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ENeuro 2022The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence...
The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence because of availability of alternative nondrug rewards. We used hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/d), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine whether fentanyl relapse is associated with activity (indicated by ) in OFC and Pir cells expressing [which encodes cannabinoid 1 (CB1) receptors] or and (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a dopamine D1 receptor antagonist (1.0 or 3.0 µg SCH39166/hemisphere) into Pir to determine the effect on fentanyl relapse. Fentanyl relapse was associated with OFC cells co-expressing and and Pir cells co-expressing and However, injections of the CB1 receptor antagonist AM251 or agonist WIN55,212-2 into OFC or the dopamine D1 receptor antagonist SCH39166 into Pir had no effect on fentanyl relapse. Fentanyl relapse is associated with activation of -expressing OFC cells and -expressing Pir cells, but pharmacological manipulations do not support causal roles of OFC CB1 receptors or Pir dopamine D1 receptors in fentanyl relapse.
Topics: Animals; Cannabinoids; Dopamine; Dopamine Antagonists; Female; Fentanyl; Male; Piriform Cortex; Rats; Receptor, Cannabinoid, CB1; Receptors, Dopamine D1; Recurrence
PubMed: 35768212
DOI: 10.1523/ENEURO.0496-21.2022 -
Brain Research Bulletin Apr 2023Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the...
Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease.
Topics: Rats; Animals; Male; Sulpiride; Rats, Wistar; Acute Pain; Receptors, Dopamine D2; Receptors, Dopamine D1; Dopamine Antagonists; Nucleus Accumbens; Analgesics
PubMed: 36889361
DOI: 10.1016/j.brainresbull.2023.03.003 -
International Clinical... Nov 2022Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of... (Review)
Review
Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D 2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.
Topics: Antipsychotic Agents; Aripiprazole; Dopamine; Dopamine Agonists; Dopamine Antagonists; Humans; Polypharmacy; Psychotic Disorders; Quinolones; Thiophenes
PubMed: 35815937
DOI: 10.1097/YIC.0000000000000417 -
Journal of Experimental & Clinical... Jan 2024Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study...
BACKGROUND
Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context.
METHODS
GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo.
RESULTS
Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice.
CONCLUSIONS
DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.
Topics: Animals; Humans; Mice; Brain; CCAAT-Enhancer-Binding Proteins; Dopamine; Glioblastoma; Glioma; Mice, Nude; Multigene Family; Receptors, Dopamine D1; Ubiquitin-Protein Ligases; Dopamine Antagonists; Proto-Oncogene Proteins c-myc
PubMed: 38246990
DOI: 10.1186/s13046-024-02947-7 -
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 -
The Journal of Pharmacology and... Mar 2023Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration...
Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D/D/sigma receptor antagonist (haloperidol), and a 5-HT receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in high- and low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). VK4-40, VK4-116, haloperidol, and CP-809,101 were equipotent and effective at reducing drug-taking in all three groups of rats, including the high-responders; however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared with male rats. Together, these studies suggest that drugs targeting dopamine D or 5-HT receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders. SIGNIFICANCE STATEMENT: There are no United States Food and Drug Administration-approved treatments for stimulant use disorder, perhaps in part because candidate medications are most often evaluated in preclinical models using male subjects with well-regulated drug-taking. In an attempt to better model aberrant drug taking, this study found compounds acting at dopamine D or 5-HT receptors can attenuate drug-taking in male and female rats that self-administered two different stimulants and exhibited either a high or low substance use disorder-like phenotype.
Topics: Animals; Female; Humans; Male; Rats; Cocaine; Dopamine; Dose-Response Relationship, Drug; Haloperidol; Receptors, sigma; Self Administration; Serotonin; Synthetic Cathinone
PubMed: 36627204
DOI: 10.1124/jpet.122.001419 -
The Journal of Neuroscience : the... Sep 2019Episodic memory is sensitive to the influence of neuromodulators, such as dopamine and noradrenaline. These influences are considered important in the expression of... (Randomized Controlled Trial)
Randomized Controlled Trial
Episodic memory is sensitive to the influence of neuromodulators, such as dopamine and noradrenaline. These influences are considered important in the expression of several known memory biases, though their specific role in memory remains unclear. Using pharmacological agents with relatively high selectivity for either dopamine (400 mg amisulpride) or noradrenaline (40 mg propranolol) we examined their specific contribution to incidental memory. In a double-blind placebo-controlled human study (30 females, 30 males in total), we show that a memory selectivity bias was insensitive to propranolol but sensitive to amisulpride, consistent with a dominant influence from dopamine. By contrast, a putative arousal-induced memory boosting effect was insensitive to amisulpride but was sensitive to propranolol, consistent with a dominant noradrenaline effect. Thus, our findings highlight specific functional roles for dopamine and noradrenaline neurotransmission in the expression of incidental memory. Why some information is preferentially encoded into memory while other information is not is a central question in cognitive neuroscience. The neurotransmitters dopamine and noradrenaline are often assumed critical in influencing this selectivity, but their specific contributions remain obscure. In this double-blind, placebo-controlled, between-subjects drug study, we investigate the contributions of noradrenaline and dopamine to episodic memory. Using an incidental memory task, we find that blocking dopamine (400 mg amisulpride) eliminates a neural-gain related memory selectivity bias. Blocking noradrenaline function (40 mg propranolol), in contrast, abolishes an arousal-related memory enhancement. In this assessment of dopamine and noradrenaline neuromodulatory effects we reveal their specific contributions to episodic memory.
Topics: Adrenergic beta-Antagonists; Adult; Amisulpride; Arousal; Dopamine; Dopamine Antagonists; Double-Blind Method; Female; Humans; Male; Memory, Episodic; Neurotransmitter Agents; Norepinephrine; Propranolol; Pupil; Young Adult
PubMed: 31405924
DOI: 10.1523/JNEUROSCI.0401-19.2019 -
Neuropsychopharmacology Reports Sep 2021Several reports have shown that risperidone increases prolactin concentrations, while aripiprazole decreases prolactin concentrations. The frequency of abnormal...
AIM
Several reports have shown that risperidone increases prolactin concentrations, while aripiprazole decreases prolactin concentrations. The frequency of abnormal prolactin concentrations in patients with schizophrenia receiving these drugs is still unknown. Furthermore, although hyperprolactinemia leads to sexual dysfunction, the relationship between hyperprolactinemia and testosterone, which may be directly related to male sexual function, is not well understood.
METHODS
The subjects were 94 male schizophrenia outpatients receiving risperidone or paliperidone (risperidone group) and 83 male schizophrenia outpatients receiving aripiprazole. We measured the serum prolactin and total and free testosterone concentrations. We compared the prolactin and testosterone levels in patients receiving risperidone or paliperidone and patients receiving aripiprazole.
RESULTS
The average serum prolactin concentration was 27.5 ± 13.1 ng/mL for the risperidone group and 3.9 ± 3.5 ng/mL for the aripiprazole group, and the concentrations were significantly different (P < .001). Hypoprolactinemia was observed in 75% of the aripiprazole group and hyperprolactinemia in 65% of the risperidone group. A positive correlation between prolactin levels and the risperidone daily dose was found, whereas a negative correlation between prolactin levels and the aripiprazole daily dose was observed. In the risperidone group, total testosterone concentrations were correlated with age, while free testosterone concentrations were inversely correlated with age and prolactin levels.
CONCLUSION
We found very common hyperprolactinemia and hypoprolactinemia in the risperidone or paliperidone group and aripiprazole group, respectively. Testosterone concentrations were associated with elevated prolactin levels in patients receiving risperidone or paliperidone. Further studies are needed to determine the clinical relevance of abnormal prolactin concentrations in male and female patients with schizophrenia.
Topics: Antipsychotic Agents; Aripiprazole; Female; Genetic Diseases, Inborn; Humans; Hyperprolactinemia; Lactation Disorders; Male; Paliperidone Palmitate; Prolactin; Risperidone; Schizophrenia; Testosterone
PubMed: 34189861
DOI: 10.1002/npr2.12190 -
Journal of Psychopharmacology (Oxford,... Feb 2023The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine...
The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decrease operant responding for nicotine and food and locomotor activity in male and female rats.
BACKGROUND
The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake.
AIM
The goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats.
METHODS
The effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated.
RESULTS
There were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists.
CONCLUSIONS
Blockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.
Topics: Rats; Male; Female; Animals; Flupenthixol; Nicotine; Receptors, Dopamine D2; Dopamine; Receptors, Dopamine D1; Locomotion; Conditioning, Operant
PubMed: 36680471
DOI: 10.1177/02698811221147141 -
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