Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Atypical, but Not Typical, Antipsychotic Drugs Reduce Hypersynchronized Prefrontal-Hippocampal Circuits during Psychosis-Like States in Mice: Contribution of 5-HT2A and 5-HT1A Receptors.

Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.

A randomized, double-blind, placebo-controlled phase 2 study of intratympanic OTO-313 in patients with moderate to severe subjective tinnitus.

PURPOSE: This was a randomized, double-blind, placebo-controlled Phase 2 study to evaluate the efficacy and safety of intratympanic OTO-313 in patients with subjective unilateral tinnitus. METHODS: Patients with moderate to severe unilateral tinnitus of 2-12 months duration were enrolled. A single intratympanic injection of OTO-313 or placebo was administered to the affected ear and patients were evaluated during a 16-weeks follow-up period. Efficacy was assessed using the Tinnitus Functional Index (TFI), daily ratings of tinnitus loudness and annoyance, and Patient Global Impression of Change (PGIC). RESULTS: Intratympanic administration of OTO-313 and placebo produced reductions in tinnitus with a similar percentage of TFI responders at Weeks 4, 8, 12, and 16. Reductions in daily ratings of tinnitus loudness and annoyance, and PGIC scores were also similar between OTO-313 and placebo groups. No significant differences in mean TFI scores between OTO-313 and placebo were observed for pre-specified strata regarding tinnitus duration (≥ 2 to ≤ 6 months and > 6 to ≤ 12 months) and TFI baseline scores (≥ 32 to ≤ 53 points and ≥ 54 to 100 points), although the results numerically favored OTO-313 in patients in the ≥ 2 to ≤ 6 months strata. These results also demonstrated an unexpectedly high placebo response particularly amongst patients with chronic tinnitus, despite training implemented to mitigate placebo response. OTO-313 was well-tolerated with a similar incidence of adverse events compared to placebo. CONCLUSIONS: OTO-313 did not demonstrate a significant treatment benefit relative to placebo due in part to a high placebo response. OTO-313 was safe and well-tolerated.

NRX-101, a Rapid-Acting Anti-Depressant, Does Not Cause Neurotoxicity Following Ketamine Administration in Preclinical Models.

Agents that act at the N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have gained increasing attention as rapid-acting antidepressants; however, their use has been limited by potential neurotoxicity. Recent FDA guidance requires a demonstration of safety on histologic parameters prior to the initiation of human studies. D-cycloserine (DCS) is a partial NMDA agonist that, along with lurasidone, is being investigated as a treatment for depression. The current study was designed to investigate the neurologic safety profile of DCS. To this end, female Sprague Dawley rats (n = 106) were randomly divided into 8 study groups. Ketamine was administered via tail vein infusion. DCS and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with 3 different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E, silver, and Fluoro-Jade B stains. No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 (positive control) group. We conclude that NRX-101, a fixed-dose combination of DCS/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at supratherapeutic doses of DCS.

Rediscovery of Methadone to Improve Outcomes in Pain Management.

Clinically, methadone is most known for its use in the treatment of opioid maintenance therapy. However, methadone's pharmacological profile makes it an excellent analgesic that can enhance acute and chronic pain management. It is a potent µ-receptor agonist with a longer elimination half-life than most clinically used opioids. In addition, methadone inhibits serotonin and norepinephrine uptake, and it is an N-methyl-D-aspartate antagonist. These distinct analgesic pathways mediate hyperalgesic, allodynic, and neuropathic pain. Its unique analgesic properties provide several essential benefits in perioperative use, neuropathic pain, cancer, and noncancer pain. Despite these proven clinical utilities, methadone has not been used widely to treat acute and chronic pain in opioid naïve patients. This article describes the unique pharmacology of methadone and provides emerging evidence to support its application in acute and chronic pain management. Pain management options and guidelines for surgical patients on methadone are discussed as well.

Ketamine Alters Lateral Prefrontal Oscillations in a Rule-Based Working Memory Task.

Acute administration of N-methyl-D-aspartate receptor (NMDAR) antagonists in healthy humans and animals produces working memory deficits similar to those observed in schizophrenia. However, it is unclear whether they also lead to altered low-frequency (≤60 Hz) neural oscillatory activities similar to those associated with schizophrenia during working memory processes. Here, we recorded local field potentials (LFPs) and single-unit activity from the lateral prefrontal cortex (LPFC) of three male rhesus macaque monkeys while they performed a rule-based prosaccade and antisaccade working memory task both before and after systemic injections of a subanesthetic dose (≤0.7 mg/kg) of ketamine. Accompanying working-memory impairment, ketamine enhanced the low-gamma-band (30-60 Hz) and dampened the beta-band (13-30 Hz) oscillatory activities in the LPFC during both delay periods and intertrial intervals. It also increased task-related alpha-band activities, likely reflecting compromised attention. Beta-band oscillations may be especially relevant to working memory processes because stronger beta power weakly but significantly predicted shorter saccadic reaction time. Also in beta band, ketamine reduced the performance-related oscillation as well as the rule information encoded in the spectral power. Ketamine also reduced rule information in the spike field phase consistency in almost all frequencies up to 60 Hz. Our findings support NMDAR antagonists in nonhuman primates as a meaningful model for altered neural oscillations and synchrony, which reflect a disorganized network underlying the working memory deficits in schizophrenia.SIGNIFICANCE STATEMENT Low doses of ketamine, an NMDAR blocker, produce working memory deficits similar to those observed in schizophrenia. In the lateral prefrontal cortex, a key brain region for working memory, we found that ketamine altered neural oscillatory activities in similar ways that differentiate schizophrenic patients and healthy subjects during both task and nontask periods. Ketamine induced stronger gamma (30-60 Hz) and weaker beta (13-30 Hz) oscillations, reflecting local hyperactivity and reduced long-range communications. Furthermore, ketamine reduced performance-related oscillatory activities, as well as the rule information encoded in the oscillations and in the synchrony between single-cell activities and oscillations. The ketamine model helps link the molecular and cellular basis of neural oscillatory changes to the working memory deficit in schizophrenia.

Effects of NMDA antagonist dizocilpine (MK-801) are modulated by the number of distractor stimuli in the rodent odor span task of working memory.

The rodent odor span task (OST) uses an incrementing non-matching to sample procedure in which a series of odors is presented and selection of the session-novel odor is reinforced. An OST is frequently used to test the effects of neurobiological variables on memory capacity as the number of odors to remember increases during the course of the session. In this regard, one important finding has been that NMDA receptor antagonists selectively impair OST performance at doses that spare accuracy on control tasks. However, in many versions of the odor span task the number of stimuli to remember is confounded with the number of distractor odors presented to the rat on each trial. The present study compared the effects of the NMDA antagonist dizocilpine when the number of choices was held constant at two (one novel odor-S+ and one previously presented distractor odor-S-) and when the number of choice stimuli was permitted to increase up to 10 (one S+ and 9 S-). Dizocilpine impaired OST accuracy at doses that had no effect on a reference memory control task in both 2-choice and 10-choice conditions; however, the dose-response function was shifted to the left in the 10-choice tests. The impairments produced by dizocilpine were exacerbated as the memory load increased in both 2- and 10-choice conditions. These findings support the hypothesis that NMDA antagonism reduces the number of stimuli that rats can remember accurately, but the interaction between the effective DZP dose and the number of distractors shows that drug effects on OST performances may involve attentional factors in addition to memory capacity. The findings also demonstrate that variations in number of OST distractors can be used to alter sensitivity of the task.

Phencyclidine Discoordinates Hippocampal Network Activity But Not Place Fields.

We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires cognitive control even when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium-freguency gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium-frequency and slow gamma oscillations in CA1 LFPs such that medium-frequency gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP, but the drug discoordinates the subsecond temporal organization of discharge among place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the subsecond timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as the root of PCP-induced cognitive impairment.SIGNIFICANCE STATEMENT Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the LFP and the discharge of a subset of pyramidal neurons called "place cells" is spatially organized such that discharge is restricted to locations called a cell's "place field." Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition.

Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation.

Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures. METHODS: Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50µL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34+/CD45+ cells) were employed and ß-hexosaminidase in cell-free supernatants were measured to assess degranulation. RESULTS: A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of ß-hexosaminidase. The rank order of drug-induced hMC ß-hexosaminidase release was similar to that for flares. CONCLUSIONS: A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.

Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates.

N-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture.NEW & NOTEWORTHY This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Acute systemic MK-801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex.

The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate-early genes (IEGs) Arc and Homer1a in spatial context-specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non-competitive NMDAR antagonists such as MK-801 is used to model psychosis in animals and humans. Acute systemic MK-801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate-early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK-801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK-801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK-801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK-801-induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganization in psychosis. © 2016 Wiley Periodicals, Inc.

Population pharmacokinetic analysis of lanicemine (AZD6765), an NMDA channel blocker, in healthy subjects and patients with major depressive disorder.

WHAT IS KNOWN AND OBJECTIVE: Lanicemine (AZD6765) is a low-trapping N-methyl-d-aspartate receptor channel blocker that has demonstrated antidepressant efficacy in three of four clinical studies. The aim of this study was to develop a population pharmacokinetic model describing the concentration vs time profile of intravenously administered lanicemine in healthy subjects and patients with major depressive disorder (MDD) and to use the model to evaluate the impact of demographic and clinical factors and concomitant medication on the pharmacokinetics of lanicemine. METHODS: Data were derived from four studies: two Phase I trials in healthy subjects (studies 8 [NCT01069822] and 13 [NCT00785915]) and two Phase II trials in patients with MDD (studies 1 [NCT00491686] and 9 [NCT00781742]). Population pharmacokinetic analysis was performed by nonlinear mixed-effects modelling. The covariates evaluated within the model included sex, race, age and body weight parameters, clinically relevant laboratory measures, and use of concomitant medications. Goodness-of-fit plots, bootstrap and visual predictive checks were conducted to confirm concordance with observed data. RESULTS AND DISCUSSION: A total of 2531 plasma lanicemine concentrations were available for analysis from 191 healthy subjects and patients with MDD. The pharmacokinetics of lanicemine following intravenous infusion was best described by a two-compartment model with zero-order input and first-order elimination. Mean systemic clearance (CL) was estimated at 9.43 L/h (90% CI 9.12-9.77), central compartment volume of distribution (V1) was 106 L (90% CI 93.7-115), peripheral volume of distribution (V2) was 47.3 (95% CI 39.6-56.6), and intercompartmental clearance (Q) was 75.7 (90% CI 51.8-127). Lean body mass and body surface area had a statistically significant effect on CL and V1, respectively. WHAT IS NEW AND CONCLUSIONS: The population pharmacokinetic model developed adequately described the clinical observation of lanicemine in patients with MDD and healthy volunteers. Lean body mass and body surface area were identified as covariates that significantly influence the pharmacokinetics of lanicemine.

Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression II: response to antidepressant augmentation strategies.

OBJECTIVE: Post-traumatic stress disorder (PTSD) displays high co-morbidity with major depression and treatment-resistant depression (TRD). Earlier work demonstrated exaggerated depressive-like symptoms in a gene×environment model of TRD and an abrogated response to imipramine. We extended the investigation by studying the behavioural and monoaminergic response to multiple antidepressants, viz. venlafaxine and ketamine with/without imipramine. METHODS: Male Flinders sensitive line (FSL) rats, a genetic model of depression, were exposed to a time-dependent sensitisation (TDS) model of PTSD and compared with stress naive controls. 7 days after the TDS procedures, immobility and coping (swimming and climbing), behaviours in the forced swim test (FST) as well as hippocampal and cortical 5-hydroxyindoleacetic acid (5HIAA) and noradrenaline (NA) levels were analysed. Response to imipramine, venlafaxine and ketamine treatment (all 10 mg/kg×7 days) alone and in combination were subsequently studied. RESULTS: TDS exacerbated depressive-like behaviour of FSL rats in the FST. Imipramine, venlafaxine and ketamine were ineffective as monotherapy in TDS-exposed FSL rats. However, combining imipramine with either venlafaxine or ketamine resulted in significant anti-immobility effects and enhanced coping behaviours. Only ketamine+imipramine (frontal-cortical 5HIAA and NA), ketamine alone (frontal-cortical and hippocampal NA) and venlafaxine+imipramine (frontal-cortical NA) altered monoamine responses versus untreated TDS-exposed FSL rats. CONCLUSION: Exposure of FSL rats to TDS inhibits antidepressant response at behavioural and neurochemical levels. Congruent with TRD, imipramine plus venlafaxine or ketamine overcame treatment resistance in these animals. These data further support the hypothesis that exposure of FSL rats to a PTSD-like paradigm produces a valid animal model of TRD and warrants further investigation.

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K(+)ATP pathway.

CONTEXT: Magnesium and MK-801 (dizocilpine), antagonists of N-methyl-d-aspartate receptors, are involved in the processing of pain. OBJECTIVE: This study determines whether magnesium sulfate (MS) and MK-801 affects visceral inflammatory pain and determines a possible mechanism of action. MATERIALS AND METHODS: Analgesic activity was assessed using the acetic acid-induced writhing test in rats. MS (1-45 mg/kg) or MK-801 (0.005-0.03 mg/kg) was administrated subcutaneously (s.c.). To assess possible mechanisms of action, we examined the effects of l-NAME (10 mg/kg, intraperitoneal), methylene blue (0.5 mg/kg, s.c.), and glibenclamide (3 mg/kg, s.c.) on the effect of MS or MK-801. RESULTS: MS and MK-801 showed biphasic and linear dose-response pattern, respectively. MS reduces the number of writhing on the dose of 1, 5, and 15 mg/kg by 60, 50, and 78%, respectively, while it has no effects on the doses of 30 and 45 mg/kg. MK-801 (0.005-0.03 mg/kg) showed decrease in the number of writhing by 33-79%. The mean effective doses of MS and MK-801 were 6.6 (first phase) and 0.009 mg/kg, respectively. Both drugs did not impair the rotarod performance. l-NAME, methylene blue, and glybenclamide reduced the effect of MK-801 by 100, 43, and 64%, respectively, but not the effect of MS. CONCLUSIONS: The results suggest that MS and MK-801 may be useful analgesics in the management of visceral inflammatory pain, at doses that do not induce motor impairment. The modulation of NO/cGMP/K+ATP pathway plays an important role in the antinociceptive mechanism of MK-801, but does not contribute to the antinociceptive effect of MS.

Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. METHODS: Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. RESULTS: The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. CONCLUSIONS: Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.

Efficacy of Preemptive Analgesia with Amantadine for Controlling Postoperative Pain in Cats Undergoing Ovariohysterectomy.

This study aimed to evaluate the effect of the preemptive administration of amantadine on postoperative analgesia in cats undergoing ovariohysterectomy and its influence on the physiological parameters. Twenty healthy domestic cats scheduled to undergo ovariohysterectomy at the Santa Cruz State University, Ilhéus, were divided into two groups: the control group (Group C; n = 10) and the amantadine group (Group A; n = 10). The cats in Group C received placebo capsules 30 min prior to the standard anesthetic protocol, whereas those in Group A received 5 mg/kg of amantadine orally 30 min prior to the standard anesthetic protocol. Postoperative pain was assessed using the visual analog scale and the UNESP-Botucatu multidimensional scale for the evaluation of postoperative pain in cats. The administration of amantadine had no effect on the physiological parameters evaluated. The pain scores in Group A were lower than those in Group C, indicating that the frequency of rescue analgesic administration cats in Group A was lower. That way, preemptive oral administration of amantadine at a dose of 5 mg/kg was effective at controlling postoperative pain in cats undergoing ovariohysterectomy. Moreover, no adverse effects or alterations in the physiological patterns were observed in the treated animals.

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism.

BACKGROUND: Autism spectrum disorder (ASD) is the fastest-growing child neuropsychiatric condition. Cognitive dysfunctions such as memory impairments are experienced by patients along with social disturbances and repetitive/stereotypic movements. We have used the radial arm maze (RAM), for measurement of working and reference memory errors in an animal model of autism. In addition, the potential effects of agmatine, an endogenous NMDA antagonist, on RAM performance and autistic-like behaviors were assessed. METHODS: Autism was modeled by valproic acid (VPA) administration at gestational Day 12.5. Autism-associated behaviors in male offspring were examined in an open field test (OFT) and three-chambered test (TCT) on postnatal days 50-51. Thereafter, the animals were trained in the RAM (PND 55) until they attained the criteria of 80% correct choices during five consecutive trials. Forty-eight hours after the acquisition of criteria, agmatine was injected 30 min before subsequent behavioral testing, which included the retention phase of the RAM, OFT, and TCT. RESULTS: VPA-treated and intact rats showed the same performance in RAM, and acute injection of agmatine rescued social and anxiety-like behavior induced by VPA without the effect on RAM. CONCLUSION: In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

Ketamine causes poor maternal care in rats with postpartum depression and leads to few behavioral and neurochemical alterations on male offspring.

Ketamine is an anesthetic drug that also has antidepressant properties, with quick action. Despite the great number of studies showing its effectiveness as a treatment for major depression, there is little information about its effects on postpartum depression, as pharmacological treatments bring risks to the health of both mother and child. Thus, this study aimed to evaluate the effects of prolonged treatment with subanesthetic doses of ketamine in a rat model of postpartum depression. Female dams were induced to postpartum depression by the maternal separation model from lactating day (LD) 2-12. They were divided into four groups: one control and three experimental groups, which were treated with different doses of ketamine (5, 10 or 20 mg/kg) from LD 2-21 i.p. Maternal studies were conducted from LD5 to LD21 and the offspring studies from postnatal day 2 through 90. Ketamine causes poor maternal care, with few neurochemical alterations. However, the highest dose used in this study had an antidepressant effect. Regarding the male offspring, indirect exposure to ketamine through breast milk caused few behavioral changes during infancy, but they were not permanent, as they faded in adulthood. Nevertheless, this exposure was able to cause alterations in their monoaminergic neurotransmission systems that were found in both infancy and adulthood periods.

Acute MK-801 increases measures of both sign-tracking and goal-tracking in male Sprague-Dawley rats.

Sign-tracking is a Pavlovian conditioned approach behavior thought to be important in understanding cue-driven relapse to drug use, and strategies for reducing sign-tracking may have some benefit in preventing relapse. A previous study successfully employed the NMDA receptor antagonist MK-801 in preventing the development of sign-tracking (but not goal-tracking) in a conditioned approach task. In this study, we focused on whether MK-801 would have similar effects on previously established sign-tracking behavior. MK-801 was administered after training in a standard sign-/goal-tracking task using a retractable lever as a conditioned stimulus and a sucrose pellet as unconditioned stimulus. It was found that MK-801 increased measures of both sign- and goal-tracking in subjects who had previously learned the task. The NMDA receptor appears to play a complex role in governing behavior related to sign-tracking.

Oral and Dental Pain Management.

Pain has been defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. Pets often experience the same pain as people; however, dental pain is often overlooked, discounted, or unseen/hidden in patients, as the inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain. This article discusses types of pain and the methods and medications available to treat and prevent oral pain.