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. 2012 Sep;167(1):183-95.
doi: 10.1111/j.1476-5381.2012.01981.x.

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

Francisco Navarrete  1 , José M Pérez-Ortiz, Jorge Manzanares
Affiliations

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

Francisco Navarrete et al. Br J Pharmacol. 2012 Sep.

Abstract

Background and purpose: Impulsivity 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 approach: The 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). α(2A) -Adrenoceptor, D(2) -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 results: Acute 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 α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA.

Conclusions and implications: These 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 α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively.

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Figures

Figure 1
Figure 1
Evaluation of anxiety-like behaviour in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., 1 h before testing) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., 1 h before testing) in the LDB paradigm. Columns represent the means and vertical lines ± SEM of the time spent in the lighted side (A,C) and the number of transitions (B,D). *Values of drug-treated DBA/2 mice that are significantly different (P < 0.05) from its corresponding vehicle group.
Figure 2
Figure 2
Analysis of novelty-seeking behaviour in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., 1 h prior testing) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., 1 h before testing) on the HBT. Columns represent the means and vertical lines ± SEM of the % preference to explore holes containing an object with pregabalin (A) or topiramate (B). *Values of drug-treated DBA/2 mice that are significantly different (P < 0.05) from its corresponding vehicle group.
Figure 3
Figure 3
Assessment of cognitive impulsivity (delay discounting) in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., for 10 days and 1 h before testing) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., for 10 days and 1 h before testing) in the DRT. Dots represent the means and vertical lines ± SEM of % preference for delayed reinforcement with pregabalin (A) or topiramate (B) treatment.
Figure 4
Figure 4
Motor impulsivity evaluation (ineffective responding) in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., for 10 days and 1 h before testing) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., for 10 days and 1 h before testing) in the DRT. Dots represent the means and vertical lines ± SEM of number of lever presses in the immediate lever during delay onset with pregabalin (A) or topiramate (B) treatment. *Values for topiramate 50 mg·kg−1 group that are significantly different (P < 0.05) from its corresponding vehicle group; **values for topiramate 25 mg·kg−1 group that are significantly different (P < 0.05) from its corresponding vehicle group; #values for topiramate 12.5 mg·kg−1 group that are significantly different (P < 0.05) from its corresponding vehicle group.
Figure 5
Figure 5
Assessment of cognitive impulsivity (delay discounting) in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., twice a day for 27 days) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., twice a day for 27 days) in the DRT. Dots represent the means and vertical lines ± SEM of % preference for delayed reinforcement with pregabalin (A) or topiramate (B) treatment. *Values from topiramate 50 mg·kg−1 treated mice that are significantly different (P < 0.05) from its corresponding vehicle group; **values from topiramate 25 mg·kg−1 treated mice that are significantly different (P < 0.05) from its corresponding vehicle group.
Figure 6
Figure 6
Motor impulsivity evaluation (ineffective responding) in DBA/2 mice treated with pregabalin (10, 20 or 40 mg·kg−1, p.o., twice a day for 27 days) or topiramate (12.5, 25 or 50 mg·kg−1, p.o., twice a day for 27 days) in the DRT. Dots represent the means and vertical lines ± SEM of number of lever presses in the immediate lever during delay onset with pregabalin (A) or topiramate (B) treatment. *Values from pregabalin 40 mg·kg−1 group that are significantly different (P < 0.05) from its corresponding vehicle group; **values from pregabalin 20 mg·kg−1 group that are significantly different (P < 0.05) from its corresponding vehicle group.
Figure 7
Figure 7
α2A-adrenoceptor, D2-receptor and TH relative gene expressions evaluation in the PFC, ACC and VTA, respectively, of pregabalin (10, 20 or 40 mg·kg−1, p.o., twice a day for 27 days)- or topiramate (12.5, 25 or 50 mg·kg−1, p.o., twice a day for 27 days)-treated mice by real time-PCR. Columns represent the means and vertical lines ± SEM of relative (2−ΔΔCt method) α2A-adrenoceptor gene expression in PFC (A,D), D2-receptor gene expression in ACC (B,E) and TH gene expression in VTA (C,F) of DBA/2 treated mice. *Values of drug-treated DBA/2 mice that are significantly different (P < 0.05) from its corresponding vehicle group.
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