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Impulsivity 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 adaptation to uncertainty (Marazziti et al., 2010), there are several neuropsychiatric disorders such as ADHD (attention-deficit hyperactivity disorder), drug abuse, pathological gambling, bipolar disorder, obsessive compulsive disorder, aggression, anorexia/bulimia nervosa, suicide, trichotillomania, intermittent explosive disorder, self-injurious behaviour or kleptomania, presenting a high level of impulsivity as a core symptom (Rapport et al., 1985; August and Garfinkel, 1989; Jensen et al., 1990; Fahy and Eisler, 1993). Therefore, novel pharmacological strategies that alleviate impulsive behaviours could be very helpful in the management of these disorders.
In recent years, there has been an increase in the use of anticonvulsant drugs in the treatment of distinct neuropsychiatric disorders characterized by impulse control problems. Carbamazepine was one of the first to be used and it enabled a reduced dose of other antipsychotic drugs to be effective in the treatment of agitation and disruptive behaviours, such as aggressiveness, impulsivity, perversity or suicidal attempts (Vogelaer, 1981). Valproate has been widely used in the management of personality disorders, improving some symptoms like aggression, irritability and high impulsivity (Wilcox, 1994; 1995; Kavoussi and Coccaro, 1998).
Some of the so-called new anticonvulsants that appeared in the 1990s (Bourgeois, 1996; Wilson and Brodie, 1996) have demonstrated efficacy in the treatment of drug abuse disorders by alleviating withdrawal symptoms (Zullino et al., 2004), reducing craving (urge to consume) (Furieri and Nakamura-Palacios, 2007; Vengeliene et al., 2007; Miranda et al., 2008; Reis et al., 2008) or attenuating the pleasurable effects of drug intake, thus avoiding relapse (Bisaga et al., 2006; Martinotti et al., 2007). Among these new antiepileptic drugs, topiramate stands out in substance abuse intervention (mainly alcohol dependence) due to its ability to reduce consumption and relapse (Kampman et al., 2004; Cubells, 2006; Nguyen et al., 2007; Kenna et al., 2009; Johnson and Ait-Daoud, 2010). Topiramate has a complex and not well known mechanism of action, but its main effects include the modulation of voltage-gated sodium channels (Zona et al., 1997; Taverna et al., 1999), an increase in GABA neurotransmission (White et al., 1997; 2000) and the blockade of α-amino-3-hydroxy-5-methylisoxozole-proprionic acid (AMPA)/kainate receptors (Gibbs et al., 2000; Poulsen et al., 2004). Although it has been hypothesized that topiramate's usefulness in the management of drug abuse may be related to its anti-craving effect diminishing the pleasurable effects of drugs mediated by modulation of the dopaminergic mesolimbic pathways (Johnson et al., 2003; Johnson, 2004b), it has been proposed that topiramate could also modulate impulsive behaviours (Smathers et al., 2003; Dolengevich Segal et al., 2006; Rubio et al., 2009).
Another anticonvulsant, pregabalin, which is indicated for the treatment of generalized anxiety disorders and neuropathic pain, is emerging as a potential therapeutic tool in the field of alcoholism. This drug ameliorates alcohol withdrawal symptoms (Martinotti et al., 2008; Di Nicola et al., 2010; Oulis and Konstantakopoulos, 2010) and relapse through a mechanism less related to alcohol craving and more associated with the treatment of the comorbid psychiatric symptomatology such as an increased anxiety level (Martinotti et al., 2010). In addition, a very recent study shows for the first time that pregabalin is able to reduce alcohol consumption (Stopponi et al., 2011). Pregabalin acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the α2-δ subunit of voltage-gated calcium channels (Stahl, 2004). Through this mechanism, it has been proposed that pregabalin reduces the increase in dopamine in the nucleus accumbens resulting from acute morphine administration (Andrews et al., 2001).
The efficacy of pregabalin or topiramate in impulsive-related disorders (mainly drug abuse) remains poorly understood. In the present study, we evaluated anxiety-like behaviour [light–dark box (LDB)], novelty seeking [hole board test (HBT)] and cognitive and motor impulsivity [delayed reinforcement task (DRT)] in DBA/2 mice, a strain with a high endogenous impulsivity level (Helms et al., 2006; Patel et al., 2006; Navarrete et al., 2012). Dopaminergic and adrenergic key targets gene expression analyses were focused in brain regions from the mesolimbic and mesocortical pathways [ventral tegmental area (VTA), nucleus accumbens (ACC) and prefrontal cortex (PFC)] due to their involvement in impulsive behaviour (Wang et al., 2002; Basar et al., 2010; Kim and Lee, 2010). Tyrosine hydroxylase (TH) and the type 2 dopamine receptor (D2-receptor) were analysed in dopaminergic cell bodies (VTA) and in terminals (ACC), respectively. On the other hand, the α2A-adrenoceptor was studied in the PFC. The main purpose of this study was to elucidate if topiramate and/or pregabalin regulate certain impulsivity dimensions (novelty seeking or intolerance to delay) and if this regulation involves changes in dopaminergic and/or adrenergic pathways. Furthermore, the effects of both anticonvulsants on the high anxiety-like behaviour expressed by DBA/2 mice were evaluated in order to make a better distinction between pregabalin and topiramate.
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To our knowledge, the results of the present study provide information for the first time about the differential effects of pregabalin and topiramate on anxiety- and impulsive-like behaviours employing different administration schedules. Topiramate reduced novelty seeking and as expected, according to previous clinical studies by our group (Rubio et al., 2009), acutely modulated motor impulsivity and chronically modulated cognitive impulsivity in the DBA/2 strain of mice with a high-impulsive basal level (Navarrete et al., 2012). On the other hand, pregabalin did not have any effect on either object preference or acutely in the DRT, whereas when administered chronically, it exacerbated motor impulsivity levels in DBA/2 mice. In addition, anxiety-like behaviour evaluation showed that pregabalin has a clear anxiolytic profile in comparison with topiramate, suggesting that the therapeutic usefulness of pregabalin in drug dependence management is more related to this emotional aspect. Furthermore, real-time PCR analyses clearly showed that both drugs modulated α2A-adrenoceptors, D2-receptors and TH gene expressions differently in the cortico-mesolimbic pathway, providing novel insight about the neurochemical modulatory effects of pregabalin and topiramate and their possible relationship with impulsivity regulation.
When administered acutely, none of the doses of pregabalin tested (10, 20 and 40 mg·kg−1) or topiramate (12.5, 25 and 50 mg·kg−1) modified the delay discounting progression of DBA/2 mice compared to the corresponding vehicle group. This lack of effect suggests that this schedule of administration (each session during the delay phase of the task) was not adequate to produce any effect on cognitive impulsivity. On the other hand, when motor impulsivity was evaluated by counting the number of immediate lever presses during the delay onset, pregabalin did not produce any effect, but topiramate clearly enhanced behavioural inhibition, mainly at the highest dose (50 mg·kg−1). A possible explanation for this discrepancy may be related to differences in their mechanisms of action. Pregabalin modulates voltage-gated calcium channels binding to the α2-δ subunit mainly in hyperexcitability states (Taylor et al., 2007), whereas topiramate acts through several mechanisms leading to a potent inhibitory state (White et al., 1997; Zona et al., 1997; Reis et al., 2002; Braga et al., 2009) independent of neuronal excitability. This fact may contribute to a more efficacious behavioural inhibition in DBA/2 mice, lowering the number of ineffective responses during the time delay. In the DRT, mice consistently learn to make a response (lever press) to achieve a reward (food). Development of such automatic processes seems to depend on glutamatergic neurotransmission through the activation of N-methyl d-aspartate receptors (Kelley et al., 1997) and the activation of AMPA receptors is needed for their expression (Backstrom and Hyytia, 2003). Topiramate, acting as an AMPA receptor antagonist may improve the ability to these mice to wait, so reducing the number of ineffective (not rewarded) responses. In the same way, this mechanism could also explain the significant reduction in novelty-seeking behaviour of DBA/2 mice that was not achieved with pregabalin. Novelty seeking has been associated with drug abuse (Lange et al., 2010; Cummings et al., 2011). Hence, topiramate's ability to reduce novelty exploration behaviour may account for its usefulness as a drug-dependence treatment.
Since acute administration of either drug did not alleviate the high cognitive impulsivity level in DBA/2 mice, it was hypothesized that chronic administration with a pretreatment phase before the beginning of the DRT and the administration of the drug twice a day would be appropriate to identify whether pregabalin or topiramate is able to modulate delay discounting. Although chronic administration of topiramate was without effect on motor impulsivity, the medium (25 mg·kg−1) and highest (50 mg·kg−1) doses of topiramate significantly reduced delay discounting in DBA/2-treated mice. The percentage of preference for the delayed lever was maintained significantly higher than in the control group from 12 s until 54 s of delay. This effect was not present in the final stages of the experiment, probably due to a tolerance effect. These results suggest that the schedule of dosing and duration of the treatment play a crucial role in the modulatory effect of topiramate on impulsive choice. Indeed, depending on the administration schedule, this drug modulated either motor or cognitive impulsivity behaviours. In contrast, pregabalin failed to alter the preference for the delayed lever and even significantly increased motor impulsivity when administered chronically at a 40 mg·kg−1 dose. This effect could be related to the anxiolytic effect of pregabalin (Lauria-Horner and Pohl, 2003; Frampton and Foster, 2006). A decrease in the anxiety level in spontaneously anxious DBA/2 mice (Griebel et al., 2000; Ohl et al., 2003; Yilmazer-Hanke et al., 2003) may be responsible for behavioural disinhibition, leading to an increase in the number of immediate lever presses. The inability of pregabalin to diminish cognitive or motor impulsivity seems to indicate that its potential beneficial effects on drug abuse may be due to the regulation of other behavioural mechanisms such as co-morbid psychiatric symptomatology (Martinotti et al., 2010). Data shown in Figure 1 clearly indicate that pregabalin presents a potent anxiolytic effect, increasing the time spent in the lighted and open side at all doses tested, supporting the previous hypothesis. Indeed, recent data from a study by our group demonstrated that pregabalin reduces the increase in the anxiety level produced by spontaneous cannabinoid withdrawal in mice (Aracil-Fernandez et al., 2011).
It is important to note that the measurement of motor impulsivity in the DRT is different from the evaluation in the five-choice serial reaction time or Go/NoGo tasks. The former evaluates the inability to wait until the reinforcement is delivered (a response that does not have consequences) and the latter the inability to withhold a prepotent response (a response that has negative consequences). The analysis of motor impulsivity in animal experimental models has been classically developed in tasks in which the animal has to refrain from responding to achieve a goal (reward). In the present study, the number of lever presses during the delay onset would determine the level of restlessness in mice. As stated by other authors, this behavioural parameter also takes part in the definition of motor impulsivity (Dellu-Hagedorn, 2006; Boes et al., 2009). Indeed, the Barratt Impulsiveness Scale (BIS-11), a widely used and well-validated tool to measure human impulsivity, considers motor impulsiveness as ‘acting without thinking and restlessness’ (Patton et al., 1995).
Gene expression analyses were focused on dopaminergic and adrenergic neurotransmission systems. There is much evidence for the critical involvement of dopamine in impulsive behaviour (van Gaalen et al., 2006; Buckholtz et al., 2010) and special attention has been paid to the role of D2-receptors in this effect (Dalley et al., 2007; Hamidovic et al., 2009; Lee et al., 2009). On the other hand, PFC adrenergic circuit involvement in decision making is well known (Dalley et al., 2008; Kim and Lee, 2010). Agonists of α2A-adrenoceptors have been shown to be useful in the treatment of inattention, hyperactivity and impulsiveness in ADHD (Scahill, 2009); and, recently, the α2A-adrenoceptor agonist guanfacine was found to ameliorate impulsive choice behaviours in primates (Kim et al., 2011). For these reasons, in the present study we investigated whether the effects of pregabalin and topiramate on impulsivity dimensions are related to their modulation of α2A-adrenoceptor, D2-receptor and TH gene expression. These studies were carried out in the mesolimbic–mesocortical pathways for three reasons: (1) the critical involvement of this pathway in the regulation of impulsive behaviours (van Gaalen et al., 2006; Dalley et al., 2007; Lee et al., 2009; Basar et al., 2010; Buckholtz et al., 2010; Kim and Lee, 2010); (2) its crucial role in reinforcement effects of drugs of abuse (Phillips and Fibiger, 1973; Leshner and Koob, 1999; Hyman and Malenka, 2001); and (3) dopaminergic and adrenergic tone are both modulated by pregabalin (Andrews et al., 2001; Gajraj, 2005; Takeuchi et al., 2007) and topiramate (Johnson, 2004a,b). The neuropharmacological action of topiramate includes facilitation of GABA-mediated neurotransmission and blockade of AMPA/kainate glutamate receptors. According to Johnson's hypothesis (Johnson et al., 2003), because mesocorticolimbic dopamine release is under tonic inhibitory control via GABAergic neurons and excitatory control via glutamatergic neurons, topiramate may inhibit dopamine release and consequently reduce receptor activation. Maintenance of this effect with chronic administration could produce a compensatory effect. Real-time PCR results support this hypothesis since topiramate dramatically increased TH gene expression in the VTA and also up-regulated D2-receptors in the ACC. Furthermore, it is widely accepted that low D2-receptor availability in the brains of animals or humans is related with a high impulsivity level (Dalley et al., 2007; Lee et al., 2009), probably due to a high basal dopaminergic tone. Indeed, it has been reported that pharmacological modulation by D2-receptor antagonists induced impulsive choice, suggesting that these receptors normally promote choice of the delayed reinforcement (Wade et al., 2000). DBA/2 mice present low D2-receptor gene expression in comparison with a low-impulsive strain (Navarrete et al., 2012). Therefore, it seems that the enhancement of D2-receptor expression in the ACC, achieved with the chronic administration of topiramate, could be closely associated with the cognitive impulsivity modulation. On the other hand, pregabalin showed no effect on cognitive impulsivity, a fact that could be partially explained by a distinct dopaminergic modulation that entails an opposite effect on D2-receptor gene expression and a smaller increase in TH in the VTA in comparison with topiramate.
Interestingly, the administration of topiramate up-regulated the α2A-adrenoceptor gene expression in the PFC dose-dependently, which would fit with a direct/indirect adrenergic blockade not previously described in the literature for this drug. Genetic variants of the α2A-adrenoceptor are involved in drug abuse (Feng et al., 1998; Prestes et al., 2007) and ADHD (Xu et al., 2001; Schmitz et al., 2006). Furthermore, α2A-adrenoceptor gene expression in the PFC has been inversely correlated with lever pressing to obtain a reward (Pickering et al., 2007), suggesting that animals with a low responding rate present higher α2A-adrenoceptor gene expression levels. This finding seems to agree with the chronic pregabalin effect on motor impulsivity since the dose-dependent increase in the number of ineffective responses is associated with a dose-dependent decrease in α2A-adrenoceptor gene expression in the PFC. In the same way, it could be hypothesized that the lack of effect of chronic topiramate on behavioural inhibition in comparison with the acute schedule may be related to the significant increase in α2A-adrenoceptor mRNA levels in the PFC.
In conclusion, the present study demonstrates that the chronic administration of topiramate regulated cognitive impulsivity, whereas acute drug treatment regulated motor impulsivity expressed by DBA/2 mice. These results point out the relevance of the administration schedule to regulate distinct dimensions of impulsive behaviour. In addition, topiramate reduced novelty-seeking behaviour, which is closely associated with drug abuse vulnerability. These findings suggest that the therapeutic utility of topiramate in addictive behaviours, such as alcohol-dependence, may be due to its ability to control impulsive-like behaviours. The impulsivity modulation showed by topiramate seems to be associated with differential gene expression changes in mesolimbic–mesocortical dopaminergic and adrenergic neurotransmission. The present results suggest that the up-regulation of D2-receptor gene expression induced by topiramate could be the main mechanism responsible for the reduction in novelty seeking and cognitive impulsivity in DBA/2 mice. On the other hand, the therapeutic utility of pregabalin in impulsive-related disorders appears to be more associated with its ability to regulate other behavioural aspects such as anxiety, since no beneficial effects were achieved in either the HBT or in the DRT.