Nucleus accumbens and dorsal medial striatal dopamine and neural activity are essential for action sequence performance.

Separable striatal circuits have unique functions in Pavlovian and instrumental behaviors but how these roles relate to performance of sequences of actions with and without associated cues are less clear. Here, we tested whether dopamine transmission and neural activity more generally in three striatal subdomains are necessary for performance of an action chain leading to reward delivery. Male and female Long-Evans rats were trained to press a series of three spatially distinct levers to receive reward. We assessed the contribution of neural activity or dopamine transmission within each striatal subdomain when progression through the action sequence was explicitly cued and in the absence of cues. Behavior in both task variations was substantially impacted following microinfusion of the dopamine antagonist, flupenthixol, into nucleus accumbens core (NAc) or dorsomedial striatum (DMS), with impairments in sequence timing and numbers of rewards earned after NAc flupenthixol. In contrast, after pharmacological inactivation to suppress overall activity, there was minimal impact on total rewards earned. Instead, inactivation of both NAc and DMS impaired sequence timing and led to sequence errors in the uncued, but not cued task. There was no impact of dopamine antagonism or reversible inactivation of dorsolateral striatum on either cued or uncued action sequence completion. These results highlight an essential contribution of NAc and DMS dopamine systems in motivational and performance aspects of chains of actions, whether cued or internally generated, as well as the impact of intact NAc and DMS function for correct sequence performance.

Delays to Reward Delivery Enhance the Preference for an Initially Less Desirable Option: Role for the Basolateral Amygdala and Retrosplenial Cortex.

Temporal costs influence reward-based decisions. This is commonly studied in temporal discounting tasks that involve choosing between cues signaling an imminent reward option or a delayed reward option. However, it is unclear whether the temporal delay before a reward can alter the value of that option. To address this, we identified the relative preference between different flavored rewards during a free-feeding test using male and female rats. Animals underwent training where either the initial preferred or the initial less preferred reward was delivered noncontingently. By manipulating the intertrial interval during training sessions, we could determine whether temporal delays impact reward preference in a subsequent free-feeding test. Rats maintained their initial preference if the same delays were used across all training sessions. When the initial less preferred option was delivered after short delays (high reward rate) and the initial preferred option was delivered after long delays (low reward rate), rats expectedly increased their preference for the initial less desirable option. However, rats also increased their preference for the initial less desirable option under the opposite training contingencies: delivering the initial less preferred reward after long delays and the initial preferred reward after short delays. These data suggest that sunk temporal costs enhance the preference for a less desirable reward option. Pharmacological and lesion experiments were performed to identify the neural systems responsible for this behavioral phenomenon. Our findings demonstrate the basolateral amygdala and retrosplenial cortex are required for temporal delays to enhance the preference for an initially less desirable reward.SIGNIFICANCE STATEMENT The goal of this study was to determine how temporal delays influence reward preference. We demonstrate that delivering an initially less desirable reward after long delays subsequently increases the consumption and preference for that reward. Furthermore, we identified the basolateral amygdala and the retrosplenial cortex as essential nuclei for mediating the change in reward preference elicited by sunk temporal costs.

The steroid hormone 20-hydroxyecdysone binds to dopamine receptor to repress lepidopteran insect feeding and promote pupation.

Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.

ß2* nAChRs on VTA dopamine and GABA neurons separately mediate nicotine aversion and reward.

Evidence shows that the neurotransmitter dopamine mediates the rewarding effects of nicotine and other drugs of abuse, while nondopaminergic neural substrates mediate the negative motivational effects. ß2* nicotinic acetylcholine receptors (nAChR) are necessary and sufficient for the experience of both nicotine reward and aversion in an intra-VTA (ventral tegmental area) self-administration paradigm. We selectively reexpressed ß2* nAChRs in VTA dopamine or VTA γ-amino-butyric acid (GABA) neurons in ß2-/- mice to double-dissociate the aversive and rewarding conditioned responses to nicotine in nondependent mice, revealing that ß2* nAChRs on VTA dopamine neurons mediate nicotine's conditioned aversive effects, while ß2* nAChRs on VTA GABA neurons mediate the conditioned rewarding effects in place-conditioning paradigms. These results stand in contrast to a purely dopaminergic reward theory, leading to a better understanding of the neurobiology of nicotine motivation and possibly to improved therapeutic treatments for smoking cessation.

Fast-Scan Cyclic Voltammetry (FSCV) Reveals Behaviorally Evoked Dopamine Release by Sugar Feeding in the Adult Drosophila Mushroom Body.

Drosophila melanogaster, the fruit fly, is an excellent model organism for studying dopaminergic mechanisms and simple behaviors, but methods to measure dopamine during behavior are needed. Here, we developed fast-scan cyclic voltammetry (FSCV) to track in vivo dopamine during sugar feeding. First, we employed acetylcholine stimulation to evaluate the feasibility of in vivo measurements in an awake fly. Next, we tested sugar feeding by placing sucrose solution near the fly proboscis. In the mushroom body medial tip, 1 pmol acetylcholine and sugar feeding released 0.49±0.04 µM and 0.31±0.06 µM dopamine, respectively but sugar-evoked release lasted longer than with acetylcholine. Administering the dopamine transporter inhibitor nisoxetine or D2 receptor antagonist flupentixol significantly increased sugar-evoked dopamine. This study develops FSCV to measure behaviorally evoked release in fly, enabling Drosophila studies of neurochemical control of reward, learning, and memory behaviors.

Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol.

AIMS: To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentrations in the perphenazine-treated patients. METHODS: Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP-genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose-adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses. RESULTS: Mean dose-adjusted serum concentrations of perphenazine (564 samples) were 3.9-fold and 1.6-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose-adjusted serum concentrations were about 1.5-fold and 1.3-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose-adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function). CONCLUSIONS: This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles.

[Analysis of the flupenthixol distribution in the internal organs of laboratory animals for the diagnosis of acute poisoning]. / Analiz raspredeleniya flupentiksola vo vnutrennikh organakh laboratornykh zhivotnykh dlya diagnostiki ostrykh otravlenii.

Flupentixol has been used for a long time in Russia in psychiatric practice; however, there are cases of its overdose and poisoning with it. In the literature, there are no systematic studies to identify flupenthixol in the diagnosis of acute poisoning. OBJECTIVE: The purpose of the work is to analyze the distribution of flupenthixol in the internal organs of laboratory animals in acute poisoning. The studies were carried out on Wistar rats of both sexes. Sample preparation and isolation of flupenthixol from model samples and internal organs of laboratory animals was carried out according to proposed methods. To detect flupenthixol in extracts the TLC was used. HPLC and liquid mass spectrometry were used for confirmatory analysis and quantitative determination of flupenthixol in the extracts. Amethod was developed for the detection of flupenthixol in extracts from the internal organs of laboratory animals using the TLC method. HPLC/MS/MS was used as a confirmatory method for detecting flupenthixol in extracts from internal organs of laboratory animals. In all mass spectra of extracts from internal organs, a pronounced molecular ion of flupenthixol was present. In the mass spectrum of kidney extraction at 30 minutes a molecular ion of the metabolite (m/z 629.13), corresponding to flupentixolglucuronide was detected. After acute poisoning of laboratory animals, the flupenthixol was found in the maximum amount in the liver, spleen and brain, in smaller amounts in the stomach, intestines with contents and kidneys.

Compulsive Alcohol Seeking Results from a Failure to Disengage Dorsolateral Striatal Control over Behavior.

The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aDLS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine-dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist α-flupenthixol (0, 5, 10, and 15 µg/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.SIGNIFICANCE STATEMENT Over the course of addictive drug exposure, there is a transition in the control over drug seeking from ventral to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms, but it is unclear whether this is causally involved in the development of compulsive drug seeking. We tested the hypothesis that individual differences in the reliance of alcohol seeking on aDLS dopamine predicts and underlies the emergence of compulsive alcohol seeking. We identified individual differences in the reliance of well established alcohol seeking, but not taking behavior, on aDLS mechanisms and also showed that this predicted the subsequent development of compulsive alcohol-seeking behavior. Thus, those individuals in whom alcohol seeking depended on aDLS mechanisms were vulnerable subsequently to display compulsivity.

The combination therapy with esomeprazole and flupenthixol/melitracen in symptom improvement of erosive gastritis complicated with negative feelings compared with Esomeprazole alone.

The purpose of this study was to evaluate the co-prescription efficacy of esomeprazole and flupenthixol/melitracen relative to that of solitary esomeprazole on erosive gastritis complicated with negative feelings. 140 erosive gastritis patients complicated with negative feelings enrolled in the present study. Seventy cases in the control group took esomeprazole, and 70 cases in the observation group received esomeprazole plus flupenthixol/Melitracen, both for 4 weeks. We gastroscopically checked the clinical symptoms, mucosal erosion, PGE2 and MDA levels in gastric mucosa, anxiety, depression, and recurrence before and after treatment in the groups. After treatment, the observation group had lower scores of clinical symptoms, mucosal erosions, Hamilton Depression Rating Scale (HAMD), and Hamilton Depression Rating Scale (HAMA) than the control group (p<0.05); as well, the observation group showed higher PGE2 and lower MDA levels than the control group (p<0.05); during six months of follow-up (100% follow-up rate), 16 and 34 recurrent cases occurred, respectively, in the observation and control groups (p<0.05).  Co-prescription of esomeprazole and flupenthixol/melitracen improved the clinical symptoms and mucosal erosions, relieved negative feelings and reduced the recurrence rate. The efficacy of the co-prescription is higher than that of the solitary prescription.

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

BACKGROUND: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). METHODS: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. RESULTS: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. CONCLUSIONS: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Electroconvulsive therapy for treatment-resistant schizophrenia.

BACKGROUND: Electroconvulsive therapy (ECT) involves the induction of a seizure by the administration of an electrical stimulus via electrodes usually placed bilaterally on the scalp and was introduced as a treatment for schizophrenia in 1938. However, ECT is a controversial treatment with concerns about long-term side effects such a memory loss. Therefore, it is important to determine its clinical efficacy and safety for people with schizophrenia who are not responding to their treatment. OBJECTIVES: Our primary objective was to assess the effects (benefits and harms) of ECT for people with treatment-resistant schizophrenia.Our secondary objectives were to determine whether ECT produces a differential response in people: who are treated with unilateral compared to bilateral ECT; who have had a long (more than 12 sessions) or a short course of ECT; who are given continuation or maintenance ECT; who are diagnosed with well-defined treatment-resistant schizophrenia as opposed to less rigorously defined treatment-resistant schizophrenia (who would be expected to have a greater affective component to their illness). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including clinical trial registries on 9 September 2015 and 4 August 2017. There were no limitations on language, date, document type, or publication status for the inclusion of records in the register. We also inspected references of all the included records to identify further relevant studies. SELECTION CRITERIA: Randomised controlled trials investigating the effects of ECT in people with treatment-resistant schizophrenia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. For binary outcomes, we calculated the risk ratio (RR) and its 95% confidence intervals (CIs), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between the groups and its 95% CIs. We employed the fixed-effect model for all analyses. We assessed risk of bias for the included studies and created 'Summary of findings' tables using the GRADE framework. MAIN RESULTS: We included 15 studies involving 1285 participants (1264 completers with an average age of 18 to 46 years) with treatment-resistant schizophrenia. We rated most studies (14/15, 93.3%) as at high risk of bias due to issues related to the blinding of participants and personnel. Our main outcomes of interest were: (i) clinically important response to treatment; (ii) clinically important change in cognitive functioning; (iii) leaving the study early; (iv) clinically important change in general mental state; (v) clinically important change in general functioning; (vi) number hospitalised; and (vii) death. No trial reported data on death.The included trials reported useable data for four comparisons: ECT plus standard care compared with sham-ECT added to standard care; ECT plus standard care compared with antipsychotic added to standard care; ECT plus standard care compared with standard care; and ECT alone compared with antipsychotic alone.For the comparison ECT plus standard care versus sham-ECT plus standard care, only average endpoint BPRS (Brief Psychiatric Rating Scale) scores from one study were available for mental state; no clear difference between groups was observed (short term; MD 3.60, 95% CI -3.69 to 10.89; participants = 25; studies = 1; very low-quality evidence). One study reported data for service use, measured as number readmitted; there was a clear difference favouring the ECT group (short term; RR 0.29, 95% CI 0.10 to 0.85; participants = 25; studies = 1; low-quality evidence).When ECT plus standard care was compared with antipsychotics (clozapine) plus standard care, data from one study showed no clear difference for clinically important response to treatment (medium term; RR 1.23, 95% CI 0.95 to 1.58; participants = 162; studies = 1; low-quality evidence). Clinically important change in mental state data were not available, but average endpoint BPRS scores were reported. A positive effect for the ECT group was found (short-term BPRS; MD -5.20, 95% CI -7.93 to -2.47; participants = 162; studies = 1; very low-quality evidence).When ECT plus standard care was compared with standard care, more participants in the ECT group had a clinically important response (medium term; RR 2.06, 95% CI 1.75 to 2.42; participants = 819; studies = 9; moderate-quality evidence). Data on clinically important change in cognitive functioning were not available, but data for memory deterioration were reported. Results showed that adding ECT to standard care may increase the risk of memory deterioration (short term; RR 27.00, 95% CI 1.67 to 437.68; participants = 72; studies = 1; very low-quality evidence). There were no clear differences between groups in satisfaction and acceptability of treatment, measured as leaving the study early (medium term; RR 1.18, 95% CI 0.38 to 3.63; participants = 354; studies = 3; very low-quality evidence). Only average endpoint scale scores were available for mental state (BPRS) and general functioning (Global Assessment of Functioning). There were clear differences in scores, favouring ECT group for mental state (medium term; MD -11.18, 95% CI -12.61 to -9.76; participants = 345; studies = 2; low-quality evidence) and general functioning (medium term; MD 10.66, 95% CI 6.98 to 14.34; participants = 97; studies = 2; very low-quality evidence).For the comparison ECT alone versus antipsychotics (flupenthixol) alone, only average endpoint scale scores were available for mental state and general functioning. Mental state scores were similar between groups (medium-term BPRS; MD -0.93, 95% CI -6.95 to 5.09; participants = 30; studies = 1; very low-quality evidence); general functioning scores were also similar between groups (medium-term Global Assessment of Functioning; MD -0.66, 95% CI -3.60 to 2.28; participants = 30; studies = 1; very low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence indicates that relative to standard care, ECT has a positive effect on medium-term clinical response for people with treatment-resistant schizophrenia. However, there is no clear and convincing advantage or disadvantage for adding ECT to standard care for other outcomes. The available evidence was also too weak to indicate whether adding ECT to standard care is superior or inferior to adding sham-ECT or other antipsychotics to standard care, and there was insufficient evidence to support or refute the use of ECT alone. More good-quality evidence is needed before firm conclusions can be made.

Toward 19F magnetic resonance thermometry: spin-lattice and spin-spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T.

OBJECTIVE: This study examines the influence of the environmental factor temperature on the 19F NMR characteristics of fluorinated compounds in phantom studies and in tissue. MATERIALS AND METHODS: 19F MR mapping and MR spectroscopy techniques were used to characterize the 19F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T1 and T2 mapping were performed, while temperature in the samples was changed (T = 20-60 °C) and monitored using fiber optic measurements. In tissue, T1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T1-measured at room temperature. RESULTS: Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T1 and T2. T1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature. DISCUSSION: The impact of temperature on the 19F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19F MR techniques in vivo.

Prolactin, flupenthixol decanoate and first episode schizophrenia - clinical and laboratory correlates.

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.

[A preliminary study of resting-state fMRI in patients with diarrhea-type irritable bowel syndrome after pinaverium bromide combined treatment with flupentixol-melitracen].

Objective: To observe the difference of brain activity in patients with diarrhea-type irritable bowel syndrome (IBS-D) treated with pinaverium bromide (PB) combined with flupentixol-melitracen (FM), and to explore the mechanism of efficacy of combined with anxiolytic/antidepressant drugs in IBS-D patients at the central level, using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight patients with IBS-D, including 28 males, 20 females, mean age 22-48 (33±7) years, were selected from the Affiliated Hospital of Hangzhou Normal University from October 2015 to October 2018.All patients with IBS-D underwent rs-fMRI scans before and after receiving either PB (basic treatment group, n=16), PB combined with FM (combination therapy group, n=16), or no medication (no treatment group, n=16). Rs-fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared using One-way ANOVA analysis and post analysis.Partial correlation and mediation analyses were performed on ReHo values and the improvement of symptoms scores (gastrointestinal symptom rating scale(GSRS) and hospital anxiety/depression scale (HAD)) in the two medicated groups. Results: No significant differences in ReHo values were observed among the three groups before treatment. Compared with patients on no-medication, patients receiving either PB or PB-FM showed decreased ReHo in the striatum, insular lobe, medial prefrontal cortex (MPFC) and subcallosal gyrus, and increased ReHo in the occipital cortex. In particular, the combined treatment group showed more extensive decreased ReHo in the left thalamus and left temporal pole, and increased in the left precuneus. Compared with the basic treatment group, the combined treatment group showed decreased ReHo in the right putamen, right insula, right MPFC and subcallosal gyrus, and increased ReHo in the left precuneus. In addition, the combined treatment group demonstrated a positive correlation between ReHo values in the left thalamus and the improvement of HAD score (r=0.653, P=0.011) , and a negative correlation between ReHo values in left precuneus and the improvement of GSRS and HAD score (r=-0.771, P=0.001; r=-0.716, P=0.004). ReHo values in the left precuneus were observed to mediate between gastrointestinal symptoms and anxiety-depressive symptoms in the combined treatment group. Conclusions: The efficacy of PB combined with FM is superior to PB alone in the treatment of IBS. In addition to more extensive changes in pain-related brain areas, IBS-D patients treated with anxiolytic/antidepressant also show changes in default network and brain areas related to emotional regulation, and are associated with improvement in gastrointestinal symptoms, anxiety and depression.

Benzofurazan-based fluorophore for the selective determination of flupentixol dihydrochloride: Application to content uniformity testing.

One of the most commonly used drugs in treatment of schizophrenia is flupentixol dihydrochloride, therefore it is important to develop a simple, low cost and sensitive spectrofluorimetric method for the estimation of flupentixol dihydrochloride. The yellow fluorescent product that is generated from the nucleophilic substitution reaction of the free lone pair of the alcoholic hydroxyl group of the drug and 4-chloro-7-nitrobenzofurazan (NBD-Cl) in Mcllvaine buffer pH 7.0 was estimated at 510 nm (λex 460 nm). The variables that affect the development of the reaction product were explored and optimized. The linear range of this method was 0.5-2.5 µg ml-1 with a limit of quantitation equal to 0.29 µg ml-1 . Our method was successfully applied for the assurance of flupentixol in tablet form with average percentage recovery of 99.08 ± 1.01% without obstruction from the basic excipients exhibits. Furthermore, our strategy was extended to study the content uniformity testing of flupentixol in Fluaxnol® tablets.

Crystalline retinopathy association with flupentixol intake.

AIM: To report the first case report of an association between flupentixol and crystalline retinopathy. STUDY DESIGN: Observational, Case report. CASE REPORT: We report a case of crystalline retinopathy in a 36-year-old female who was suffering from depression and being treated with tablet flupentixol in a cumulative dose of 4380 mg over two years. Fundus examination of both eyes showed multiple, discrete, yellowish white refractile intraretinal deposits over the macula and peripapillary region, located in the inner retina as shown by OCT. CONCLUSION: We propose regular retinal evaluation in patients with chronic flupentixol intake and larger studies to establish causal relationship between flupentixol and crystalline retinopathy.

Modulating cancer cell survival by targeting intracellular cholesterol transport.

BACKGROUND: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. METHODS: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs. RESULTS: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects. CONCLUSIONS: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.

Dopaminergic neurotransmission in ventral and dorsal striatum differentially modulates alcohol reinforcement.

Dopaminergic neurotransmission in the striatum has been widely implicated in the reinforcing properties of substances of abuse. However, the striatum is functionally heterogeneous, and previous work has mostly focused on psychostimulant drugs. Therefore, we investigated how dopamine within striatal subregions modulates alcohol-directed behaviour in rats. We assessed the effects of infusion of the dopamine receptor antagonist alpha-flupenthixol into the shell and core of the nucleus accumbens (NAcc) and the dorsolateral striatum (DLS) on responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement. Bilateral infusion of alpha-flupenthixol into the NAcc shell reduced responding for alcohol under both the FR1 (15 µg/side) and the PR schedule (3.75-15 µg/side) of reinforcement. Infusion of alpha-flupenthixol into the NAcc core (7.5-15 µg/side) also decreased responding for alcohol under both schedules. By contrast, alpha-flupenthixol infusion into the DLS did not affect FR1 responding, but reduced responding under the PR schedule (15 µg/side). The decreases in responding were related to earlier termination of responding during the session, whereas the onset and rate of responding remained largely unaffected. Together, these data suggest that dopamine in the NAcc shell is involved in the incentive motivation for alcohol, whereas DLS dopamine comes into play when obtaining alcohol requires high levels of effort. In contrast, NAcc core dopamine appears to play a more general role in alcohol reinforcement. In conclusion, dopaminergic neurotransmission acts in concert in subregions of the striatum to modulate different aspects of alcohol-directed behaviour.

Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment.

BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.