Dopamine, activation of ingestion and evaluation of response efficacy: a focus on the within-session time-course of licking burst number.

RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.

Benefits of a ketogenic diet on repetitive motor behavior in mice.

Repetitive motor behaviors are repetitive and invariant movements with no apparent function, and are common in several neurological and neurodevelopmental disorders, including autism spectrum disorders (ASD). However, the neuropathology associated with the expression of these abnormal stereotypic movements is not well understood, and effective treatments are lacking. The ketogenic diet (KD) has been used for almost a century to treat intractable epilepsy and, more recently, disorders associated with inflexibility of behavioral routines. Here, we show a novel application for KD to reduce an abnormal repetitive circling behavior in a rodent model. We then explore potential mediation through the striatum, as dysregulation of cortico-basal ganglia circuitry has previously been implicated in repetitive motor behavior. In Experiments 1 and 2, adult FVB mice were assessed for levels of repetitive circling across a 3-week baseline period. Mice were then switched to KD and repetitive circling was assessed for an additional 3 weeks. In Experiment 1, time on KD was associated with reduced repetitive behavior. In Experiment 2, we replicated these benefits of KD and assessed dendritic spine density in the striatum as one potential mechanism for reducing repetitive behavior, which yielded no differences. In Experiment 3, adult female circling mice were given a single administration of a dopamine D2 receptor antagonist (L-741,646) that was associated with reduced repetitive behavior over time. Future research will explore the relationship between KD and dopamine within basal ganglia nuclei that may be influencing the benefits of KD on repetitive behavior.

Randomised trial of IV metoclopramide vs IV ketorolac in treatment of acute primary headaches.

INTRODUCTION: Headache is one of the most common neurological conditions among emergency department visits (ED), although the best therapy has not been identified yet. Therefore, in the current study, we aimed to compare the pain-relieving effect of metoclopramide and ketorolac in acute primary headaches patients. METHODS: This double-blind, randomised clinical trial was conducted at Golestan Hospital, Ahvaz, Iran. This research involved all adult patients with acute primary (migraine or tension-type) headaches presented to the ED. Pain intensity was assessed with 0 to 10 verbal Numeric Rating Scales (NRS). The subjects were randomised into 10 mg intravenous (IV) metoclopramide or 30 mg IV ketorolac groups. Pain score and drug adverse reactions were compared between the two groups at baseline, 15, 30, and 60 min after baseline. RESULTS: 108 patients completed this trial and were equally divided into two groups (mean age of 34 ± 8.54 years; 57.4% female). Before treatment, the mean pain score was 6.9 and 6.8 in metoclopramide and ketorolac groups, respectively (p > 0.05). Metoclopramide failed to provide more improvement in pain score at 30 min (p = 0.55) and 60 min (p = 0.15) from baseline. There were no serious adverse events in this study. Only five patients required rescue medication which four of them were in ketorolac group. CONCLUSION: We were unable to reject the null hypothesis that there would be no difference in pain outcomes between metoclopramide and ketorolac.

Rotigotine-loaded microspheres exerts the antinociceptive effect via central dopaminergic system.

Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy. The expressions of D2 and D3 receptors in the striatum and periaqueductal gray were measured by Western blotting. Intracerebroventricular injection of domperidone abated the antinociceptive effect of RoMS. However, intraperitoneal injection of domperidone had no significant effect on the antinociceptive action of RoMS. Intracerebroventricular injection with D2D3 shRNA significantly attenuated the expressions of D2 and D3 receptors in the striatum and the periaqueductal gray. D2 and D3 receptors silence significantly weakened RoMS-mediated antinociceptive effect. Intracerebroventricular injection of naloxone also alleviated the antinociceptive effect of RoMS. The results suggest that RoMS-mediated antinociceptive efficacy is associated with activating central dopamine D2 and D3 receptors. Opioid receptors play a role in the antinociceptive effect of RoMS.

High dose antipsychotic polypharmacy and dopamine partial agonists - time to rethink guidelines?

Guidelines for the treatment of schizophrenia limit the use of antipsychotic agents to clinically-established maximum doses. This acknowledges both the absence of additional efficacy of dopamine D2 receptor antagonists above a receptor occupancy threshold, and the increases in side effects that can occur at higher doses. These limits restrict the dosing of combinations of antipsychotics as they do single agents; drugs sharing the major antipsychotic mechanism of D2 receptor antagonism will act additively in blocking these receptors.Several newer antipsychotic drugs, including aripiprazole and cariprazine, act as partial agonists at the D2 receptor site and avoid action at several other receptors, effects at which are responsible for some non-dopaminergic adverse effects. This pharmacology imparts different characteristics to the drugs resulting often in a more favourable side effect profile. Their partial agonism, along with high affinities for the D2 receptor, also means that these drugs given adjunctively may in part replace, rather than enhance, the D2 antagonism of other antipsychotic agents. This can result in an improvement in certain side effects without loss of antipsychotic efficacy.This article makes the case for distinguishing the D2 partial agonists from antagonists in defining maximum doses of combined treatments, which would increase the options available to the prescriber, emphasising that pharmacological mechanisms need to be understood in identifying optimal treatments for psychotic illness.

Juvenile stress increases cocaine-induced impulsivity in female rats.

In humans, adverse childhood experiences are associated with an increased risk of developing a neuropsychiatric disorder. Changes in social behavior and cognitive function are hallmarks of numerous neuropsychiatric disorders. Here we examined the effects of exposure to variable stress during the juvenile period on social behavior, reward, and cognitive function (as measured in the 5-choice serial reaction time task (5CSRTT)) in rats. From postnatal days (PND) 25-29 male and female rats were exposed to a variable stress protocol. In adulthood, social interactions and sucrose preference were assessed prior to training on the 5CSRTT. Once successfully trained, rats were challenged with different task versions, and then the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. A follow-up experiment examined the ability of the D2 receptor antagonist eticlopride (0.0, 0.025, 0.05 mg/kg, IP) to block the effects of cocaine on 5CSRTT performance in female rats. Male rats exposed to juvenile stress tended to engage in less social behavior and had an increased correct response latency in the 5CSRTT following cocaine administration. Female rats exposed to juvenile stress exhibited a trend towards increased social behavior and demonstrated increased cocaine-induced impulsivity. The increase in impulsivity was not blocked by co-administration of eticlopride. Juvenile stress had minimal effects on adult behavior in male rats, but increased cocaine-induced impulsivity in female rats. Such an effect could contribute to the enhanced escalation of drug-use observed in females that experience juvenile stress. This possibility awaits further testing.

Childhood dystonic reactions in the middle Black Sea region.

ABSTRACT: Acute dystonic reactions are a worrying reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. It must be diagnosed and treated quickly. The aim of this study was to examine the clinical presentations, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute dystonic reactions in children.Nine pediatric patients who were treated for acute dystonic reactions between May, 2018 and May, 2020 and had adequate follow-up were included in the study. Medical record data were reviewed age, gender, etiology, features of family, treatment, and results.Three of the patients were female and 6 were male. Their average age was 11 years (4-17). All patients were evaluated as a drug-induced acute dystonic reaction. Of the 9 patients, 5 were due to metoclopramide, 3 were due to risperidone, and 1 was due to aripiprazole. It was learned that a similar situation against other drugs developed in the family history of 3 patients. As a treatment, all of them were intramuscularly applied biperiden suitable for their weight and 30 minutes dramatic improvement was observed. Additional dose had to be administered in only 1 case. All cases were discharged for 24 hours. No problem was observed in their follow-up.Drug-induced acute dystonic reaction can be diagnosed and has a clinical picture that completely resolves when effective treatment is applied. However, it should not be forgotten that it can reach life-threatening dimensions clinically.

Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson's disease.

Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.

Impact of Morphine Treatment With and Without Metoclopramide Coadministration on Myocardial and Microvascular Injury in Acute Myocardial Infarction: Insights From the Randomized MonAMI Trial.

Background Intravenous morphine administration can adversely affect platelet inhibition induced by P2Y12 receptor inhibitors after acute myocardial infarction. In contrast, some evidence suggests that opioid agonists may have cardioprotective effects on the myocardium. The aim of this prospective, randomized MonAMI (Impact of Morphine Treatment With and Without Metoclopramide Coadministration on Platelet Inhibition in Acute Myocardial Infarction) trial was, therefore, to investigate the impact of morphine with or without metoclopramide coadministration on myocardial and microvascular injury. Methods and Results Patients with acute myocardial infarction (n=138) were assigned in a 1:1:1 ratio to ticagrelor 180 mg plus: (1) intravenous morphine 5 mg (morphine group); (2) intravenous morphine 5 mg and metoclopramide 10 mg (morphine+metoclopramide group); or (3) intravenous placebo (control group) administered before primary percutaneous coronary intervention. Cardiac magnetic resonance imaging was performed in 104 patients on day 1 to 4 after the index event. Infarct size was significantly smaller in the morphine only group as compared with controls (percentage of left ventricular mass, 15.5 versus 17.9; P=0.047). Furthermore, the number of patients with microvascular obstruction was significantly lower after morphine administration (28% versus 54%; P=0.022) and the extent of microvascular obstruction was smaller (percentage of left ventricular mass, 0 versus 0.74; P=0.037). In multivariable regression analysis, morphine administration was independently associated with a reduced risk for the occurrence of microvascular obstruction (odds ratio, 0.37; 95% CI, 0.14-0.93 [P=0.035]). There was no significant difference in infarct size (P=0.491) and extent (P=0.753) or presence (P=0.914) of microvascular obstruction when comparing the morphine+metoclopramide group with the control group. Conclusions In this randomized study, intravenous administration of morphine before primary percutaneous coronary intervention resulted in a significant reduction of myocardial and microvascular damage following acute myocardial infarction. This effect was not observed in the morphine plus metoclopramide group. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02627950.

The anti-cancer effect of metoclopramide on triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancers. Chemotherapy is the most important therapeutic option for TNBC, and chemotherapy-induced nausea and vomiting (CINV) is inevitable. Metoclopramide is a good and cost-effective therapeutic option for chemotherapy-induced nausea and vomiting. However, it is not commonly used in breast cancer because it can increase serum prolactin levels by blocking dopamine D2 receptor. This study aimed at elucidating the effect of metoclopramide on triple-negative breast cancer, MDA-MB-231 cells were treated with various concentrations of metoclopramide, the cell proliferation was detected by MTT method, the apoptosis rate was detected by Annexin V/PI double staining method, the expression change of death-related protein was detected by Western Blot. We found that metoclopramide inhibits cell proliferation and induces cell apoptosis of MDA-MB-231 in a concentration-dependent manner, and the Bcl family was involved in this process.

Randomized Study of Metoclopramide Plus Diphenhydramine for Acute Posttraumatic Headache.

OBJECTIVE: To determine whether IV metoclopramide 20 mg + diphenhydramine 25 mg (M + D) was more efficacious than IV placebo for acute moderate or severe posttraumatic headache in the emergency room. METHODS: We conducted this randomized, double-blind, placebo-controlled, parallel-group study in 2 urban emergency departments (EDs). Participants who experienced head trauma and presented to our EDs within 10 days with a headache fulfilling criteria for acute posttraumatic headache were included. We randomized participants in a 1:1 ratio to M + D or placebo. Participants, caregivers, and outcome assessors were blinded to assignment. The primary outcome was improvement in pain on a scale of 0 to 10 between baseline and 1 hour after treatment. RESULTS: This study was completed between August 2017 and March 2020. We screened 414 patients for participation and randomized 160: 81 to M + D and 79 to placebo. Baseline characteristics were comparable between the groups. All enrolled participants provided primary outcome data. Patients receiving placebo reported mean improvement of 3.8 (SD 2.6), while those receiving M + D improved by 5.2 (SD 2.3), for a difference favoring metoclopramide of 1.4 (95% confidence interval [CI] 0.7-2.2, p < 0.01). Adverse events were reported by 35 of 81 (43%) patients who received metoclopramide and 22 of 79 (28%) of patients who received placebo (95% CI 1-30 for difference of 15%, p = 0.04). CONCLUSION: M + D was more efficacious than placebo with regard to relief of posttraumatic headache in the ED. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03220958. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with acute moderate or severe posttraumatic headache, IV M + D significantly improved pain compared to placebo.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand.

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

The effect of risperidone on reward-related brain activity is robust to drug-induced vascular changes.

Dopamine (DA) mediated brain activity is intimately linked to reward-driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward-driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double-blind, placebo-controlled, randomised, three-period cross-over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath-hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose-dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide-ranging influence on DA-mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs.

Temporary inactivation of the infralimbic cortex impairs while the blockade of its dopamine D2 receptors enhances auditory fear extinction in rats.

Fear extinction is defined as decline in conditioned fear responses that occurs with repeated and non-reinforced exposure to a feared conditioned stimulus. Experimental evidence suggests that the extinction of fear memory requires the integration of the medial prefrontal cortex (mPFC); nevertheless, the role of its sub-regions in regulating the expression and extinction of auditory fear has been rarely addressed in literature. The present study examined the roles of the infra-limbic (IL) and pre-limbic (PL) regions of the mPFC in the expression and extinction of auditory fear by temporally deactivating these regions using lidocaine (10 µg/0.5 µl) before training male Wistar rats in auditory fear-conditioning tasks. The results showed increased freezing levels and impaired extinction through deactivating the IL rather than the PL cortex. Given the role of the dopaminergic pathways in regulating fear memory, this study also investigated the role of D2 receptors located in the IL cortex in fear extinction. Fear extinction was improved in an inverted U-shape pattern through the intra-IL infusion of 15.125, 31.25, 62.5, 125, 250 and 500 ng/0.5 µl of the D2 receptor antagonist sulpiride. In other words, the moderate doses, i.e. 31.25, 62.5, 125, 250 ng/0.5 µl, enhanced auditory fear extinction, whereas the lowest and highest doses, i.e. 15.125 and 500 ng/0.5 µl, were ineffective. These findings demonstrated the key roles of the IL cortex and its dopamine D2 receptors in regulating auditory fear in rats.

Chronic antipsychotic treatment exerts limited effects on the mania-like behavior of dopamine transporter knockdown mice.

BACKGROUND: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS: DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.

Formulation of instant disintegrating buccal films without using disintegrant: An in-vitro study.

The current study was conducted to fabricate Metoclopramide HCL (MCH) and Sumatriptan succinate (SS) instant release buccal films (IRBF) without using any super disintegrant. The solvent casting method was used for the preparation of IRBFs and prepared IRBFs were physicochemically evaluated. Spectrophotometric analysis was done to determine the lambda max followed by the linearity determination of both drugs. Different concentrations such as 100, 125, and 150mg of hydrophilic polymer (HPMC E5) were employed but the concentration of glycerol was variable. Comparatively better results were observed for the formulation with 150mg of HPMC E5 and 30% glycerol. Formulated IRBFs showed good tensile strength with a mean disintegration time of 12.4-28.4 seconds and rapid dissolution with more than 50% drug release within 2 minutes. It was concluded that the chosen combination of polymers was appropriate for the fabrication of MCH and SS buccal strips.