Concept: Dopamine receptor
Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.
The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.
Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor–expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor–expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor–expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions.
Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a key mechanism in the treatment of schizophrenia. However, the downstream molecular mechanisms related to GABA potentiation remain unexplored. Recent studies have suggested that dopamine D2 receptor antagonists, which are used in the clinical treatment of schizophrenia, modulate protein kinase B (Akt)/glycogen synthase kinase (GSK)-3 signaling. Here we report that activation of GABAB receptors significantly inhibits Akt/GSK-3 signaling in a beta-arrestin-dependent pathway. Agonist stimulation of GABAB receptors enhances the phosphorylation of Akt (Thr-308) and enhances the phosphorylation of GSK-3alpha (Ser-21)/beta (Ser-9) in both HEK-293T cells expressing GABAB receptors and rat hippocampal slices. Furthermore, knocking down the expression of beta-arrestin2 using siRNA abolishes the GABAB receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABAB receptor agents may exert therapeutic effects in the treatment of schizophrenia.
BACKGROUND: The use of mother’s own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants' prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply.Methods/designEMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha = 0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36–40 months. DISCUSSION: The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk.Trial registrationClinical Trials.gov Identifier: NCT01512225.
INTRODUCTION: The aetiology of attention deficit hyperactivity disorder (ADHD) is attributed to different factors: genetic, environmental, and biological (neurotransmitters: dopaminergic system). Iron is essential for the correct functioning of the dopaminergic system. Iron deficiency is common in patients with ADHD, and its correction may be useful in the treatment. OBJECTIVES: To analyse a possible relationship between iron deficiency and symptoms of inattention, hyperactivity and impulsivity in ADHD patients, and the potential benefit of iron therapy. PATIENTS AND METHODS: A prospective study was conducted on non-anaemic and cognitively normal children, newly diagnosed with ADHD, according to DSM-IV criteria. Specific scales were used (SNAP-IV, ADHS) and serum ferritin was determined. Those with ferritin ≤ 30ng/ml were treated with ferrous sulphate (4mg/kg/day) for 3 months, with its effect quantified being subsequently quantified. RESULTS: A total of 60 patients, with a mean age of 9.02 years (range: 6-14), were analysed. The inattentive subtype was the most frequent one (53.3%). Almost two-thirds (63.3%) had iron deficiency, which was more frequent among the inattentive group (38 vs 22, P<.02). The iron treatment was completed by 17 patients. The treatment was not effective in 7 of the 8 non-inattentive subtypes, with a partial response in the remaining one. Of the 9 inattentive subtypes: the treatment was successful in the total control of symptoms in 5 of them, partially effective in other 3, and ineffective in one patient. The probability of complete response after treatment with iron was higher in inattentive patients with ADHD (P=.02). CONCLUSIONS: Treatment with iron supplements can be an effective alternative to treat patients with ADHD and iron deficiency, especially the inattentive subtype.
Reversal of dopamine d2 agonist-induced inhibition of ventral tegmental area neurons by gq-linked neurotransmitters is dependent on protein kinase C, g protein-coupled receptor kinase, and dynamin
- The Journal of pharmacology and experimental therapeutics
- Published over 6 years ago
Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction.
Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. We showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D2R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics.
Genetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS.
Though Internet gaming disorder (IGD) is considered to share similar genetic vulnerability with substance addictions, little has been explored about the role of the genetic variants on IGD. This pilot study was designed to investigate the association of the Taq1A polymorphism of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and C957T and - 141C of the dopamine D2 receptor (DRD2) with IGD and their role on the personality and temperament traits in IGD among adult population.