InterVivo Solutions Inc.

Toronto, Canada

InterVivo Solutions Inc.

Toronto, Canada
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Lau W.,InterVivo Solutions Inc. | Dykstra C.,InterVivo Solutions Inc. | Thevarkunnel S.,InterVivo Solutions Inc. | Silenieks L.B.,InterVivo Solutions Inc. | And 4 more authors.
Neuropharmacology | Year: 2013

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol®) and pregabalin (Lyrica®) against these end-points with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition. © 2013 Elsevier Ltd. All rights reserved.

Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,King's College
ACS Chemical Neuroscience | Year: 2017

In the current issue of ACS Chemical Neuroscience, Kim et al. report on the early characterization of 4-(3-[18F] fluorophenethoxy)pyrimidine (18F-FPP) as a new positron emission tomography radiotracer for imaging brain 5-HT2C receptors (Kim, J., et al. (2017) A potential PET radiotracer for the 5-HT2c receptor: Synthesis and in vivo evaluation of 4-(3-[18F]Fluorophenethoxy)pyrimidine. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.6b00445). At the present time, the tracer properties of 18F-FPP have only been reported in rats. If 18F-FPP is indeed shown to be suitable as a 5-HT2C receptor PET tracer in humans, it will very likely have an important impact both in the development of any new chemical entities (NCEs) targeted to 5-HT2C receptors, as well as a tool to advance understanding of 5-HT2C receptor function both in normal and abnormal brain states. © 2017 American Chemical Society.

Fletcher P.J.,Center for Addiction and Mental Health | Fletcher P.J.,University of Toronto | Rizos Z.,Center for Addiction and Mental Health | Noble K.,Center for Addiction and Mental Health | And 2 more authors.
Neuropharmacology | Year: 2011

Previous work has shown that 5-HT2C receptor agonists and 5-HT2A receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT2C receptor agonist Ro60-0175, and the 5-HT2A receptor antagonist M100907 on impulsive action induced by amphetamine, cocaine and the NMDA receptor antagonist MK801 (dizocilpine). Impulsive action was measured in adult male Long-Evans rats as premature responding in the 5-choice serial reaction time (5-CSRT) test. Initially, we determined that amphetamine (0.3 mg/kg), cocaine (15 mg/kg) and MK801 (0.03 mg/kg) induced comparable premature response rates of approximately 50-70 per session, compared to 10-15 responses under baseline conditions. Each drug and its vehicle were then tested in combination with Ro60-0175 (0.1 and 0.6 mg/kg) or its vehicle, or M100907 (0.5 mg/kg) or its vehicle. At 0.1 mg/kg Ro60-0175 did not modify the effects of amphetamine, cocaine or MK801. In contrast, the 0.6 mg/kg dose reduced premature responses induced by amphetamine, cocaine and MK801. M100907 also reduced premature responding induced by all three of these drugs. In general, treatment with Ro60-0175 or M100907 by itself did not consistently alter any of the other aspects of task performance in the 5-CSRT test including number of trials completed, and accuracy of responding. These data show that activation of 5-HT2C receptors and blockade of 5-HT2A receptors have seemingly similar functional effects on a measure of impulsive action. © 2011 Elsevier Ltd. All rights reserved.

Harvey-Lewis C.,Campbell Family Mental Health Research Institute | Li Z.,Campbell Family Mental Health Research Institute | Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,University of Toronto | And 2 more authors.
Neuropharmacology | Year: 2016

Lorcaserin (Lorqess, Belviq®) is a selective 5-HT2C receptor agonist that has received FDA approval for the treatment of obesity. 5-HT2C receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. © 2015 Elsevier Ltd.

Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,University of Toronto | Silenieks L.B.,InterVivo Solutions Inc. | Rossmann A.,InterVivo Solutions Inc. | And 5 more authors.
Neuropsychopharmacology | Year: 2012

Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT 2C receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT 2C receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT 2C agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Zeeb F.D.,Center for Addiction and Mental Health | Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,University of Toronto | Fletcher P.J.,Center for Addiction and Mental Health | Fletcher P.J.,University of Toronto
ACS Chemical Neuroscience | Year: 2015

Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphé nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3-1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to nicotine prevented the reward-enhancing effect of nicotine across multiple test sessions. These results demonstrated that lorcaserin reduces the rewarding value of BSR and also prevents nicotine from facilitating ICSS. Hence, lorcaserin may be effective in treating psychiatric disorders, including obesity and nicotine addiction, by reducing the value of food or drug rewards. © 2015 American Chemical Society.

Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,University of Toronto | Sellers E.M.,DecisionLine | Fletcher P.J.,Center for Addiction and Mental Health | Fletcher P.J.,University of Toronto
Trends in Pharmacological Sciences | Year: 2013

The recent US Food and Drug Administration (FDA) approval of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor agonist lorcaserin for the treatment of obesity represents a new therapeutic drug class available to the clinic. Preclinical evidence supports the potential for this drug class to treat other related conditions such as substance abuse. In the present article we review this evidence and further suggest that overlapping neurobiological systems may contribute to an anti-addictive and anti-obesity profile. The availability of selective 5-HT2C agonists provides an opportunity to evaluate their potential as treatments for nicotine dependence or psychostimulant abuse, conditions for which there is significant medical need but only limited available treatment options. © 2013 Elsevier Ltd. Allrights reserved.

Fletcher P.J.,Center for Addiction and Mental Health | Fletcher P.J.,University of Toronto | Soko A.D.,Center for Addiction and Mental Health | Higgins G.A.,University of Toronto | Higgins G.A.,InterVivo Solutions Inc
Psychopharmacology | Year: 2013

Rationale: Depletion of brain serotonin (5-HT) results in impulsive behaviour as measured by increased premature responding in the five-choice serial reaction time (5-CSRT) test. Acute selective blockade of 5-HT 2C receptors also increases this form of impulsive action, whereas 5-HT2C receptor stimulation reduces premature responding. Objectives: These experiments determined the impact of genetic disruption of 5-HT 2C receptor function on impulsive responding in the 5-CSRT test. Methods: Food-restricted 5-HT2C receptor null mutant and wild-type (WT) mice were trained on the 5-CSRT test in which subjects detect and correctly respond to brief light stimuli for food reinforcement. Impulsivity is measured as premature responses that occur prior to stimulus presentation. Results: Both lines of mice quickly learned this task, but there were no genotype differences in premature responding or any other aspect of performance. A series of drug challenges were then given. The 5-HT2C receptor agonist Ro60-0175 (0.6 mg/kg) reduced premature responding in WT mice but not mutant mice. The 5-HT2C receptor antagonist SB242084 increased premature responding in WT mice only. Cocaine increased premature responding at 7.5 mg/kg but not at a higher dose that disrupted overall responding; these effects were observed in both lines of mice. Amphetamine (0.25 and 0.5 mg/kg) did not affect premature responding, but disrupted other aspects of performance in both genotypes. Conclusions: Genetic deletion of 5-HT2C receptor function does not induce an impulsive state or exacerbate that state induced by psychomotor stimulants but does prevent the acute effects of 5-HT2C receptor stimulation or blockade on impulsive action. © 2012 Springer-Verlag Berlin Heidelberg.

Higgins G.A.,InterVivo Solutions Inc. | Higgins G.A.,University of Toronto | Fletcher P.J.,Section of Biopsychology and Campbell Family Mental Health Research Institute | Fletcher P.J.,University of Toronto
ACS Chemical Neuroscience | Year: 2015

The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014. © 2015 American Chemical Society.

Fan J.,InterVivo Solutions Inc. | De Lannoy I.A.M.,InterVivo Solutions Inc.
Biochemical Pharmacology | Year: 2014

Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE) after its administration to the body. Following a brief introduction as to why knowledge of the PK properties of an NCE is critical to its selection as a lead candidate in a drug discovery program and/or its use as a functional research tool, the present article presents an overview of PK principles, including practical guidelines for conducting PK studies as well as the equations required for characterizing and understanding the PK of an NCE and its metabolite(s). A review of the determination of in vivo PK parameters by non-compartmental and compartmental methods is followed by a brief overview of allometric scaling. Compound absorption and permeability are discussed in the context of intestinal absorption and brain penetration. The volume of distribution and plasma protein and tissue binding are covered as is the clearance (systemic, hepatic, renal, biliary) of both small and large molecules. A section on metabolite kinetics describes how to estimate the PK parameters of a metabolite following administration of an NCE. Lastly, mathematical models used to describe pharmacodynamics (PD), the relationship between the NCE/compound concentration at the site of action and the resulting effect, are reviewed and linked to PK models in a section on PK/PD. © 2013 Published by Elsevier Inc.

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