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Translational Cancer Research Nov 2016
PubMed: 32999862
DOI: 10.21037/tcr.2016.11.17 -
Frontiers in Behavioral Neuroscience 2022Rats work very hard for intracranial self-stimulation (ICSS) and tradeoff effort or time allocation for intensity and frequency parameters producing a sigmoidal function...
Rats work very hard for intracranial self-stimulation (ICSS) and tradeoff effort or time allocation for intensity and frequency parameters producing a sigmoidal function of the subjective reward magnitude of ICSS. Previous studies using electrical intracranial stimuli (ICS) as a discriminative cue focused on estimating detection thresholds or on the discrimination between intensities. To our knowledge, there is no direct comparison of the reinforcer tradeoff functions with the discriminative functions. Rats were trained to press and hold the lever for ICSS using the maximum reinforcing intensity below motor alterations or avoidance behavior. First, rats were trained to hold the lever for 1 s; after stability, they undergo trials where intensity or frequency was decreased on 0.1 log step. Thereafter, they undergo further training with a hold of 2 and later of 4 s to determine tradeoff with intensity or frequency. The same rats were trained on a discrimination task where the previously used ICSS signaled a lever where a 1 s hold response was followed by a reinforcing ICSS; on randomly alternating trials, a -0.6 log ICS signaled an alternate lever where a similar hold response led to a reinforcer. After mastering discrimination, generalization tests were carried out with varying intensity or frequency. Rats completed training with 2 and later 4 s hold response. After the completion of each task, the rats had different doses of a pimozide challenge while their intensity and hold-down requirement were varied. With regards to the rats' tradeoff response time allocation as a function of intensity or frequency, sigmoid functions were displaced to the right when long responses were required. Rats that learned the discrimination task attained a discrimination index of 90-98%. Discrimination accuracy decreased slightly with the increase of hold requirement, but generalization gradients were not displaced to the right as a function of the response requirement. Pimozide induced a dose-dependent displacement of the time-allocation gradients, but it did not affect the generalization gradients. It is concluded that rats integrate response requirements as part of the reinforcement tradeoff function, but the response cost is not integrated into the discriminative function of ICSS.
PubMed: 35264936
DOI: 10.3389/fnbeh.2022.799015 -
Annals of the Academy of Medicine,... Jan 2004Delusional parasitosis (DP) is a condition in which a person has the unshakeable and mistaken belief of being infested with parasites. (Review)
Review
INTRODUCTION
Delusional parasitosis (DP) is a condition in which a person has the unshakeable and mistaken belief of being infested with parasites.
PATIENTS AND METHODS
All patients with DP seen by the Division of Dermatology, Department of Medicine, National University Hospital were reviewed. The case histories of 8 Chinese patients are discussed.
RESULTS
The patients with DP were predominantly women above 50 years of age, with medical co-morbidities and presented with a variety of symptoms and signs. The patients were prescribed various antipsychotics including the atypical antipsychotics. Response was variable, and the patients often defaulted follow-up. An approach to the management of DP is proposed together with a review of the literature.
Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Delusions; Female; Humans; Male; Middle Aged; Parasitic Diseases; Pimozide; Referral and Consultation; Retrospective Studies
PubMed: 15008571
DOI: No ID Found -
International Journal of Molecular... Apr 2022The aim of this study was to assess the potency of selected antipsychotic drugs (haloperidol (HAL), bromperidol (BRMP), benperidol (BNP), penfluridol (PNF), pimozide...
The aim of this study was to assess the potency of selected antipsychotic drugs (haloperidol (HAL), bromperidol (BRMP), benperidol (BNP), penfluridol (PNF), pimozide (PIM), quetiapine (QUET) and promazine (PROM)) on the main pathological hallmarks of Alzheimer's disease (AD). Binary mixtures of donepezil and antipsychotics produce an anti-BuChE effect, which was greater than either compound alone. The combination of rivastigmine and antipsychotic drugs (apart from PNF) enhanced AChE inhibition. The tested antipsychotics (excluding HAL and PNF) significantly reduce the early stage of Aβ aggregation. BRMP, PIM, QUET and PROM were found to substantially inhibit Aβ aggregation after a longer incubation time. A test of human erythrocytes hemolysis showed that short-term incubation of red blood cells (RBCs) with QUET resulted in decreased hemolysis. The antioxidative properties of antipsychotics were also proved in human umbilical vein endothelial cells (HUVEC); all tested drugs were found to significantly increase cell viability. In the case of astrocytes, BNP, PNF, PIM and PROM showed antioxidant potential.
Topics: Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Endothelial Cells; Hemolysis; Humans; Quetiapine Fumarate; Rivastigmine
PubMed: 35563011
DOI: 10.3390/ijms23094621 -
Breast Cancer Research : BCR May 2018Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2...
BACKGROUND
Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk.
METHODS
We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1.
RESULTS
We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression.
CONCLUSIONS
Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.
Topics: Animals; Antipsychotic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Differentiation; Female; Humans; Hyperprolactinemia; Janus Kinase 2; Mice; Pimozide; Precancerous Conditions; Risk Factors; Risperidone; STAT5 Transcription Factor; Signal Transduction
PubMed: 29778097
DOI: 10.1186/s13058-018-0969-z -
Dermatology Online Journal Mar 2003Pimozide is widely used in psychiatry for chronic psychoses, schizophrenia, the syndrome of Gilles de la Tourette and to a certain extent, also in dermatology. The only... (Review)
Review
Pimozide is widely used in psychiatry for chronic psychoses, schizophrenia, the syndrome of Gilles de la Tourette and to a certain extent, also in dermatology. The only dermatological indication is for delusions of parasitosis. Though there is a good rationale for using pimozide in this disease, the majority of the studies on pimozide in dermatology are uncontrolled trials and case reports.
Topics: Antipsychotic Agents; Drug Interactions; Pimozide
PubMed: 12639456
DOI: No ID Found -
MSphere 2016The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are...
The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several compounds with significant antiparasitic activities. Among these were pimozide and tamoxifen, which are well-characterized drugs prescribed to treat patients with psychiatric disorders and breast cancer, respectively. The mechanisms by which these compounds target these disorders are known, but we show here that these drugs kill Toxoplasma through novel pathways, highlighting the potential utility of off-target effects in the treatment of infectious diseases.
PubMed: 27303726
DOI: 10.1128/mSphere.00042-15 -
Biomedicine & Pharmacotherapy =... Jun 2022The Warburg effect is a promising target for the diagnosis and treatment of cancer, referring to the ability of cancer cells to generate energy through high levels of...
The Warburg effect is a promising target for the diagnosis and treatment of cancer, referring to the ability of cancer cells to generate energy through high levels of glycolysis even in the presence of oxygen, allowing them to grow and proliferate rapidly. The antipsychotic Pimozide has strong anti-breast cancer effects both in vivo and in vitro, whether Pimozide has an inhibitory effect on aerobic glycolysis has not been elucidated. In this study, Pimozide inhibited the Warburg effect of breast cancer cells by hindering glucose uptake, ATP level and lactate production; reducing the extracellular acidification rate (ECAR); suppressing the expression of PKM2, a rate-limiting enzyme in glycolysis. Intriguingly, Pimozide was significantly involved in reprogramming glucose metabolism in breast cancer cells through a p53-dependent manner. Mechanistic studies demonstrated Pimozide increased the expression of p53 through inhibition of the PI3K/Akt/MDM2 signaling pathway, which in turn downregulated the expression of PKM2. In sum, our results suggest that Pimozide mediates the p53 signaling pathway through PI3K/AKT/MDM2 to inhibit the Warburg effect and breast cancer growth, and it may be a potential aerobic glycolysis inhibitor for the treatment of breast cancer.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Glycolysis; Humans; Phosphatidylinositol 3-Kinases; Pimozide; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 35658233
DOI: 10.1016/j.biopha.2022.113063 -
Frontiers in Pharmacology 2021Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of...
Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Several antidepressants and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7, B.1.351, and B.1.617.2. Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the B.1 lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine, known as anesthetic at high doses, and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudoviruses with common receptor binding domain mutations, N501Y, K417N, and E484K, as well as B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of SARS-CoV-2. Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern, however, extensive clinical studies must be performed to confirm our findings.
PubMed: 35126106
DOI: 10.3389/fphar.2021.755600 -
Behavioural Brain Research Jan 2022Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a...
Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a well-validated rodent model of PD resting tremor. TJMs can be induced by typical antipsychotics and are known to be reduced by different drugs, including adenosine A receptor antagonists. The aim of the present study was to search for brain structures involved in the tremorolytic action of SCH58261, a selective A receptor antagonist, in TJMs induced by subchronic pimozide. Besides TJMs, we evaluated in the same animals the expression of zif-268 mRNA (neuronal responsiveness marker), and mRNA levels for glutamic acid decarboxylase 65-kDa isoform (GAD65) and vesicular glutamate transporters 1 and 2 (vGluT1/2) in selected brain structures, as markers of GABAergic and glutamatergic neurons, respectively. We found that SCH58261 reduced the pimozide-induced TJMs. Pimozide increased the zif-268 mRNA level in the striatum, nucleus accumbens (NAc) core, and substantia nigra pars reticulata (SNr). Additionally, it increased GAD65 mRNA in the striatum and SNr, and vGluT2 mRNA levels in the subthalamic nucleus (STN). A positive correlation between zif-268, GAD65 and vGluT2 mRNAs and TJMs was found. SCH58261 reversed the pimozide-increased zif-268 mRNA in the striatum and NAc core and GAD65 mRNA in the striatum and SNr. In contrast, SCH58261 did not influence vGluT2 mRNA in STN. The present study suggests an importance of the striato-subthalamo-nigro-thalamic circuit in neuroleptic-induced TJMs. The tremorolytic effect of A receptor blockade seems to involve this circuit bypassing, however, STN.
Topics: Animals; Antipsychotic Agents; Brain; Corpus Striatum; Dopamine Antagonists; Early Growth Response Protein 1; Glutamate Decarboxylase; Jaw; Male; Movement; Parkinson Disease, Secondary; Pimozide; Pyrimidines; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Subthalamic Nucleus; Tremor; Triazoles
PubMed: 34536428
DOI: 10.1016/j.bbr.2021.113585