number of fights and cumulative time of fight in the left eyestalk ablation (L-X vs. L-X) group were more and longer than those in the intact eyestalk (C vs. C), right eyestalk ablation (R-X vs. R-X) and bilateral eyestalk ablation (D-X vs. D-X) groups. In short, E. sinensis shows special agonistic behaviour modulated by 5-HT or DA-cAMP-PKA pathway and eyestalk, especially the left eyestalk.

Novel Insight into Differential Gene Expression and Clinical Significance of Dopamine Receptors, COMT, and IL6 in BPH and Prostate Cancer.

BACKGROUND: Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are the most prevalent diseases in male population, implicated with fundamental differences between benign and malignant growth of prostate cells. An imbalance through a network of nervous, endocrine, and immune systems initiate a signal of altered growth from the brain to the prostate gland, leading to adverse effects such as inflammation. OBJECTIVE: The aim of this study was to evaluate the gene expression of dopamine receptor family, COMT, and IL6 to identify novel correlations in BPH and PCa in both blood and tumor of the patients. METHODS: Peripheral blood mononuclear cells from BPH (n= 30) and PCa (n= 30) patients, and prostate tumor tissues (n= 14) along with pathologically normal adjacent tissues (n= 14) were isolated, mRNA was extracted, and cDNA was synthesized, respectively. Quantitative real- time PCR was applied for DRD1- DRD5, COMT, and IL6 genes in all samples. RESULTS: We found, for the first time, that the expression of COMT and IL6 genes were inversely correlated with the expression of DRD1 and DRD2 genes through the extent of differentiation of PCa from BPH condition. In addition, the PSA levels were correlated with the expression of DRD1 in BPH cases and DRD1, DRD4, DRD5, and IL6 in PCa cases. CONCLUSION: Results implicate a potential cross- talk between the signaling pathways derived by IL6 cytokine and dopamine receptors in PCa. Thus, it seems promising to reassemble the consequent signaling pathways by adequate agonists and antagonists to help increase therapeutic efficacy.

Adult rat morphine exposure changes morphine preference, anxiety, and the brain expression of dopamine receptors in male offspring.

Addiction to drugs, including opioids is the result of an interplay between environmental and genetic factors. It has been shown that the progeny of addict people is at higher risk for drug addiction. However, the mechanisms of such trans-generational effects of drugs are not so clear. Here we have evaluated the effects of parental morphine consumption on anxiety, morphine preference, and mRNA expression of dopamine receptors in F1 and F2 male offspring. Morphine was chronically administered to adult male and female Wistar rats followed by 14-day abstinence before mating. Morphine preference and anxiety-like behavior in the offspring were measured by two-bottle-choice paradigm and elevated-plus maze, respectively. Real-time PCR was used to measure the mRNA expression level of dopamine receptors in the striatum, nucleus accumbens, prefrontal cortex, and hippocampus of F1 animals. The results indicated that F1 but not the F2 male progeny of morphine-exposed parents had a greater preference for morphine, and more anxiety-like behavior compared to the offspring of saline-treated parents. In F1 male progeny of morphine-treated parents, D1 and D5 dopamine receptors were significantly increased in the prefrontal cortex and nucleus accumbens. D5 and D2 receptors were decreased in the hippocampus. D4 dopamine receptor was augmented in striatum and hippocampus and decreased in the prefrontal cortex. Adulthood exposure to chronic morphine in male and female rats before conception leads to higher morphine preference and increased anxiety in F1 but not F2 male progeny. Alterations of dopamine receptor expression in the reward system may be one mechanism responsible for observed changes in F1 offspring.

The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents.

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity.

The Unique Dopamine/Ecdysteroid Receptor Modulates Ethanol-Induced Sedation in Drosophila.

Steroids profoundly influence behavioral responses to alcohol by activating canonical nuclear hormone receptors and exerting allosteric effects on ion channels. Accumulating evidence has demonstrated that steroids can also trigger biological effects by directly binding G-protein-coupled receptors (GPCRs), yet physiological roles of such unconventional steroid signaling in controlling alcohol-induced behaviors remain unclear. The dopamine/ecdysteroid receptor (DopEcR) is a GPCR that mediates nongenomic actions of ecdysteroids, the major steroid hormones in insects. Here, we report that Drosophila DopEcR plays a critical role in ethanol-induced sedation.DopEcR mutants took longer than control flies to become sedated during exposure to ethanol, despite having normal ethanol absorption or metabolism. RNAi-mediated knockdown of DopEcR expression revealed that this receptor is necessary after eclosion, and is required in particular neuronal subsets, including cholinergic and peptidergic neurons, to mediate this behavior. Additionally, flies ubiquitously overexpressing DopEcR cDNA had a tendency to become sedated quickly upon ethanol exposure. These results indicate that neuronal subset-specific expression of DopEcR in adults is required for normal sedation upon exposure to ethanol. We also obtained evidence indicating that DopEcR may promote ethanol sedation by suppressing epidermal growth factor receptor/extracellular signal-regulated kinase signaling. Last, genetic and pharmacological analyses suggested that in adult flies ecdysone may serve as an inverse agonist of DopEcR and suppress the sedation-promoting activity of DopEcR in the context of ethanol exposure. Our findings provide the first evidence for the involvement of nongenomic G-protein-coupled steroid receptors in the response to alcohol, and shed new light on the potential roles of steroids in alcohol-use disorders. SIGNIFICANCE STATEMENT: Alcohol abuse is an alarming personal and societal burden. The improvement of prevention and treatment strategies for alcohol-use disorders requires a better understanding of their biological basis. Steroid hormones profoundly affect alcohol-induced behaviors, but the contribution of their unconventional, nongenomic actions during these responses has not yet been elucidated. We found that Drosophila DopEcR, a unique G-protein-coupled receptor (GPCR) with dual specificity for dopamine and steroids, mediates noncanonical steroid actions to promote ethanol-induced sedation. Because steroid signaling and the behavioral response to alcohol are evolutionarily well conserved, our findings suggest that analogous mammalian receptors likely play important roles in alcohol-use disorders. Our work provides a foundation for further characterizing the function and mechanisms of action of nonclassical steroid GPCR signaling.

Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.

Expression of dopaminergic receptors on human CD4+ T lymphocytes: flow cytometric analysis of naive and memory subsets and relevance for the neuroimmunology of neurodegenerative disease.

Dopamine (DA) is a crucial transmitter in the neuroimmune network, where it contributes to the nervous system-immune system interplay as well as in the communication among immune cells. DA acts through five different dopaminergic receptors (DR) grouped into two families: the D1-like (D1 and D5) and the D2-like (D2, D3 and D4). By use of 5-color flow cytometric analysis, we examined the expression of DR on human CD4+ naive T lymphocytes (CD3+CD4+CD45RA+CCR7+), central memory (TCM, CD3+CD4+CD45RA-CCR7+) and effector memory T cells (TEM, CD3+CD4+CD45RA-CCR7-). In addition, in cultured CD4+ T cells we investigated the changes in DR expression induced by stimulation with antiCD3/antiCD28 antibodies. Results showed that CD4+ T cells always expressed all the five DR: D1-like DR were identified on average on 11.6-13.1 % and D2-like DR on 3.1-8.1 % of the cells. DR on CD4+ naive T cells, TCM, and TEM had distinct expression patterns: naive T cells expressed more D1-like than D2-like DR, which on the contrary were increased in TCM and TEM cells. In cultured CD4+ T cells stimulation with anti-CD3/anti-CD28 antibodies increased the expression of D1-like DR by 71-84 % and of D2-like DR by 55-97 %. The frequency of DR was higher in apoptotic cells in comparison to viable cells, however stimulation increased all DR on viable cells, without affecting their expression on apoptotic cells. The present results contribute to unravel the complexity of dopaminergic pathways in human CD4+ T lymphocytes, suggesting their involvement in memory functions as well as in apoptotic processes. In view of the role of CD4+ memory T cells in neuroinflammation and neurodegeneration during Parkinson's disease, the relevance of these findings must be assessed in the clinical setting.

Lowered insulin signalling ameliorates age-related sleep fragmentation in Drosophila.

Sleep fragmentation, particularly reduced and interrupted night sleep, impairs the quality of life of older people. Strikingly similar declines in sleep quality are seen during ageing in laboratory animals, including the fruit fly Drosophila. We investigated whether reduced activity of the nutrient- and stress-sensing insulin/insulin-like growth factor (IIS)/TOR signalling network, which ameliorates ageing in diverse organisms, could rescue the sleep fragmentation of ageing Drosophila. Lowered IIS/TOR network activity improved sleep quality, with increased night sleep and day activity and reduced sleep fragmentation. Reduced TOR activity, even when started for the first time late in life, improved sleep quality. The effects of reduced IIS/TOR network activity on day and night phenotypes were mediated through distinct mechanisms: Day activity was induced by adipokinetic hormone, dFOXO, and enhanced octopaminergic signalling. In contrast, night sleep duration and consolidation were dependent on reduced S6K and dopaminergic signalling. Our findings highlight the importance of different IIS/TOR components as potential therapeutic targets for pharmacological treatment of age-related sleep fragmentation in humans.

Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake.

Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5­HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutrition­induced prenatal undernutrition (UN) was investigated in mice and the expression of 5­HT1A, dopamine (D)1, D2 and Ob­Rb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5­HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. Ob­Rb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by Ob­Rb, 5­HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity.

Schizophrenia and dopamine receptors.

Schizophrenia patients are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate, meaning that patients respond to such drugs with increased psychotic symptoms, as compared to control subjects. A basis of such supersensitivity may be an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of D2High receptors in active stages of schizophrenia. While the pre-synaptic release of dopamine is normal in stable patients with schizophrenia, brain imaging studies find that D2 receptors are increased by an average of 5.8% in antipsychotic-free schizophrenia patients. It is possible that the behavioral supersensitivity may stem from more D2High receptors in schizophrenia. Although the antipsychotic/dopamine D2 receptor can exist in vitro in a state of high affinity for dopamine (as D2High), or in a state of low affinity for dopamine (as D2Low), there is no clear evidence that D2High states can be selectively labeled or stably exist in vivo. Nevertheless, two studies revealed an 80% increase in apparent D2High receptors in schizophrenia patients after reducing endogenous dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in vitro in animal models of psychosis, including dopamine-supersensitive animals pretreated with amphetamine, marijuana, or phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including those for glutamate receptors. The elevation of D2High receptors in vitro and the increased apparent D2High receptors in vivo is consistent with behavioral dopamine supersensitivity in schizophrenia patients.

The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats.

Rearing young rodents in socially isolated or environmentally enriched conditions has been shown to affect numerous components of the dopamine system as well as behavior. Methylphenidate (MPH), a commonly used dopaminergic agent, may affect animals differently based on rearing environment. Here we examined the interaction between environment and chronic MPH treatment at clinically relevant doses, administered via osmotic minipump. Young Sprague Dawley rats (PND 21) were assigned to environmentally enriched, pair-housed, or socially isolated rearing conditions, and treated with either 0, 2, 4, or 8 mg/kg/day MPH for 3 weeks. At the end of the treatment period, animals were tested for locomotor activity and anxiety-like behavior. The densities of D1-like and D2-like receptors were measured in the striatum using in vitro receptor autoradiography. Locomotor activity and anxiety-like behavior were increased in isolated animals compared to pair-housed and enriched animals. The density of D1-like receptors was greater in isolated animals, but there were no differences between groups in D2-like receptor density. Finally, there were no effects of MPH administration on any reported measure. This study provides evidence for an effect of early rearing environment on the dopamine system and behavior, and also suggests that MPH administration may not have long-term consequences.

Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake.

Obesity has reached global epidemic proportions and creating an urgent need to understand mechanisms underlying excessive and uncontrolled food intake. Ghrelin, the only known circulating orexigenic hormone, potently increases food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic reward system and to the increased food reward behavior remains unclear. Here we examine whether VTA-NAc dopaminergic signaling is required for the effects of ghrelin on food reward and intake. In addition, we examine the possibility of endogenous ghrelin acting on the VTA-NAc dopamine neurons. A D1-like or a D2 receptor antagonist was injected into the NAc in combination with ghrelin microinjection into the VTA to investigate whether this blockade attenuates ghrelin-induced food reward behavior. VTA injections of ghrelin produced a significant increase in food motivation/reward behavior, as measured by sucrose-induced progressive ratio operant conditioning, and chow intake. Pretreatment with either a D1-like or D2 receptor antagonist into the NAc, completely blocked the reward effect of ghrelin, leaving chow intake intact. We also found that this circuit is potentially relevant for the effects of endogenously released ghrelin as both antagonists reduced fasting (a state of high circulating levels of ghrelin) elevated sucrose-motivated behavior but not chow hyperphagia. Taken together our data identify the VTA to NAc dopaminergic projections, along with D1-like and D2 receptors in the NAc, as essential elements of the ghrelin responsive circuits controlling food reward behavior. Interestingly results also suggest that food reward behavior and simple intake of chow are controlled by divergent circuitry, where NAc dopamine plays an important role in food reward but not in food intake.

Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra.

Parkinson's disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive individuals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1-D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control.

Modulation of ventral tegmental area dopamine receptors inhibit nicotine-induced anxiogenic-like behavior in the central amygdala.

Nicotine, the major addictive substance in tobacco, increases the activity of the central amygdala (CeA). Amygdala is directly implicated in anxiety modulation and sends projections to the vicinity of the midbrain dopamine neurons, including the ventral tegmental area (VTA) which is a key area that controls nicotine dependence processes. In this study, the role of dopamine D(1) and D(2)/(3) receptors of the VTA on anxiogenic-like behavior induced with intra-CeA injection of nicotine has been investigated. Male Wistar rats with cannula aimed to the left CeA and the left VTA were submitted to the elevated plus-maze (EPM). The nicotine injection (1 µg/rat) into the CeA decreased the percentage of open arm time and open arm entries, but not locomotor activity, indicating an anxiogenic-like response. Intra-VTA injection of a dopamine D1 receptor antagonist, SCH23390 (0.25 µg/rat), and a dopamine D2/3 receptor antagonist, sulpiride (0.7 µg/rat), inhibited the anxiogenic-like response caused by intra-CeA injection of nicotine. These results suggest that the relationship between the VTA and the CeA may be involved in nicotine-induced anxiogenic-like behavior via dopamine D(1) and D(2)/(3) receptors. An understanding of these cellular processes will be crucial for the development of new intervention to combat nicotine effect.