Effects Of Haloperidol Research Articles

Haloperidol Induced Cell Cycle Arrest and Apoptosis in Glioblastoma Cells.

Although several antipsychotic drugs have been shown to possess anticancer activities, haloperidol, a “first-generation” antipsychotic drug, has not been extensively evaluated for potential antineoplastic properties. The aim of this study was to investigate the antitumoral effects of haloperidol in glioblastoma (GBM) U87, U251 and T98 cell lines, and the effects of combined treatment with temozolomide (TMZ) and/or radiotherapy, using 4 Gy of irradiation. The viability and proliferation of the cells were evaluated with trypan blue exclusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis, using the annexin-propidium iodide (PI), and cell cycle, cluster of differentiation (CD) expression and caspase-8 activation were measured using flow cytometry. Treatment with haloperidol significantly reduced cell viability in U87, U251 and T98 GBM cell lines. Haloperidol induced apoptosis in a dose-dependent manner, inhibited cell migration and produced an alteration in the expression of CD24/CD44. The additional effect of haloperidol, combined with temozolomide and radiation therapy, increased tumor cell death. Haloperidol was observed to induce apoptosis and to increase caspase-8 activation. In conclusion, haloperidol may represent an innovative strategy for the treatment of GBM and further studies are warranted in glioma xenograft models and other malignancies.

Antipsychotic Drugs Reverse MK801-Inhibited Cell Migration and F-actin Condensation by Modulating the Rho Signaling Pathway in B35 Cells

Background and Aim. MK801-induced psychotic symptoms and also the Ras homolog family member A (RhoA) expression and cell division control protein 42 (cdc42) mRNA modulation in the rat brain have been investigated. Antipsychotic drugs (APDs) have been reported to induce Rho GDP-dissociation inhibitor (RhoGDI) pathway regulation related to cytoskeleton reorganization in neuronal cells. It will be necessary to clarify the effects of APDs on MK801-induced RhoGDI signaling regulation in neuronal cells. Methods. B35 neuronal cells were treated with MK801 for 7 days then treated with MK801 in combination with haloperidol or clozapine for a further 7 days. Cell migration, F-actin condensation, and RhoGDI signaling regulation were examined to investigate the regulatory effects of MK801, haloperidol, and clozapine in B35 neuronal cells. Results. MK801 reduced B35 cell migration, whereas both haloperidol and clozapine reversed the reduction in cell migration induced by MK801. Haloperidol and clozapine restored F-actin condensation after it was diminished by MK801 in B35 cell nuclei. MK801 increased the RhoGDI1 and RhoA expression, which was diminished by the addition of haloperidol and clozapine. MK801 reduced the CDC42 expression, which was restored by haloperidol and clozapine. MK801 reduced the Rho-associated coiled-coil containing protein kinase 1 (ROCK1), profilin1 (PFN1), and neuronal Wiskott–Aldrich Syndrome protein (N-WASP) expression, which was further reduced by haloperidol and clozapine. MK801 also increased the phosphorylated myosin light chain 2 (p-MLC2), postsynaptic density protein 95 (PSD-95), and c-jun expression, which was decreased by haloperidol and clozapine. p21 (RAC1-) activated kinase 1 (PAK1) expression was not affected by MK801.

Synergistic interaction between haloperidol and gabapentin in a model of neuropathic nociception in rat

Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d=+1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABAAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.

P.8135-HT6 agonist, but not antagonist, alleviates pro-depressive effect of haloperidol in the modified forced swim test in rats

P.8135-HT6 agonist, but not antagonist, alleviates pro-depressive effect of haloperidol in the modified forced swim test in rats

Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice.

Diosmin (DSM), commonly isolated from various plants, is a citrus nutrient that has been shown to increase intracellular antioxidant capacity and assuage symptoms associated with neurological disorders. Deficiency in the antioxidant system has been implicated in the pathogenesis of schizophrenia. The use of antioxidants as neuroprotectants to suppress schizophrenia pathology is increasingly being sought. Hence, this study investigated the effects of DSM on schizophrenia-like behavior and the underlying changes in biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in mice. The acute antipsychotic effect of DSM (25, 50, and 100mg/kg, intraperitoneally [i.p.]), haloperidol (1mg/kg, i.p.), and risperidone (RIS) (0.5mg/kg, i.p.) was investigated on stereotyped behaviors induced by apomorphine (2mg/kg, i.p.) and ketamine (10mg/kg, i.p.). The effect of DSM on ketamine-induced hyperlocomotion, immobility enhancement, and its woodblock cataleptogenic potential was evaluated. Also, the subacute antipsychotic potential of DSM was assessed following intraperitoneal injection of DSM (25-100mg/kg, i.p.) alone and in combination with ketamine (20mg/kg, i.p.) for 10 days. The behaviors of the animals were assessed in the open-field, Y-maze, and forced swim tests. Brains of the animals were afterward processed for spectrophotometric assay of oxidative stress and AChE contents. DSM (25, 50, and 100mg/kg) attenuated apormorphine-induced stereotypy and devoid of cataleptogenic effect. DSM and RIS reversed acute and subacute ketamine-induced schizophrenia-like behaviors. Disomin alone increased cognitive function and reduced despair-like phenotype. Furthermore, DSM increased superoxide dismutase and glutathione and decreased malondialdehyde and AChE levels in naïve and ketamine schizophrenic mice. DSM prevents schizophrenia-like behavior, attenuates oxidative stress, and AChE activity in naïve and ketamine schizophrenic mice.

Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice.

Objectives Diosmin (DSM), commonly isolated from various plants, is a citrus nutrient that has been shown to increase intracellular antioxidant capacity and assuage symptoms associated with neurological disorders. Deficiency in the antioxidant system has been implicated in the pathogenesis of schizophrenia. The use of antioxidants as neuroprotectants to suppress schizophrenia pathology is increasingly being sought. Hence, this study investigated the effects of DSM on schizophrenia-like behavior and the underlying changes in biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in mice. Methods The acute antipsychotic effect of DSM (25, 50, and 100mg/kg, intraperitoneally [i.p.]), haloperidol (1mg/kg, i.p.), and risperidone (RIS) (0.5mg/kg, i.p.) was investigated on stereotyped behaviors induced by apomorphine (2mg/kg, i.p.) and ketamine (10mg/kg, i.p.). The effect of DSM on ketamine-induced hyperlocomotion, immobility enhancement, and its woodblock cataleptogenic potential was evaluated. Also, the subacute antipsychotic potential of DSM was assessed following intraperitoneal injection of DSM (25-100mg/kg, i.p.) alone and in combination with ketamine (20mg/kg, i.p.) for 10 days. The behaviors of the animals were assessed in the open-field, Y-maze, and forced swim tests. Brains of the animals were afterward processed for spectrophotometric assay of oxidative stress and AChE contents. Results DSM (25, 50, and 100mg/kg) attenuated apormorphine-induced stereotypy and devoid of cataleptogenic effect. DSM and RIS reversed acute and subacute ketamine-induced schizophrenia-like behaviors. Disomin alone increased cognitive function and reduced despair-like phenotype. Furthermore, DSM increased superoxide dismutase and glutathione and decreased malondialdehyde and AChE levels in naïve and ketamine schizophrenic mice. Conclusions DSM prevents schizophrenia-like behavior, attenuates oxidative stress, and AChE activity in naïve and ketamine schizophrenic mice.

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment

Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI–induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.

Haloperidol Interactions with the dop-3 Receptor in Caenorhabditis elegans.

Haloperidol is a typical antipsychotic drug commonly used to treat a broad range of psychiatric disorders related to dysregulations in the neurotransmitter dopamine (DA). DA modulates important physiologic functions and perturbations in Caenorhabditis elegans (C. elegans) and, its signaling have been associated with alterations in behavioral, molecular, and morphologic properties in C. elegans. Here, we evaluated the possible involvement of dopaminergic receptors in the onset of these alterations followed by haloperidol exposure. Haloperidol increased lifespan and decreased locomotor behavior (basal slowing response, BSR, and locomotion speed via forward speed) of the worms. Moreover, locomotion speed recovered to basal conditions upon haloperidol withdrawal. Haloperidol also decreased DA levels, but it did not alter neitherdop-1, dop-2, and dop-3 gene expression, nor CEP dopaminergic neurons' morphology. These effects are likely due to haloperidol's antagonism of the D2-type DA receptor, dop-3. Furthermore, this antagonism appears to affect mechanistic pathways involved in the modulation and signaling of neurotransmitters such as octopamine, acetylcholine, and GABA, which may underlie at least in part haloperidol's effects. These pathways are conserved in vertebrates and have been implicated in a range of disorders. Our novel findings demonstrate that the dop-3 receptor plays an important role in the effects of haloperidol.

Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments.

The cannabinoid type 1 (CB1 ) receptor and the dopamine type 2 (D2 ) receptor are co-localized on medium spiny neuron terminals in the globus pallidus where they modulate neural circuits involved in voluntary movement. Physical interactions between the two receptors have been shown to alter receptor signaling in cell culture. The objectives of the current study were to identify the presence of CB1 /D2 heteromers in the globus pallidus of C57BL/6J male mice, define how CB1 /D2 heteromer levels are altered following treatment with cannabinoids and/or antipsychotics, and determine if fluctuating levels of CB1 /D2 heteromers have functional consequences. Using in situ proximity ligation assays, we observed CB1 /D2 heteromers in the globus pallidus of C57BL/6J mice. The abundance of the heteromers increased following treatment with the nonselective cannabinoid receptor agonist, CP55,940. In contrast, treatment with the typical antipsychotic haloperidol reduced the number of CB1 /D2 heteromers, whereas the atypical antipsychotic olanzapine treatment had no effect. Co-treatment with CP55,940 and haloperidol had similar effects to haloperidol alone, whereas co-treatment with CP55,940 and olanzapine had similar effects to CP55,940. The observed changes were found to have functional consequences as the differential effects of haloperidol and olanzapine also applied to γ-aminobutyric acid release in STHdhQ7/Q7 cells and motor function in C57BL/6J male mice. This work highlights the clinical relevance of co-exposure to cannabinoids and different antipsychotics over acute and prolonged time periods.

Mortality and HRQoL in ICU patients with delirium: Protocol for 1-year follow-up of AID-ICU trial.

Intensive care unit (ICU)-acquired delirium is frequent and associated with poor short- and long-term outcomes for patients in ICUs. It therefore constitutes a major healthcare problem. Despite limited evidence, haloperidol is the most frequently used pharmacological intervention against ICU-acquired delirium. Agents intervening against Delirium in the ICU (AID-ICU) is an international, multicentre, randomised, blinded, placebo-controlled trial investigates benefits and harms of treatment with haloperidol in patients with ICU-acquired delirium. The current pre-planned one-year follow-up study of the AID-ICU trial population aims to explore the effects of haloperidol on one-year mortality and health related quality of life (HRQoL). The AID-ICU trial will include 1000 participants. One-year mortality will be obtained from the trial sites; we will validate the vital status of Danish participants using the Danish National Health Data Registers. Mortality will be analysed by Cox-regression and visualized by Kaplan-Meier curves tested for significance using the log-rank test. We will obtain HRQoL data using the EQ-5D instrument. HRQoL analysis will be performed using a general linear model adjusted for stratification variables. Deceased participants will be designated the worst possible value. We expect to publish results of this study in 2022. We expect that this one-year follow-up study of participants with ICU-acquired delirium allocated to haloperidol vs. placebo will provide important information on the long-term consequences of delirium including the effects of haloperidol. We expect that our results will improve the care of this vulnerable patient group.

Evidence that haloperidol impairs learning and motivation scores in a probabilistic task by reducing the reward expectation

Activation of midbrain dopamine neurons in response to positive prediction errors and reward predictive cues is proposed to “energize” reward seeking behaviors and approach responses to places where the reward is expected. In the present study, we tested the effect of the D2-dopamine receptor antagonist haloperidol on response latencies to enter two arms of a Y-maze with different reward probabilities. Adult male Wistar rats were trained to explore the Y-maze with sucrose pellets placed 30% of times at the end of one arm and 70% of times at the opposite arm. Therefore, the reward expectation was different among arms, and was updated in the trials when the reward was omitted. After training, rats received 0.05, 0.10, 0.15 mg/kg haloperidol, or saline 30 min before the test session. In the last, but not in the first trials, haloperidol caused a dose-dependent increase in arm choice latency and response latency. Saline, but not haloperidol, treated rats presented significantly longer response latencies for the 30% compared to the 70% reward probability arm. Haloperidol also caused a dose-dependent decrease in the number of entries in the 70% reward probability arm, increased the number of non-responses, and caused a dose-dependent increase in the number of re-entries in the 30% reward probability arm after non-rewarded trials. Control experiments suggested that haloperidol did not cause motor impairment or satiation, but rather impaired learning and motivation scores by reducing the reward expectation.

Neuropharmacological Analysis of the Antidepressant Action of 2-[3-Methyl-7-(Thietan-3-Yl)-1-Ethylxanth-8-YLTHIO] Acetic Acid Hydrazide

A compound with low toxicity and pronounced antidepressant activity upon single and long-term administration was discovered by us earlier among a series of new thietanylxanthine derivatives. The present article focused on the central mechanisms of action of 2-[3-methyl-7-(thietan-3-yl)-1-ethylxanth-7-ylthio]acetic acid hydrazide (laboratory code M-20). Neuropharmacological analysis showed that M-20 at doses of 0.97 and 12 mg/kg exhibited effects indicative of possible stimulatory action on adrenergic and inhibitory action on GABA-ergic neurotransmission in brains of outbred white mice. M-20 at a dose of 12 mg/kg produced an activating effect on the serotoninergic system in addition to action on the adrenergic and GABA-ergic systems and altered the activity of the cholinergic system. M-20 at doses of 0.97 and 12 mg/kg did not alter the effects of haloperidol and L-DOPA, which indicated that it did not influence dopaminergic neurotransmission and MAO-inhibiting activity. The results indicated that M-20 was promising (at the low dose) for use with depression associated with decreased activity of the serotoninergic system without side effects on the dopaminergic and cholinergic systems.

Should we still monitor QTc duration in frail older patients on low-dose haloperidol? A prospective observational cohort study.

Haloperidol at high dosage is associated with QTc prolongation and polymorphic ventricular arrhythmia but the effects of low-dose haloperidol remain unknown. To evaluate the effects of low-dose haloperidol on QTc-duration in frail hospitalized elderly patients with delirium. A prospective observational study including hospitalized patients aged ≥70years with Groningen Frailty Index-score > 3. We included 150 patients who received haloperidol and 150 age- and frailty-matched control patients. Serial ECG recordings were performed at hospital admission and during hospitalization. QT-interval was corrected according to Framingham (QTc). Patients were grouped according to baseline QTc in normal (nQTc), borderline (bQTc) or abnormal (aQTc). Primary outcome was change in QTc-duration between first and second ECG. Potentially dangerous QTc was defined as QTc >500ms or an increase of >50ms. Patients in the haloperidol group (48% male, mean age 85y, nQT n = 98, bQT n = 31, aQT n = 20) received an average dose of 1.5mg haloperidol per 24hours. QTc decreased in patients with borderline (mean-15 ± 29ms, P< 0.05) or abnormal (-19 ± 27ms, P< 0.05) QTc at baseline, no patients developed dangerous QTc-duration. In the control group (41% male, mean age 84y, nQT n = 99 bQT n = 29, aQT n = 22) QTc decreased to a similar extent (bQT -7 ± 16ms, aQTc -23 ± 20ms). A trend to QTc shortening was seen, especially in patients with borderline or abnormal QTc at baseline, regardless of haloperidol use. These findings suggest that ECG monitoring of frail elderly patients who receive low-dose haloperidol, may not be necessary.

Ca2+ signaling as a mechanism of haloperidol-induced cytotoxicity in human astrocytes and assessing the protective role of a Ca2+ chelator.

Haloperidol, a typical antipsychotic medication, has been shown to possess various biological effects in different brain models. However, the impact of haloperidol on Ca2+ signaling in astrocytes is elusive. This study explored the effect of haloperidol on cytosolic free Ca2+ levels ([Ca2+]i) and viability, and established these two connections in Gibco® Human Astrocytes (GHAs) and DI TNC1 rat astrocytes. Haloperidol (5-20μM) caused [Ca2+]i rises in a concentration-dependent manner in GHAs but not in DI TNC1 cells. Furthermore, removal of extracellular Ca2+ reduced haloperidol's effect by approximately 30% in GHAs. Haloperidol (20-40μM) evoked concentration-dependent cytotoxicity in GHAs and DI TNC1 cells. However, chelating cytosolic Ca2+ with the Ca2+ chelator BAPTA/AM significantly reversed haloperidol's cytotoxicity only in GHAs. In GHAs, haloperidol-induced Ca2+ entry was inhibited by store-operated Ca2+ modulators (2-APB and SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. This Ca2+ entry induced by haloperidol was confirmed by Mn2+ entry-induced quench of fura-2 fluorescence. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished haloperidol-induced [Ca2+]i rises. Conversely, treatment with haloperidol inhibited 45% of BHQ-evoked [Ca2+]i rises. Moreover, haloperidol-induced Ca2+ release from the endoplasmic reticulum was abolished by inhibition of phospholipase C (PLC) by U73122. Together, in GHAs but not in DI TNC1 cells, haloperidol caused Ca2+-associated cell death, induced Ca2+ entry via PKC-sensitive store-operated Ca2+ channels, and evoked PLC-dependent Ca2+ release from the endoplasmic reticulum. The protective effect of Ca2+ chelating on haloperidol-induced cytotoxicity in human astrocytes was also demonstrated.

133 - Impact of an Employee Behavioral Health Program on All-Cause Healthcare Utilization

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25 mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25 mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13 mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25 mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13 mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner.

Exploring the Effects of an Acute Dose of Antipsychotic Medication on Motivation-mediated BOLD Activity Using fMRI and a Perceptual Decision-making Task

The left inferior frontal gyrus and the bilateral ventral striatum are thought to be involved in motivation-mediated decision-making. Antipsychotics may influence this relationship, and atypical antipsychotics improve secondary negative symptoms in schizophrenia, such as loss of motivation, although the acute effects of pharmacological medication on motivation are not fully understood. In this single-blinded, randomized controlled trial, 49 healthy volunteers were randomized into three groups to receive a single dose of haloperidol, aripiprazole or placebo. Between 4.0 and 5.6 h later, participant’s brain blood-oxygen-level dependent (BOLD) activity was recorded using functional magnetic resonance imaging (fMRI) while completing a perceptual decision-making fMRI task consisting of one neutral and one motivated condition. Response bias, reflecting the participant’s willingness to say that the target stimulus is present, was calculated using signal detection theory. Concurrent with widespread changes in BOLD signal in the motivated vs. neutral condition, a less conservative, mathematically optimal response bias was observed in the motivated condition across the whole sample. Within-group differences in BOLD signal in the left inferior frontal gyrus and bilateral ventral striatum were observed between conditions in the aripiprazole and haloperidol groups, but not in the placebo group. No robust between-group differences in brain activity in the left inferior frontal gyrus or the bilateral ventral striatum were found. Overall, we found no robust evidence for an effect of either aripiprazole or haloperidol on motivationally mediated behavior. An interesting pattern of correlations possibly related to pharmacologically induced alterations in the dopamine system was observed, although findings remain inconclusive and must be replicated in larger samples.

Нейрофармакологический анализ антидепрессивного действия гидразида 2-[3-метил-7-(тиетанил-3)-1-этилксантинил-8-тио]уксусной кислоты

Ранее нами в ряду новых производных тиетанилксантина было обнаружено соединение, обладающее низкой токсичностью и выраженной антидепрессивной активностью при однократном и длительном введении. Данная статья посвящена изучению центральных механизмов действия гидразида 2-[3-метил-7-(тиетанил-3)-1-этилксантинил-8-тио]уксусной кислоты (лабораторный шифр М-20). По результатам нейрофармакологического анализа было показано, что соединение М-20 в дозах 0,97 и 12 мг/кг проявляет эффекты, указывающие на возможное стимулирующее действие на адренергическую и угнетающее на ГАМК-ергическую нейропередачу в головном мозге белых беспородных мышей. В дозе 12 мг/кг соединение М-20, помимо взаимодействия с адренергической и ГАМК-ергической системами, оказывало активирующее действие на серотонинергическую и изменяло активность холинергической системы. Соединение М-20 в дозах 0,97 и 12 мг/кг не влияло на эффекты галоперидола и L-ДОФА, что свидетельствует об отсутствии у него действия на дофаминергическую нейропередачу, а также МАО-ингибирующей активности. Полученные результаты указывают на перспективность применения вещества М-20 при депрессиях, связанных с дефицитом активности серотонинергической системы, при отсутствии побочных эффектов со стороны дофаминергической и холинергической (в низкой дозе) систем.

Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex

D2 autoreceptors provide an important regulatory mechanism of dopaminergic neurotransmission. However, D2 receptors are also expressed as heteroreceptors at postsynaptic membranes. The expression and the functional characteristics of both, D2 auto- and heteroreceptors, differ between brain regions. Therefore, one would expect that also the net response to a D2 antagonist, i.e. whether and to what degree overall neural activity increases or decreases, varies across brain areas. In the current study we systematically tested this hypothesis by parametrically increasing haloperidol levels (placebo, 2 and 3 mg) in healthy volunteers and measuring brain activity in the three major dopaminergic pathways. In particular, activity was assessed using fMRI while participants performed a working memory and a reinforcement learning task. Consistent with the hypothesis, across brain regions activity parametrically in- and decreased. Moreover, even within the same area there were function-specific concurrent de- and increases of activity, likely caused by input from upstream dopaminergic regions. In the ventral striatum, for instance, activity during reinforcement learning decreased for outcome processing while prediction error related activity increased. In conclusion, the current study highlights the intricacy of D2 neurotransmission which makes it difficult to predict the function-specific net response of a given area to pharmacological manipulations.