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Proceedings of the National Academy of... May 2020Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over...
Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Dopamine Antagonists; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioma; Glycogen Synthase Kinase 3; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Phenotype; RNA, Messenger; Radiation Tolerance; Receptors, Dopamine; SOXB1 Transcription Factors; Trifluoperazine; Xenograft Model Antitumor Assays; beta Catenin
PubMed: 32358191
DOI: 10.1073/pnas.1920154117 -
Scientific Reports Aug 2022Dopamine has been implicated in the reinforcing effects of smoking. However, there remains a need for a better understanding of the effects of dopamine D1-like receptor...
Dopamine has been implicated in the reinforcing effects of smoking. However, there remains a need for a better understanding of the effects of dopamine D1-like receptor agonists on nicotine intake and the role of sex differences in the effects of dopaminergic drugs on behavior. This work studied the effects of D1-like receptor stimulation and blockade on operant responding for nicotine and food and locomotor activity in male and female rats. The effects of the D1-like receptor antagonist SCH 23390 (0.003, 0.01, 0.03 mg/kg) and the D1-like receptor agonist A77636 (0.1, 0.3, 1 mg/kg) on responding for nicotine and food, and locomotor activity were investigated. The effects of SCH 23390 were investigated 15 min and 24 h after treatment, and the effects of the long-acting drug A77636 were investigated 15 min, 24 h, and 48 h after treatment. Operant responding for nicotine and food and locomotor activity were decreased immediately after treatment with SCH 23390. Treatment with SCH 23390 did not have any long-term effects. Operant responding for nicotine was still decreased 48 h after treatment with A77636, and food responding was decreased up to 24 h after treatment. Treatment with A77636 only decreased locomotor activity at the 48 h time point. There were no sex differences in the effects of SCH 23390 or A77636. In conclusion, the D1-like receptor antagonist SCH 23390 reduces nicotine intake and causes sedation in rats. Stimulation of D1-like receptors with A77636 decreases nicotine intake at time points that the drug does not cause sedation.
Topics: Animals; Benzazepines; Conditioning, Operant; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Male; Nicotine; Rats; Receptors, Dopamine D1; Smoking
PubMed: 35986048
DOI: 10.1038/s41598-022-18081-3 -
Biomedicine & Pharmacotherapy =... Jun 2021Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including...
Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
Topics: Animals; Autistic Disorder; Cerebellum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Hippocampus; Histamine Antagonists; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Histamine H3
PubMed: 33773463
DOI: 10.1016/j.biopha.2021.111517 -
The Cochrane Database of Systematic... Oct 2007Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal adverse... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical.
OBJECTIVES
To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses.
SEARCH STRATEGY
For this 2007 update, we searched the Cochrane Schizophrenia Group's Register (January 2007).
SELECTION CRITERIA
We included all randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments.
DATA COLLECTION AND ANALYSIS
We independently inspected abstracts ordered papers, re-inspected and quality assessed these. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed effects model.
MAIN RESULTS
We were able to include 41 studies in this review. Compared with placebo, loxapine has an antipsychotic effect (Global effect - not improved at six weeks: n=78, 2 RCTs, RR 0.30 CI 0.1 to 0.6 NNT 3 CI 3 to 5). It is as effective as typical drugs in the short term (4 -12 weeks) (Global effect: n=580, 13 RCTs, RR 0.86 CI 0.7 to 1.1; mental state: n=915, 6 RCTs, RR 0.89 CI 0.8 to 1.1). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. Loxapine is also as effective as atypicals (risperidone, quetiapine) (n=468, 6 RCTs, RR mental state not improved 1.07 CI 0.8 to 1.5). Adverse effect profile is similar to typicals but loxapine may cause more extrapyramidal adverse effects when compared with atypicals (n=340, 4 RCTs, RR 2.18 CI 1.6 to 3.1).
AUTHORS' CONCLUSIONS
Loxapine is an antipsychotic which is not clearly distinct from typical or atypical drugs in terms of its effects on global or mental state. Loxapines profile of adverse effects is similar to that of the older generation of antipsychotic drugs.
Topics: Antipsychotic Agents; Dopamine Antagonists; Humans; Loxapine; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 17943763
DOI: 10.1002/14651858.CD001943.pub2 -
Scientific Reports Jun 2021Explicit rewards are commonly used to reinforce a behavior, a form of learning that engages the dopaminergic neuromodulatory system. In contrast, skill acquisition can...
Explicit rewards are commonly used to reinforce a behavior, a form of learning that engages the dopaminergic neuromodulatory system. In contrast, skill acquisition can display dramatic improvements from a social learning experience, even though the observer receives no explicit reward. Here, we test whether a dopaminergic signal contributes to social learning in naïve gerbils that are exposed to, and learn from, a skilled demonstrator performing an auditory discrimination task. Following five exposure sessions, naïve observer gerbils were allowed to practice the auditory task and their performance was assessed across days. We first tested the effect of an explicit food reward in the observer's compartment that was yoked to the demonstrator's performance during exposure sessions. Naïve observer gerbils with the yoked reward learned the discrimination task significantly faster, as compared to unrewarded observers. The effect of this explicit reward was abolished by administration of a D1/D5 dopamine receptor antagonist during the exposure sessions. Similarly, the D1/D5 antagonist reduced the rate of learning in unrewarded observers. To test whether a dopaminergic signal was sufficient to enhance social learning, we administered a D1/D5 receptor agonist during the exposure sessions in which no reward was present and found that the rate of learning occurred significantly faster. Finally, a quantitative analysis of vocalizations during the exposure sessions suggests one behavioral strategy that contributes to social learning. Together, these results are consistent with a dopamine-dependent reward signal during social learning.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Auditory Perception; Discrimination Learning; Dopamine Antagonists; Dopaminergic Neurons; Female; Gerbillinae; Male; Reward; Social Learning; Video Recording
PubMed: 34162951
DOI: 10.1038/s41598-021-92524-1 -
The International Journal of... Oct 2006Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement... (Comparative Study)
Comparative Study
Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement produced by addictive drugs and in the attentional processing of drug-associated environmental cues. The meso-accumbens DA system is selectively enriched with DA D3 receptors, a DA receptor subtype increasingly implicated in reward-related brain and behavioural processes. From a variety of evidence, it has been suggested that selective DA D3 receptor antagonism may be a useful pharmacotherapeutic approach for treating addiction. The present experiments tested the efficacy of SB-277011A, a selective DA D3 receptor antagonist, in rat models of nicotine-enhanced electrical brain-stimulation reward (BSR), nicotine-induced conditioned locomotor activity (LMA), and nicotine-induced conditioned place preference (CPP). Nicotine was given subcutaneously within the dose range of 0.25-0.6 mg/kg (nicotine-free base). SB-277011A, given intraperitoneally within the dose range of 1-12 mg/kg, dose-dependently reduced nicotine-enhanced BSR, nicotine-induced conditioned LMA, and nicotine-induced CPP. The results suggest that selective D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence.
Topics: Analysis of Variance; Animals; Area Under Curve; Association Learning; Behavior, Animal; Brain; Conditioning, Operant; Cues; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Male; Motor Activity; Nicotine; Nicotinic Agonists; Nitriles; Rats; Rats, Long-Evans; Reward; Tetrahydroisoquinolines
PubMed: 16942635
DOI: 10.1017/S1461145706006560 -
Behavioural Pharmacology Jun 2022Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR). Despite early promising data, it recently failed to facilitate cocaine abstinence in... (Review)
Review
Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR). Despite early promising data, it recently failed to facilitate cocaine abstinence in patients and has been compared with dopamine antagonist medications (antipsychotics). Here, we review the effects of both classes on drug reinforcement. In addition to not being effective treatments for cocaine use disorder, both dopamine antagonists and lorcaserin can have biphasic effects on dopamine and reward behavior. Lower doses can cause enhanced drug taking with higher doses causing reductions. This biphasic pattern is shared with certain stimulants, opioids, and sedative-hypnotics, as well as compounds without abuse potential that include agonists for muscarinic and melatonin receptors. Additional factors associated with decreased drug taking include intermittent dosing for dopamine antagonists and use of progressive-ratio schedules for lorcaserin. Clinically relevant doses of lorcaserin were much lower than those that inhibited cocaine-reinforced behavior and can also augment this same behavior in different species. Diminished drug-reinforced behavior only occurred in animals after higher doses that are not suitable for use in patients. In conclusion, drugs of abuse and related compounds often act as biphasic modifiers of reward behavior, especially when evaluated over a broad range of doses. This property may reflect the underlying physiology of the reward system, allowing homeostatic influences on behavior.
Topics: Animals; Benzazepines; Cocaine; Cocaine-Related Disorders; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Reward; Self Administration; Substance-Related Disorders
PubMed: 35324488
DOI: 10.1097/FBP.0000000000000672 -
ELife Oct 2020The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N...
The observation of animal orofacial and behavioral reactions has played a fundamental role in research on reward but is seldom assessed in humans. Healthy volunteers (N = 131) received 400 mg of the dopaminergic antagonist amisulpride, 50 mg of the opioidergic antagonist naltrexone, or placebo. Subjective ratings, physical effort, and facial reactions to matched primary social (affective touch) and nonsocial (food) rewards were assessed. Both drugs resulted in lower physical effort and greater negative facial reactions during reward anticipation, especially of food rewards. Only opioidergic manipulation through naltrexone led to a reduction in positive facial reactions to liked rewards during reward consumption. Subjective ratings of wanting and liking were not modulated by either drug. Results suggest that facial reactions during anticipated and experienced pleasure rely on partly different neurochemical systems, and also that the neurochemical bases for food and touch rewards are not identical.
Topics: Adult; Amisulpride; Dopamine Antagonists; Emotions; Female; Food; Humans; Male; Naltrexone; Narcotic Antagonists; Pleasure; Reward; Young Adult
PubMed: 33046213
DOI: 10.7554/eLife.55797 -
Neuropharmacology Sep 2011The serotonin 5-HT(2A) receptor (5-HT(2A)R) and dopamine D(2) receptor (D(2)R) are high-affinity G protein-coupled receptor targets for two different classes of... (Comparative Study)
Comparative Study
The serotonin 5-HT(2A) receptor (5-HT(2A)R) and dopamine D(2) receptor (D(2)R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT(2A)R and of the D(2)R regulate G(q/11) protein and G(i/o) protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT(2A)R and D(2)R in brain and in HEK293 cells. D(2)R activation increases the hallucinogenic agonist affinity for 5-HT(2A)R and decreases the 5-HT(2A)R induced inositol phosphate production. In vivo, 5-HT(2A)R expression is necessary for the full effects of D(2)R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT(2A)R-D(2)R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs.
Topics: Animals; Cells, Cultured; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; HEK293 Cells; Humans; Male; Mice; Mice, 129 Strain; Mice, Knockout; Protein Multimerization; Receptor Cross-Talk; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Serotonin 5-HT2 Receptor Agonists
PubMed: 21645528
DOI: 10.1016/j.neuropharm.2011.05.023 -
Journal of Medicinal Chemistry Sep 2022To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were...
To better understand the role of dopamine D receptor (DR) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for DR were discovered starting from the brain penetrant and DR selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1)-one (). In particular, the DR antagonist , showing the highest affinity and selectivity over DR and DR within the series (D/D = 8318, D/D = 3715), and the biased ligand , partially activating DR G-/G-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds and induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Ligands; Receptors, Dopamine D4; Temozolomide; beta-Arrestins
PubMed: 36098685
DOI: 10.1021/acs.jmedchem.2c00840