Effects of 5-HT2C receptor modulation and the NA reuptake inhibitor atomoxetine in tests of compulsive and impulsive behaviour
Introduction
The translational gap between preclinical and clinical research is a significant issue highlighted by a drug attrition rate of approximately 85–90% from Phase I entry to market approval (Kola and Landis, 2004; Hay et al., 2014; Smietana et al., 2016). Across therapeutic areas, psychiatric disorders are at the higher end of this attrition range, in part a reflection that the clinical conditions themselves are incompletely understood, and increasingly recognised as heterogeneous with respect to aetiology and treatment response (Pangalos et al., 2007; Enna and Williams, 2009; Markou et al., 2009; McArthur, 2017). To meet this challenge psychiatric disorders may be fractioned into specific symptoms, or endophenotypes, which can extend across multiple diagnostic categories and represent discrete measurable entities (Hyman and Fenton, 2003; Insel et al., 2010; Fineberg et al., 2010, 2016; Robbins et al., 2012; Cuthbert, 2014; Kozak and Cuthbert, 2016). These endophenotypes include constructs such as impulsive action, compulsive action, motivation and attention. Thus complex clinical disorders can be parsed into discrete symptom clusters which may be more amenable to translational research and treatment (Day et al., 2008; Markou et al., 2009; Fernando and Robbins, 2011; Goetghebeur and Swartz, 2016; Phillips et al., 2018; McArthur, 2017).
Substance dependence, obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), as well as certain eating disorders e.g binge eating disorder (BED), might appropriately be termed ‘impulsive-compulsive spectrum disorders’ on the basis of these predisposing traits and overlapping phenomenology and neurocircuitry (Fineberg et al., 2010, 2016; van den Heuvel et al., 2010; Fontenelle et al., 2011; Robbins et al., 2012; Kessler et al., 2016). The study of impulsive and compulsive behaviours have proven amenable to preclinical investigation using tasks such as the 5-choice serial reaction time task (5-CSRTT) (Robbins, 2002; Fernando and Robbins, 2011; Higgins and Silenieks, 2017) and schedule induced polydipsia (SIP) (Falk, 1961, 1971; Moreno and Flores, 2012; Szechtman et al., 2017). Compulsive behaviours may be defined as persistent or repetitive acts with no obvious benefit. Thus, the excessive non-homeostatic drinking shown by food (but not water) restricted rats presented with intermittent and uncontrollable food reinforcement represents a compulsive act in the SIP paradigm (Falk, 1961, 1971). Similarly, the repetitive aperture responses (termed perseverative responses; PSV) made after a correct choice response and signalled food presentation, but prior to food collection, represents a compulsive act in the 5-CSRTT. Impulsive behaviour, defined in this instance as a failure of motor inhibition, is reflected by response choices made prior to visual stimulus presentation (termed premature responses; PREM) and which lead to loss of food reward (see Robbins, 2002; Bari et al., 2008; Amitia and Markou, 2010; Higgins and Silenieks, 2017).
Based on SIP and 5-CSRTT task performance, animals may show a variability of response output characteristic of impulsive-compulsive trait. For example, a high impulsive (HI) trait may be expressed by rats making exceptionally high levels of premature responses under conditions of extended delay to choice in the 5-CSRTT (Puumala et al., 1996; Blondeau and Dellu-Hagedorn, 2007; Barlow et al., 2018). An example of a high compulsive (HC) trait is based on rats consuming high volumes of water in a SIP paradigm (termed high drinkers; HD) (Mittleman and Valenstein, 1984, 1985; Moreno and Flores, 2012). Indeed there is some evidence that these two behavioural traits (HI/HD) may co-segregate suggesting linkage (Moreno et al., 2012; Ansquer et al., 2014). The segregation of animals based on a high impulsive-compulsive trait is unbiased with respect to an underlying neurobiology, and provides a useful experimental cohort with which to study the neurobiological processes that contribute to trait, or to the investigation of novel therapeutics against that trait (Puumala et al., 1996; Puumala and Sirvio, 1998; Blondeau and Dellu-Hagedorn, 2007; Dalley et al., 2007; Markou et al., 2009; Tomlinson et al., 2014; Hayward et al., 2016; Navarro et al., 2017; Merchán et al., 2019b, Merchán et al., 2019a). These high extreme endophenotypes may be associated with excessive drug taking behaviour or food consumption (e.g. Dalley et al., 2007; Velazquez-Sanchez et al., 2014; Hayward et al., 2016), supporting their associations to the related clinical conditions.
Although the 5-HT2C receptor agonist lorcaserin (LOR; Belviq®; Thomsen et al., 2008) has been approved for obesity, there is emerging preclinical evidence that this drug may be effective in treating other eating disorders, such as BED, as well as other clinical conditions characterised by addiction such as substance dependence (Di Giovanni and De Deurwaerdère, 2016; Higgins et al., 2017, 2020; Collins et al., 2018). This view is supported by the observation that lorcaserin is particularly effective against measures of impulsivity, although currently there is little available information for this drug against compulsive-type behaviours. The selective noradrenergic reuptake inhibitor atomoxetine (ATX; Strattera®; Bymaster et al., 2002), approved for ADHD (Simpson and Plosker, 2004; Garnock-Jones and Keating, 2009), has also been proposed as a treatment for BED and addictive disorders (Economidou et al., 2011; Broos et al., 2015; McElroy et al., 2007; Phillips et al., 2018) based on preclinical evidence against measures of impulsive action (Navarra et al., 2008; Baarendse and Vanderschuren, 2012; Fernando et al., 2012; Robinson, 2012; Tomlinson et al., 2014; Callahan et al., 2019). However, the effect of atomoxetine on behaviours related to compulsive action is also relatively limited (Ansquer et al., 2014; Navarro et al., 2015; Callahan et al., 2019).
A purpose of the present study was to evaluate both lorcaserin and atomoxetine in two tests with measures of compulsive action: schedule-induced polydipsia and increased perseverative (PSV) responses in an extended 10s ITI 5-choice schedule. The highly selective 5-HT2C receptor agonist CP-809101 (Siuciak et al., 2007) was also included in these studies to test the generality of any findings to other members of this pharmacological class. A second purpose was to investigate the effect of the selective 5-HT2C receptor antagonist SB-242084 (Kennett et al., 1997). While previous studies have demonstrated increases in impulsive and compulsive action following SB-242084 pretreatment in these tests (Higgins et al., 2003; Winstanley et al., 2004; Martin et al., 2002; Fletcher et al., 2007; Pennanen et al., 2013; Navarro et al., 2015), there are relatively few investigations into extreme phenotypes. We sought to establish which subgroup might be most responsive to this drug.
An overall aim of these investigations was to explore evidence to support the repositioning of lorcaserin and atomoxetine as treatments for clinical conditions within the impulsive-compulsive disorder spectrum (Fineberg et al., 2010, 2016; van den Heuvel et al., 2010; Fontenelle et al., 2011; Robbins et al., 2012). Therefore, the effect of these drugs was studied in extreme phenotypes of high-drinking (HD) rats (SIP) and high-impulsive (HI) rats (5-choice) which were thought to be most representative of this clinical disorder spectrum. Drug repositioning is a strategy designed to counter the productivity gap and high attrition rate of new chemical entities (NCE's) entering clinical development (Ashburn and Thor, 2004; Pushpakom et al., 2019).
Section snippets
Animals and housing
Male Wistar rats (source: Charles River, St. Constant, Quebec, Canada) served as test subjects for the SIP experiments. Rats of the Wistar strain tend to have a higher incidence of high intensity drinking behaviour (i.e. compulsive drinkers), relative to other strains and so have become a frequently used strain for SIP studies (Moreno and Flores, 2012; Merchán et al., 2019a). Male Long Evans rats (source: Charles River, St. Constant, QE) were used in all 5-choice experiments. All rats were
Characterisation of the SIP model
Based on a metanalysis of 84 rats made up from 4 experimental cohorts, and measured over 30 training sessions, rats showed individual differences in total water intake measured over the 60min test session. Despite all rats consuming the 60 food pellets, the rats could be separated into “High drinkers” (HD), and “Low drinkers” (LD) based on water consumption measured over the 60min test session. Based on tertiles the HD group consumed approximately 20 g water per session, while LD rats consumed
Discussion
The primary observations from the present series of experiments is that lorcaserin and CP-809101, one of the most functionally selective 5-HT2C receptor agonists reported to date (Siuciak et al., 2007), are effective at reducing compulsive behaviours measured by non-regulatory drinking induced by intermittent food delivery, and secondly by PSV responses induced by extended ITI in a 5-choice task variant. These inhibitory effects seemed most apparent in the extreme impulsive-compulsive
Author contributions
GAH conceptualized the study and wrote the MS; MB, J St. J, C MacM, LBS conducted the experiments; LBS data curation; ST conducted statistical analysis of the data.
Funding statement
All studies reported were funded by InterVivo Solutions Inc.
Declaration of competing interest
The authors declare no conflict of interest.
References (95)
- et al.
Atomoxetine decreases vulnerability to develop compulsivity in high impulsive rats
Biol. Psychiatr.
(2014) - et al.
Dimensional analysis of ADHD subtypes in rats
Biol. Psychiatr.
(2007) - et al.
Investigation of the SSRI augmentation properties of 5-HT(2) receptor antagonists using in vivo microdialysis
Neuropharmacology
(2006) - et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002) - et al.
Atomoxetine improves memory and other components of executive function in young-adult rats and aged rhesus monkeys
Neuropharmacology
(2019) - et al.
The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders
Neuropharmacology
(2018) - et al.
New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders
Pharmacol. Ther.
(2016) - et al.
Selective norepinephrine reuptake inhibition by atomoxetine prevents cue-induced heroin and cocaine seeking
Biol. Psychiatr.
(2011) The nature and determinants of adjunctive behavior
Physiol. Behav.
(1971)- et al.
Compulsivity-A new trans-diagnostic research domain for the roadmap for mental health research in europe (ROAMER) and research domain criteria (RDoC) initiatives
Eur. Neuropsychopharmacol
(2016)