Pregabalin‐ and topiramate‐mediated regulation of cognitive and motor impulsivity in DBA/2 mice

Abstract

BACKGROUND AND PURPOSEImpulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice. EXPERIMENTAL APPROACHThe effects of acute and chronic administration of pregabalin (10, 20 and 40 mg·kg -1 ) and topiramate (12.5, 25 and 50 mg·kg -1 ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). a2A-Adrenoceptor, D2-receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively. KEY RESULTSAcute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased a2A-adrenoceptor and D2-receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased a2A-adrenoceptor and D2-receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA. CONCLUSIONS AND IMPLICATIONSThese results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on a2A-adrenoceptor and D2-receptor gene expression in the PFC and ACC, respectively. AbbreviationsACC, accumbens nucleus; ADHD, attention-deficit hyperactivity disorder; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; D2-receptor, D2 dopamine receptor; DRT, delayed reinforcement task; HBT, hole board test; LDB, light-dark box; PFC, prefrontal cortex; VTA, ventral tegmental area BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 British Journal of Pharmacology (2012) IntroductionImpulsivity constitutes a complex and multidimensional personality trait (Evenden, 1999a,b) that can be studied in both humans and animals by a wide range of methods (Winstanley et al., 2006). Behavioural disinhibition (motor impulsivity), manifested by poor inhibitory control of pre-potent responses, and impulsive choice (cognitive impulsivity), which refers to the preference for smaller immediate rewards over larger delayed rewards, are the most representative dimensions (Dougherty et al., 2003;Otobe and Makino, 2004;Adriani et al., 2010). In addition, there are other behavioural dimensions such as novelty-seeking behaviour closely related to impulsivity (Petry, 2001;James et al., 2007;Evren et al., 2012). Although impulsivity is a normal behaviour in healthy humans allowing ...

Effects of topiramate on ethanol‐cocaine interactions and DNA methyltransferase gene expression in the rat prefrontal cortex

“…However, topiramate alone was not able to reduce the response to ethanol. This result agrees with those from previous studies that showed either that topiramate did not alter the responses of mice to ethanol (Navarrete et al ., ), or that topiramate was ineffective in reducing ethanol consumption in Wistar rats (Breslin et al ., ; Lynch et al ., ). However, our results contrast with other reports showing that topiramate reduced ethanol consumption and reduced the motivation to lick for beer in animal models (Hargreaves and McGregor, ; Knapp et al ., ; Nguyen et al ., ), and reduced ethanol consumption, craving and increased the number of abstinent days from ethanol use in humans (Johnson et al ., ; Rubio et al ., ; Shinn and Greenfield, ).…”

“…We focused on the prefrontal cortex because of its contribution to addictive behaviour (Lüscher and Malenka, ), the involvement in regulating cognitive behaviour in rodents and in humans (Dayas et al ., ; Vengeliene et al ., ; Abernathy et al ., ), and the susceptibility to the effects of topiramate on genetic expression (Navarrete et al ., ).…”

“…For this purpose, we assessed the genetic expression of: (i) two DNA methyltransferases (Dnmts), Dnmt1 and Dnmt3a, which methylate DNA; (ii) The RNA methyltransferases Trdmt1 (formerly known as Dnmt2) and Rnmt enzymes, which methylate tRNA and mRNA, respectively; (iii); the proteins that form Dnmt1 corepressor complexes, Hdac2, Dmap1, Pcna and Uhrf1, which are described in the Introduction; (iv) key protein receptors targeted by topiramate, which include the kainate receptor containing the GluK1 subunit (Grik1) and the carbonic anhydrase enzymes types II and IV (Ca2 and Ca4); and (v) proteins that regulate importantly the function of the reward system: the dopamine D1 and D2 receptors (for nomenclature see Alexander et al, 2013a), the tyrosine hydroxylase enzyme and the μ-opioid receptor. We focused on the prefrontal cortex because of its contribution to addictive behaviour (Lüscher and Malenka, 2011), the involvement in regulating cognitive behaviour in rodents and in humans (Dayas et al, 2007;Vengeliene et al, 2009;Abernathy et al, 2010), and the susceptibility to the effects of topiramate on genetic expression (Navarrete et al, 2012).…”

Role of murine models in psychiatric illness drug discovery: a dimensional view

“…In DBA/2J mice, which show high trait impulsivity, a CB2 agonist decreased impulsive responding and delay discounting, while a CB2 antagonist decreased novelty-seeking behavior and improved prepulse inhibition (PPI) [60]. In another study, the anticonvulsant and mood stabilizer topiramate reduced novelty-seeking behavior, impulsive responding and delay discounting in DBA/2J mice [61].…”

“…Drugs found to decrease impulsivity and/or delay discounting (externalizing endophenotypes) in the mouse, for example, could be identified as potential pharmacotherapies for human externalizing disorders. An example is topiramate, which has anti-impulsive effects in mice [61], and may be useful to treat several disorders within the 'impulse control spectrum' (e.g., [97]). Given this idea, one would predict that endocannabinoids might be effective for a range of disorders across the internalizing and externalizing dimensions.…”