RenaSci

Publication of Paper Validating Rat Model of Binge-eating Disorder

27/11/2015 02:16

Our latest paper explores the predictive validity of our rodent model of binge-eating disorder. Binge-eating was established by allowing rats unpredictable, intermittent access to chocolate. The effects of a variety of drugs shown to reduce binge-eating in humans or other animal models were evaluated including the μ-opioid antagonist, nalmefene, the orexin-1 antagonist, SB-334867, the GABAB receptor agonist, R-baclofen, the pro-drug, lisdexamfetamine and its active metabolite, d-amphetamine. Lisdexamfetamine has recently been approved by the FDA for the treatment of moderate to severe binge-eating disorder in adults. Nalmefene, SB-334867 and baclofen selectively decreased chocolate bingeing without reducing chow intake. Lisdexamfetamine dose-dependently reduced chocolate bingeing by up to 71% without significantly decreasing normal chow intake whereas d-amphetamine dose-dependently and preferentially decreased chocolate bingeing by up to 56%. In comparison, sibutramine non-selectively decreased chow and chocolate intake, olanzapine had no effect on either parameter and rolipram abolished chow and chocolate intake. These findings support the use of our model to identify novel drugs to treat binge-eating disorder. Details of the paper, which is the first to describe the effects of lisdexamfetamine in a preclinical model of binge-eating disorder are given below.

Vickers SP et al. Effects of lisdexamfetamine in a rat model of binge-eating. J Psychopharmacol doi: 10.1177/0269881115615107. Epub ahead of print.

To see the abstract please click here

Please contact us if you would like further information on the model.

New Book on Evaluation of Drug Abuse Potential

03/08/2015 01:17

One of our Directors, David Heal, has recently contributed to a new reference book titled 'Nonclinical Assessment of Abuse Potential for New Pharmaceuticals'. The aim of the book is to provide a complete overview of the international regulatory requirements for assessing the abuse potential of novel drugs before they can be approved for use in man. The book describes the three ‘gold standard’ animal models which are normally mandatory for the preclinical assessment of abuse potential (self-administration, drug discrimination and physical dependence studies) and discusses when it may be appropriate to use alternative paradigms such as conditioned place preference and intracranial self-stimulation. It includes chapters on the neurochemistry of drug abuse, on the evaluation of abuse potential of new drugs in man and on future directions for assessment of drug abuse. The book has been written by international experts in the drug abuse field from industry, academia and government bodies and will be an invaluable resource for anyone involved in development of drugs to treat CNS disorders or any other compounds that extensively cross the blood-brain barrier (regardless of the primary site of action).

The book chapter that David co-authored with Silvia Calderon (Controlled Substances Staff of the FDA) and Alessandra Giarola (Safety Pharmacology Department, GSK, UK) focuses on the regulatory landscape and reviews and compares FDA and EMA guidance for the evaluation of the abuse liability of centrally-acting drugs. The full reference for it is given below.

Silvia Calderon, Alessandra Giarola and David Heal. Chapter 10. Regulatory framework and guidance to the evaluation of the abuse liability of drugs in the United States and Europe. In: Nonclinical Assessment of Abuse Potential for New Pharmaceuticals, 1st Edition. Carrie G Markgraf, Thomas J Hudzik and David J  Compton (Eds). Academic Press, Elsevier, pp 245-268, 2015.

For further information on the preclinical models offered by RenaSci to evaluate the abuse potential of novel compounds please contact us. 

Pre-pulse Inhibition of Acoustic Startle 

02/08/2015 01:15

We have recently obtained 8 acoustic startle boxes (TSE Systems) which can be used to measure pre-pulse inhibition (PPI) of acoustic startle in rats. In brief, the acoustic startle reflex is a basic response to marked external noise stimuli. It can be inhibited by exposure to a weak stimulus (pre-pulse) before the loud acoustic stimulus. PPI is evident in a number of animal species including man. Importantly, deficits in PPI are associated with numerous neuropsychiatric conditions characterised by sensory gating disturbances, including schizophrenia and Tourette Syndrome (ie the effect of the pre-pulse is limited and the startle response is maintained even in the presence of the pre-pulse).

It is well-established that PPI inhibition of the startle response can be inhibited by direct and indirect dopaminergic agonists and NMDA receptor antagonists in rats. In our preliminary studies, we have shown that amphetamine, apomorphine and PCP inhibit PPI of acoustic startle in these animals as expected. Over the coming months we will continue to validate the methodology by testing the ability of antipsychotic agents and a range of other drugs to normalise the deficits in PPI produced by psychotomimetic drugs in rats.

Please contact us for further information about this model. 

New Animal Model of Impulsivity

31/07/2015 10:30

Impulsivity and loss of inhibitory control are important factors in binge-eating disorder. Subjects with binge-eating disorder display enhanced delay discounting, ie they will choose smaller, immediate rewards rather than wait for a larger, delayed reward. We have developed a delay discounting model to evaluate impulsivity and intolerance of delayed reward in binge-eating rats given irregular, limited access to chocolate. Binge-eating rats are trained to lever press for chocolate pellets using two-lever operant chambers. One lever delivers a small immediate reward of the palatable food and the other lever a larger but delayed food reward. Binge-eating rats show a significant reduction in preference for the larger delayed reward compared to the control group ie they show lack of tolerance to delay for the larger chocolate reward. This intolerance of delayed reward develops over time with the number of binge-eating sessions and is characteristic of impulsive behaviour.

The delay discounting model has been validated using lisdexamfetamine and can now be used to investigate the effects of novel drugs on impulsivity in either binge-eating or normal rats.

To see our flyer on the delay discounting model please click here

See Our New Diabesity Flyer

26/06/2015 09:47

We have recently produced a new flyer describing our range of assays and animal models for evaluating novel drugs to treat diabesity.

Animal models include :-

• DIO mice on high fat diet - a polygenic model of obesity and insulin resistance that can be used as an initial screen

• DIO rats on cafeteria diet - the gold standard model of obesity with excellent predictive validity for weight-loss in the clinic

• ob/ob mice - a monogenic model of obesity and insulin resistance

• db/db mice - a monogenic model of obesity and type 2 diabetes

• ZDF and ZSF1 rats - monogenic models of obesity and type 2 diabetes with renal impairment and cardiovascular complications (ZSF1)

Body weights and food and water intake are routinely measured. Optional additional studies include :-

• Glucose tolerance tests to assess effects of drugs on glycaemic control

• Blood and urine-sampling to determine levels of metabolic parameters (including HDL-C and LDL-C) and other biomarkers

• Blood and tissue-sampling for PK

• Metabolic rate and RER (CLAMS)

• Gastrointestinal transit 

• Blood pressure and heart rate

• Liver TAG, cholesterol and glycogen

• Liver function (AST, ALT, ASP)

• Markers of renal impairment/diabetic nephropathy including GFR

• Pancreatic insulin levels

• Preparation of tissues for immunohistochemistry and histopathological assessment

• Ex vivo binding in brain tissue (to confirm mode of action for centrally-acting antiobesity drugs)

• Fat pad weights

• Body composition analysis (DEXA, FoodScan, chemical analysis)

To download the flyer and see the effects of the GLP-1 receptor agonist, liraglutide, in some of our animal models of obesity and diabetes, please click here

For further information please contact us on inform@renasci.co.uk.

Kappa Opioid Receptor Agonists

20/06/2015 09:45

Our expert on drug abuse liability issues, David Heal, was recently invited to be a panel discussant at a symposium titled 'New Analgesic and Abuse Deterrent Approaches: Kappa Opioid Receptor Agonists (KORAs)'. The symposium, which was sponsored by Cara Therapeutics was held on 17 June 2015 in Phoenix, Arizona, USA, as part of the 77th Annual Meeting of the College on Problems of Drug Dependence. 

Measurement of Multiple Neurotransmitters in the Same Microdialysis Study

09/05/2015 10:15

We have recently used dual probe microdialysis to measure the effects of drugs on multiple neurotransmitters and their metabolites in the same animals. In our latest study, we have simultaneously measured dopamine, DOPAC, HVA, 5-HT, 5-HIAA, noradrenaline, GABA and glutamate in microdialysis samples taken from the nucleus accumbens of rats. In the same study, we have measured extracellular levels of acetylcholine in the prefrontal cortex. This methodology enables us to offer cost-effective analysis of the neurochemical effects of drugs in freely-moving animals. 

To see the data please click here.

For further information about our microdialysis services please contact us on inform@renasci.co.uk.

Modelling Compulsivity in Binge-eating Rats

9/05/2015 02:45

Compulsivity is a core component of the psychopathology of many psychiatric disorders including ADHD and binge-eating disorder. We have recently developed the food-associated conflict test to assess compulsive/perseverative bingeing on palatable food. Rats are trained to binge-eat using chocolate as the hedonistic food and then tested in two-chambered shuttle-boxes. Entry into a chamber containing chocolate leads to presentation of conditioned stimuli (light/tone) followed 10 sec later by mild foot-shock. Binge-eating rats develop compulsive consumption of chocolate that is resistant to the mildly aversive foot-shock compared to the control group ie compulsive/perseverative responding for chocolate.

The food-associated conflict test has been validated using lisdexamfetamine, the only drug currently approved by the FDA for the treatment of mild to severe BED in adults. Lisdexamfetamine reduced compulsive behaviour in binge-eating rats. The model can therefore be used to evaluate the effects of new drugs on the compulsivity component of binge-eating disorder psychopathology.

To see the flyer on our novel animal model of compulsivity please click here.

The data showing the effects of lisdexamfetamine in the food-associated conflict test will be presented at the ASCP Meeting, Miami, Florida, 22nd to 25th June 2015. To see the abstract please click here.

Special Issue on CNS Stimulants

23/01/2015 08:20

Two of our experts, David Heal and Sharon Smith, and our  colleague, Jack Henningfield, from Pinney Associates, USA, have recently edited a Special Issue of Neuropharmacology dedicated to CNS Stimulants (Neuropharmacology  Volume 87, pages 1 to 222, December 2014, Elsevier). The Special Issue contains 16 invited reviews and 6 original research papers from leading scientists in the field. CNS stimulants are effectively used to treat a range of CNS disorders eg attention deficit hyperactivity disorder (ADHD) and narcolepsy but are also widely abused and misused presenting a challenge for their continued clinical use. This Special Issue reviews recent advances in our understanding of the neuropharmacology of CNS stimulants. Such findings have implications for the development of better medicines to treat CNS disorders and for the improved treatment of stimulant dependence. Drugs which are typically categorised as stimulants such as the amphetamines, methylphenidate, cocaine,modafinil, MDMA and ‘designer’ drugs are described and also legal stimulants such as nicotine and alcohol. Topics include psychostimulant action at the molecular level; the preclinical pharmacology and toxicology of lisdexamfetamine, a novel pro-drug marketed for the treatment of ADHD; designer psychostimulants that mimic the subjective effects of amphetamines, cocaine and MDMA; a critical evaluation of the use of animal models to predict the abuse potential of novel drugs; assessment of the abuse-potential of stimulants in drug-experienced, human volunteers; human imaging studies of psychostimulant action; the epidemiology of stimulant use and misuse in the USA and current and new approaches for treating psychostimulant addiction (including vaccines). Regulatory aspects are covered by Silvia Calderon and Michael Klein (Controlled Substance Staff, Center for Drug Evaluation and Research, FDA) who give an overview of the regulatory framework for evaluating the abuse potential of all new drugs in the USA, including those with stimulant properties. They also describe the criteria for recommending specific levels of control (i.e. a Schedule) for new drugs under the Controlled Substances Act.

In addition to the Editorial, RenaSci have contributed the following chapter:

Heal et al.   ‘Dopamine reuptake transporter (DAT) “inverse agonism”: a novel hypothesis to explain the enigmatic pharmacology of cocaine’  pp 19-40.       .

and a research article by one of our PhD students (from an academic collaboration with University College, London):

Ash et al.  ’Contrasting changes in extracellular dopamine and glutamate along the rostrocaudal axis of the anterior cingulate cortex of the rat following an acute d-amphetamine or dopamine challenge’ pp 180-187.  

To see the full contents of the Special Issue of Neuropharmacology on CNS Stimulants please click here

REDDSTAR, Repair of Diabetic Damage by Stromal Cell Administration

16/01/2015 09:30

One of our Directors, Rob Jones, attended the REDDSTAR Exploitation Workshop, which was held on 21st October 2014 in Oporto, Portugal, in order to provide an independent review and comment on the progress made by the group. REDDSTAR is an EU funded project which aims to develop and test stromal cell therapy for the treatment of diabetes mellitis. The main objective of the project is to investigate whether stromal stem cells can be used to safely ameliorate a range of diabetic complications (nephropathy, retinopathy, cardiomyopathy, neuropathy, impaired bone repair and ulceration). REDDSTAR involves an unique collaboration between specialists in diabetes, regenerative medicine, biotech companies and clinicians. The REDDSTAR Exploitation Workshop was organised to gain steering and advice at the two year point of the project.

For further information about REDDSTAR please click here