Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats.

BACKGROUND: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is currently in Phase 3 clinical development for the treatment of schizophrenia. Unlike available antipsychotics, the efficacy of ulotaront is not mediated by blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized clinical trial, ulotaront has demonstrated significant efficacy in the treatment of adults with an acute exacerbation of schizophrenia. Given ulotaront's novel mechanism of action a series of preclinical studies were performed to evaluate its potential abuse liability. METHODS: A battery of studies were conducted in male and female rats to evaluate whether ulotaront produces behavioral changes suggestive of human abuse potential. In addition, studies were undertaken to probe the potential for ulotaront to block reinstatement of cocaine-seeking behavior in male rats. RESULTS: Ulotaront was not self-administered by rats trained to self-administer amphetamine, cocaine, or heroin. The subjective qualities of ulotaront were distinct from those produced by amphetamine in a drug discrimination procedure. Ulotaront, and buspirone, a non-scheduled anxiolytic with 5-HT1A agonism, partially generalized to the interoceptive cue elicited by 3, 4-methylenedioxymethamphetamine (MDMA). In addition, ulotaront demonstrated a trend to reduce cocaine-primed induced reinstatement, and dose-dependently reduced cue-reinstated responding. CONCLUSION: The current results suggest that the TAAR1/5-HT1A agonist ulotaront is not likely to pose a risk for recreational abuse in humans and may have potential therapeutic utility as a treatment of substance use disorders.

Introduction to the EQIPD quality system.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

CNS safety pharmacology: A focus on cognitive functions.

INTRODUCTION: The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint. METHODS: The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule. RESULTS: Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated. DISCUSSION: Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under development.

Effects of baclofen and raclopride on reinstatement of cocaine self-administration in the rat.

At present there is no satisfactory treatment against relapse of drug-seeking behavior. Relapse can be modeled in laboratory animals using reinstatement procedures, whereby previously extinguished self-administration for a drug is reinstated by different factors, such as exposure to cues or drug priming. It is thought that activation of gamma-aminobutyric acid (GABA) B receptor complexes could represent a promising approach to pharmacotherapy for diminishing relapse potential with drugs possessing reinforcing properties. The effects of baclofen (a prototypic GABAB receptor agonist) on cue-induced cocaine reinstatement were evaluated in the rat with or without a priming injection of cocaine. The effects of raclopride (an antagonist of dopamine D2 receptors) were also evaluated. Cue-induced reinstatement under vehicle resulted in a significant increase in the number of presses on the active lever, as compared with extinction lever responding. This effect was accentuated in rats receiving a priming injection of cocaine (cocaine-plus-cue-induced reinstatement). Baclofen, at doses without effects on food-motivated operant behavior (2.5 and 5mg/kg i.p.), dose-dependently decreased the number of active lever presses during cue-induced reinstatement. Baclofen had slightly weaker effects on cocaine-plus-cue-induced reinstatement. Raclopride (0.08 and 0.15 mg/kg s.c.) had similar effects against cue-induced reinstatement although it failed to inhibit cocaine-plus-cue-induced reinstatement at the lower dose. Baclofen dose-dependently and selectively decreased reinstatement of cocaine self-administration. The data obtained provide support for the potential anti-craving efficacy of baclofen in the treatment of cocaine drug-seeking.

Evaluation of pro-convulsant risk in the rat: spontaneous and provoked convulsions.

INTRODUCTION: The aim of the present study was to evaluate the utility of different tests performed in the absence or presence of factors promoting seizures in order to evaluate the pro-convulsant effects of drugs. We studied the effects of theophylline in the rat since this is a well-known pro-convulsant substance in humans. METHODS: The occurrence of spontaneous convulsions following administration of theophylline was evaluated by observation in the Irwin Test and by measuring brain activity using video-EEG recording in conscious telemetered animals. Theophylline was also tested in the electroconvulsive shock (ECS) threshold and pentylenetetrazole (PTZ)-induced convulsions tests, two commonly used models of provoked convulsions. RESULTS: In the Irwin test, theophylline induced convulsions in 1 out of 6 rats at 128 mg/kg. Paroxysmal/seizure activity was also observed by video-EEG recording in 4 out of the 12 animals tested at 128 mg/kg, in presence of clonic convulsions in 3 out of the 4 rats. Paroxysmal activity was observed in two rats in the absence of clear behavioral symptoms, indicating that some precursor signs can be detected using video-EEG. Clear pro-convulsant activity was shown over the dose-range 32-128 mg/kg in the ECS threshold and PTZ-induced convulsions tests. DISCUSSION: Evaluation of spontaneous convulsions provides information on the therapeutic window of a drug and the translational value of the approach is increased by the use of video-EEG. Tests based on provoked convulsions further complement the evaluation since they try to mimic high risk situations. Measurement of both spontaneous and provoked convulsions improves the evaluation of the pro-convulsant risk of novel pharmacological substances.

Continuous evaluation of drug withdrawal in the rat using telemetry: effects of morphine and chlordiazepoxide.

INTRODUCTION: The procedures used to assess withdrawal must be sensitive and widely applicable, i.e. not specific to any particular drug class. Furthermore, the measurements should not be affected by repeat testing. METHODS: We have used implanted telemetry devices to continuously follow body temperature, locomotor activity (LMA), heart rate (HR) and mean arterial blood pressure (mean ABP) in addition to food intake and body weight gain over 20days of treatment and 8days of withdrawal. The effects of morphine (32 and 64mg/kg p.o., b.i.d.) and chlordiazepoxide (16, 32 and 64mg/kg p.o., b.i.d.) were studied in rats. RESULTS: The results show that during the treatment phase chronic morphine reduced food intake and body weight gain, increased body temperature, HR, mean ABP and LMA. These effects continued over the 20days of treatment. In contrast, chlordiazepoxide slightly increased food intake and body weight gain throughout the treatment period. It also decreased body temperature and LMA but increased HR and mean ABP after the first few administrations but these effects disappeared over the 20days of treatment. Following discontinuation, both morphine- and chlordiazepoxide-treated rats showed a dose-related decrease in food intake and loss of weight on days 2 and 3 of discontinuation. Morphine discontinuation also induced a nocturnal hypothermia and a diurnal hypertension (i.e. during the light phase) which lasted for 4-5days and also moderate diurnal increases in locomotor activity and heart rate over the first 3days of discontinuation. Chlordiazepoxide discontinuation induced small increases in telemetry parameters some of which, such as the effect on locomotor activity, lasted for more than 5days. The intensity and duration of effects for both substances were broadly dose-related. DISCUSSION: These data show that telemetry can increase the sensitivity of withdrawal experiments to changes that might otherwise be missed and allows a better definition of the time-course of withdrawal effects. This technique is therefore useful as part of safety pharmacology abuse liability evaluation of novel test substances across a broad range of pharmacological and therapeutic classes.