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The International Journal of... Dec 2020Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing...
BACKGROUND
Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action.
METHODS
Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration.
RESULTS
Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA.
CONCLUSIONS
Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.
Topics: Animals; Benzazepines; Cocaine; Disease Models, Animal; Dopamine Antagonists; Dopamine Uptake Inhibitors; Haloperidol; Hyperthermia; Ketanserin; Male; Rats; Rats, Wistar; Risperidone; Ritanserin; Serotonin 5-HT2 Receptor Antagonists
PubMed: 32821948
DOI: 10.1093/ijnp/pyaa065 -
Psychopharmacology Sep 2022Learning the association between rewards and predictive cues is critical for appetitive behavioral responding. The mesolimbic dopamine system is thought to play an...
RATIONALE
Learning the association between rewards and predictive cues is critical for appetitive behavioral responding. The mesolimbic dopamine system is thought to play an integral role in establishing these cue-reward associations. The dopamine response to cues can signal differences in reward value, though this emerges only after significant training. This suggests that the dopamine system may differentially regulate behavioral responding depending on the phase of training.
OBJECTIVES
The purpose of this study was to determine whether antagonizing dopamine receptors elicited different effects on behavior depending on the phase of training or the type of Pavlovian task.
METHODS
Separate groups of male rats were trained on Pavlovian tasks in which distinct audio cues signaled either differences in reward size or differences in reward rate. The dopamine receptor antagonist flupenthixol was systemically administered prior to either the first ten sessions of training (acquisition phase) or the second ten sessions of training (expression phase), and we monitored the effect of these manipulations for an additional ten training sessions.
RESULTS
We identified acute effects of dopamine receptor antagonism on conditioned responding, the latency to respond, and post-reward head entries in both Pavlovian tasks. Interestingly, dopamine receptor antagonism during the expression phase produced persistent deficits in behavioral responding only in rats trained on the reward size Pavlovian task.
CONCLUSIONS
Together, our results illustrate that dopamine's control over behavior in Pavlovian tasks depends upon one's prior training experience and the information signaled by the cues.
Topics: Animals; Conditioning, Classical; Conditioning, Operant; Cues; Dopamine; Dopamine Antagonists; Male; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Reward
PubMed: 35796814
DOI: 10.1007/s00213-022-06182-w -
Psychological Medicine Oct 2022The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been...
BACKGROUND
The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of dopamine synthesis and release, and putative synaptic levels.
METHODS
We focused on the role of dopamine postsynaptic regulation using [I] iodobenzamide (IBZM) SPECT. We compared D receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia.
RESULT
The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11; = 0.00, df = 1, 69; = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = -0.01(binding ratio); 95% CI -0.01 to -0.004; = 11.5, df = 1, 69; = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores.
CONCLUSIONS
Medication-naïve patients with recent-onset schizophrenia have similar D receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release.
Topics: Humans; Infant, Newborn; Schizophrenia; Dopamine Antagonists; Dopamine; Receptors, Dopamine D2; Corpus Striatum; Tomography, Emission-Computed, Single-Photon
PubMed: 33682657
DOI: 10.1017/S0033291720005413 -
American Journal of Physiology. Renal... Oct 2019The role of dopamine D-like receptors (DR) in the regulation of renal Na transporters, natriuresis, and blood pressure is well established. However, the involvement of...
The role of dopamine D-like receptors (DR) in the regulation of renal Na transporters, natriuresis, and blood pressure is well established. However, the involvement of the angiotensin 1-7 (ANG 1-7)-Mas receptor in the regulation of Na balance and blood pressure is not clear. The present study aimed to investigate the hypothesis that ANG 1-7 can regulate Na homeostasis by modulating the renal dopamine system. Sprague-Dawley rats were infused with saline alone (vehicle) or saline with ANG 1-7, ANG 1-7 antagonist A-779, DR agonist SKF38393, and antagonist SCH23390. Infusion of ANG 1-7 caused significant natriuresis and diuresis compared with saline alone. Both natriuresis and diuresis were blocked by A-779 and SCH23390. SKF38393 caused a significant, SCH23390-sensitive natriuresis and diuresis, and A-779 had no effect on the SKF38393 response. Concomitant infusion of ANG 1-7 and SKF38393 did not show a cumulative effect compared with either agonist alone. Treatment of renal proximal tubules with ANG 1-7 or SKF38393 caused a significant decrease in Na-K-ATPase and Na/H exchanger isoform 3 activity. While SCH23390 blocked both ANG 1-7- and SKF38393-induced inhibition, the DR response was not sensitive to A-779. Additionally, ANG 1-7 activated PKG, enhanced tyrosine hydroxylase activity via Ser phosphorylation, and increased renal dopamine production. These data suggest that ANG 1-7, via PKG, enhances tyrosine hydroxylase activity, which increases renal dopamine production and activation of DR and subsequent natriuresis. This study provides evidence for a unidirectional functional interaction between two G protein-coupled receptors to regulate renal Na transporters and induce natriuresis.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Angiotensin I; Animals; Benzazepines; Cyclic GMP-Dependent Protein Kinases; Diuresis; Dopamine; Dopamine Agonists; Dopamine Antagonists; Kidney; Natriuresis; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, G-Protein-Coupled; Sodium; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase
PubMed: 31411069
DOI: 10.1152/ajprenal.00135.2019 -
Yakugaku Zasshi : Journal of the... 2016The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous... (Review)
Review
The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous opioids was determined by the inhibitory twitch response evoked by 0.1 Hz stimulation after 10 Hz stimulation (post-tetanic twitch inhibition). The effects of peptidase inhibitors increased the post-tetanic twitch inhibition, prevented by β-funaltrexamine and nor-binaltorphimine, which are selective μ- and κ-opioid receptor subtype antagonists, respectively. Dopamine receptor antagonists (haloperidol, sultopride and domperidone) increased the post-tetanic twitch inhibition. These results suggest that dopamine receptors are involved in modulation of the ileal opioid system, so as to diminish endogenous opioid release by tetanic stimulation, and dopamine antagonists increase the opioid action, that might depend more on the increased release of endogenous opioids. The post-tetanic twitch inhibition was inhibited by adrenalectomy, and showed the supersensitivity of the opioid receptors, resulting from a decrease of endogenous opioids by adrenalectomy. These findings suggest that the increase in morphine-analgesia by adrenalectomy was due to this process. In the presence of naloxone, an opioid antagonist, an increase in basal tension after tetanic stimulation (10 Hz stimulation) (post-tetanic contraction) was observed, and was blocked by spantide, a substance P antagonist, and indomethacin, a prostaglandins-biosynthesis inhibitor. This contraction increased with morphine or peptidase inhibitor exposure, depending on the length of time the ileum was exposed to the morphine or peptidase inhibitor. Post-tetanic contraction might be a useful indicator of the formation of physical dependence to morphine or endogenous opioids in the ileum.
Topics: Animals; Dopamine Antagonists; Humans; Ileum; Morphine; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid Peptides; Protease Inhibitors; Receptors, Dopamine; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors
PubMed: 27040344
DOI: 10.1248/yakushi.15-00265 -
Journal of B.U.ON. : Official Journal... 2020In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular... (Review)
Review
In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Perphenazine
PubMed: 33099901
DOI: No ID Found -
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 -
Brain : a Journal of Neurology Feb 2020The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function....
The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.
Topics: Adult; Depression; Depressive Disorder, Major; Dopamine; Dopamine Agonists; Dopamine Antagonists; Female; Humans; Learning; Male; Middle Aged; Pramipexole; Reward
PubMed: 32040562
DOI: 10.1093/brain/awaa002 -
The Journal of Neuroscience : the... Oct 2020Meso-diencephalic dopaminergic neurons are known to modulate locomotor behaviors through their ascending projections to the basal ganglia, which in turn project to the...
Meso-diencephalic dopaminergic neurons are known to modulate locomotor behaviors through their ascending projections to the basal ganglia, which in turn project to the mesencephalic locomotor region, known to control locomotion in vertebrates. In addition to their ascending projections, dopaminergic neurons were found to increase locomotor movements through direct descending projections to the mesencephalic locomotor region and spinal cord. Intriguingly, fibers expressing tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, were also observed around reticulospinal neurons of lampreys. We now examined the origin and the role of this innervation. Using immunofluorescence and tracing experiments, we found that fibers positive for dopamine innervate reticulospinal neurons in the four reticular nuclei of lampreys. We identified the dopaminergic source using tracer injections in reticular nuclei, which retrogradely labeled dopaminergic neurons in a caudal diencephalic nucleus (posterior tuberculum [PT]). Using voltammetry in brain preparations isolated , we found that PT stimulation evoked dopamine release in all four reticular nuclei, but not in the spinal cord. In semi-intact preparations where the brain is accessible and the body moves, PT stimulation evoked swimming, and injection of a D receptor antagonist within the middle rhombencephalic reticular nucleus was sufficient to decrease reticulospinal activity and PT-evoked swimming. Our study reveals that dopaminergic neurons have access to command neurons that integrate sensory and descending inputs to activate spinal locomotor neurons. As such, our findings strengthen the idea that dopamine can modulate locomotor behavior both via ascending projections to the basal ganglia and through descending projections to brainstem motor circuits. Meso-diencephalic dopaminergic neurons play a key role in modulating locomotion by releasing dopamine in the basal ganglia, spinal networks, and the mesencephalic locomotor region, a brainstem region that controls locomotion in a graded fashion. Here, we report in lampreys that dopaminergic neurons release dopamine in the four reticular nuclei where reticulospinal neurons are located. Reticulospinal neurons integrate sensory and descending suprareticular inputs to control spinal interneurons and motoneurons. By directly modulating the activity of reticulospinal neurons, meso-diencephalic dopaminergic neurons control the very last instructions sent by the brain to spinal locomotor circuits. Our study reports on a new direct descending dopaminergic projection to reticulospinal neurons that modulates locomotor behavior.
Topics: Animals; Biomechanical Phenomena; Dopamine Antagonists; Dopaminergic Neurons; Electric Stimulation; Electrophysiological Phenomena; Lampreys; Locomotion; Nerve Fibers; Receptors, Dopamine D1; Reticular Formation; Spinal Cord; Swimming; Tyrosine 3-Monooxygenase
PubMed: 32998974
DOI: 10.1523/JNEUROSCI.2426-19.2020 -
Nutrients Apr 2019Inadequate breast milk supply is a frequently reported reason for early discontinuation of breastfeeding and represents a critical opportunity for intervening to improve... (Review)
Review
Inadequate breast milk supply is a frequently reported reason for early discontinuation of breastfeeding and represents a critical opportunity for intervening to improve breastfeeding outcomes. For women who continue to experience insufficient milk supply despite the utilisation of non-pharmacological lactation support strategies, pharmacological intervention with medications used to augment lactation, commonly referred to as galactagogues, is common. Galactagogues exert their pharmacological effects through altering the complex hormonal milieu regulating lactation, particularly prolactin and oxytocin. This narrative review provides an appraisal of the existing evidence regarding the efficacy and safety of pharmaceutical treatments for lactation insufficiency to guide their use in clinical practice. The greatest body of evidence surrounds the use of domperidone, with studies demonstrating moderate short-term improvements in breast milk supply. Evidence regarding the efficacy and safety of metoclopramide is less robust, but given that it shares the same mechanism of action as domperidone it may represent a potential treatment alternative where domperidone is unsuitable. Data on remaining interventions such as oxytocin, prolactin and metformin is too limited to support their use in clinical practice. The review provides an overview of key evidence gaps and areas of future research, including the impacts of pharmaceutical galactagogues on breast milk composition and understanding factors contributing to individual treatment response to pharmaceutical galactagogues.
Topics: Domperidone; Dopamine Antagonists; Female; Galactogogues; Humans; Lactation
PubMed: 31035376
DOI: 10.3390/nu11050974