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Differential effects of bupropion on acquisition and performance of an active avoidance task in male mice
Behavioural Processes 124 (2016) 32–37
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Differential effects of bupropion on acquisition and performance of an active avoidance task in male mice M.C. Gómez, R. Redolat, M.C. Carrasco ∗ Departamento Psicobiología, Facultad de Psicología, Universitat de València, Blasco Iba˜ nez, 21, Valencia 46010, Spain
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Article history: Received 10 June 2015 Received in revised form 4 December 2015 Accepted 8 December 2015 Available online 10 December 2015 Keywords: Active avoidance Bupropion Mice Learning Memory
a b s t r a c t Bupropion is an antidepressant drug that is known to aid smoking cessation, although little experimental evidence exists about its actions on active avoidance learning tasks. Our aim was to evaluate the effects of this drug on two-way active avoidance conditioning. In this study, NMRI mice received bupropion (10, 20 and 40 mg/kg) or saline before a daily training session (learning phase, days 1–4) in the active avoidance task. Performance was evaluated on the fifth day (retention phase): in each bupropion-treated group half of the mice continued with the same dose of bupropion, and the other half received saline. Among the vehicle-treated mice, different sub-groups were challenged with different doses of bupropion. Results indicated that mice treated with 10 and 20 mg/kg bupropion exhibited more number of avoidances during acquisition. The response latency confirmed this learning improvement, since this parameter decreased after bupropion administration. No differences between groups were observed in the retention phase. In conclusion, our data show that bupropion influences the learning process during active avoidance conditioning, suggesting that this drug can improve the control of emotional responses. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Bupropion is an antidepressant that has shown to be effective in the treatment of tobacco dependence (Hughes et al., 2014) and it is included in the seven first-line pharmacological agents for smoking cessation (Hudmon et al., 2010). In addition, bupropion is a candidate for treatment of psychostimulant drug abuse (Castells et al., 2010; Schindler et al., 2011), cannabis addiction (Penetar et al., 2012), pathological gambling (Dannon et al., 2005), or excessive online game playing (Han and Renshaw, 2012). The treatment with naltrexone plus bupropion may also be useful for overweight and obesity (Greenway et al., 2010; Yanovski and Yanovski, 2015). Cognitive effects of bupropion have been reported in children and adults with attention deficit hyperactivity disorder (ADHD) (Clay et al., 1988; Wilens et al., 2005) and in patients with major depression (Herrera-Guzmán et al., 2008; Gorlyn et al., 2015), suggesting that bupropion treatment could improve neuropsychological functioning in these patients. However, some
Abbreviations: ADHD, attention deficit hyperactivity disorder; BUP, bupropion; IP, intraperitoneally; ITI, intertrial interval; nAChRs, nicotinic cholinergic receptors; NE, norepinephrine; US, unconditioned stimulus; VEH, vehicle. ∗ Corresponding author. Fax: +34 963864668. E-mail addresses: [email protected] (M.C. Gómez), [email protected] (R. Redolat), [email protected] (M.C. Carrasco). http://dx.doi.org/10.1016/j.beproc.2015.12.003 0376-6357/© 2015 Elsevier B.V. All rights reserved.
inconsistencies regarding cognitive effects of this drug have been reported. For example, acute treatment with the antidepressants bupropion and sertraline had no detectable effects on the retrieval of emotionally arousing material learned one week prior to testing in healthy adult subjects (Carvalho et al., 2006). In contrast, bupropion improves cognitive performance after overnight smoking abstinence in healthy adult smokers (Perkins et al., 2013a). The neuropharmacological actions of bupropion indicate that this agent has an atypical antidepressant profile sharing some similarities with traditional psychostimulants (Dwoskin et al., 2006). The drug is a relatively weak dopamine-uptake inhibitor which also inhibits firing of locus coeruleus norepinephrine (NE) neurons at high concentrations (Cooper et al., 1994). Bupropion also inhibits the function of the dopamine and NE transporters (Dwoskin et al., 2009). The effectiveness of bupropion (and/or its hydroxy metabolites) in the treatment of nicotine dependence has been related to its effects on mood, which are mediated by enhancement of noradrenergic and dopaminergic signals, as well as to its effects on NE transporters and on members of the diverse family of nicotinic cholinergic receptors (nAChRs) (Damaj et al., 2004). It has been reported that bupropion acts as a non-competitive nicotinic receptor antagonist (Arias, 2009; Slemmer et al., 2000), which could contribute to their efficacy as an antidepressant and as a smoking cessation agent (Dowskin et al., 2006). However, the mechanisms
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by which it increases abstinence rates in smokers are not clear (Perkins et al., 2013b; Wright and Rodgers, 2013). Monoamine neurotransmitter systems are involved in the regulation of mood and cognition (Booij et al., 2003; Hamon and Blier, 2013), suggesting that monoamine-elevating medications may be useful for emotional and cognitive improvement. There is, for example, evidence of the positive effects of antidepressant treatment on synaptic plasticity in cortical and subcortical brain circuits related with mood disorders and memory (Castrén and Hen, 2013; Sairanen et al., 2007). In animal models, bupropion has been found to induce place preference (Ortmann, 1985; Rauhut et al., 2008), to improve performance in a novel object recognition task (Kruk-Słomka et al., 2014), to disrupt latent inhibition measured in a conditioned emotional response (Lipina and Roder, 2010), to facilitate extinction of avoidance responses in a lever-press avoidance task in animals with innate vulnerability to anxiety (Jiao et al., 2014). Bupropion also improves the retrieval of an inhibitory avoidance response (Barros et al., 2002) and reverses the reserpine-induced impairment in conditioned avoidance response when administered at 40 mg/kg (Nakagawa et al., 1997), although this drug failed to alter the conditioned place preference induced by nicotine (Rauhut et al., 2008). However, the administration of a low dose of bupropion (5 mg/kg) reverses nicotine withdrawal-associated deficits in contextual fear conditioning, whereas high doses (20 or 40 mg/kg) induce deficits in contextual and cued fear conditioning (Portugal and Gould, 2007). In a Pavlovian fear learning task, Carmack et al., (2014) have recently reported that bupropion induced long-term memory-enhancing effects. This cognitive improvement was similar to that observed for animals treated with the psychostimulant methylphenidate, an agent used as a cognitive enhancer for a diversity of disorders, in particular as treatment for ADHD (Carmack et al., 2014). Despite of these findings obtained in animal models, limited work has evaluated effects of bupropion on learning and memory tasks. Specifically, its direct actions on an active avoidance conditioning using a two-way shuttle box model have not been previously studied. Therefore, our aim was to evaluate the effects of varying doses of bupropion on acquisition and performance in a two-way active avoidance task. Preclinical previous research has been reported memory-enhancing effects of bupropion using different animal models, however, no study has yet examined whether the two-way active avoidance conditioning can be improved with bupropion treatment in mice. This animal model is based on the acquisition of a relatively complex learning task that requires the control of emotional responses. Recent evidence indicates that during the active avoidance response both emotional and motivational circuitries contribute to the acquisition of the task: the amygdala plays a central role in the emotional circuitry whereas different midbrain dopaminergic structures integrate the motivational circuitry (Ilango et al., 2014). The two-way active avoidance conditioning task can be useful for gathering information about the behavioral responses displayed by the animal both during the acquisition and the retention phases. These data could provide information regarding differential effects of the drug on learning and emotional memory.
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Fig. 1. Experimental design, including the acquisition and retention phases of the study. In the retention phase, half of the mice in each bupropion-treated group continued with their dose of bupropion and the other half began to receive saline.
forms well in different learning paradigms (Ghaderi et al., 2015; Moragrega et al., 2005). All procedures complied with the “principles of laboratory animal care” and international guidelines (EU Directive 2010/63/EU) for the care and treatment of animals. 2.2. Drugs Bupropion hydrochloride (Sigma–Aldrich, Madrid, Spain) was dissolved in physiological saline. During acquisition phase (1–4 days), bupropion (40, 20, 10 mg/kg) or the vehicle was administered intraperitoneally 30 min before each daily shuttle box training session. In the performance session or retention phase (5 day), half of the mice in each bupropion-treated group (n = 12) continued with their dose of bupropion and the other half began to receive saline. This treatment challenge was performed in order to differentiate effects of drug on performance and acquisition. In this session, the control group (n = 24) was subdivided into four groups which received 10, 20, 40 mg/kg of bupropion or vehicle (see experimental design in Fig. 1). The doses employed in the current research were selected on the basis of previous studies about the effects of bupropion in NMRI mice (Carrasco et al., 2004, 2013; Gomez et al., 2009a,b; Redolat et al., 2005a,b) and are in the range of doses habitually used to assess behavioral effects of bupropion in rodents (Biała and Kruk, 2009; Lipina and Roder, 2010; Randall et al., 2014). 2.3. Apparatus and procedure
2. Material and methods 2.1. Animals Sixty male NMRI mice (Charles River, Barcelona, Spain) weighing 26–28 g were used for the experiment. The animals were housed five per cage under standard laboratory conditions, with food and water ad libitum, and exposed to a reversed 12:12 h light/dark cycle (lights off at 8:00 h). NMRI mice were selected since this strain per-
Mice were trained in an automated two-way shuttle-box (45 × 24.5 × 19 cm) (Shuttle Scan, Model SC-II, OMNITECH, Columbus, OH) which was placed in a sound-attenuating box in order to avoid disturbances. A light (6 w) was used as conditioned stimulus, preceding by 10 s the onset of the unconditioned stimulus (US) and overlapping it for 10 s. The US consisted of an electric shock (0.3 mA) applied to the grid floor, which was formed by stainless steel bars. The box was divided into two compartments with a white
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Fig. 2. Mean (±) SEM of number of avoidances shown by mice receiving different pharmacological treatments in the acquisition phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion and BUP-40: 40 mg/kg of bupropion during acquisition training sessions (days 1–4) in a two-way shuttle box. * BUP-10 vs. BUP-40 and VEH, p < 0.05. +BUP-10 and BUP-20 vs. VEH, p < 0.05.
plexiglas barrier. During the adaptation period (3 min) mice could explore the apparatus. The intertrial interval (ITI) varied between 20 and 40 s, during which the mice could move freely between compartments. The following behavioral parameters were evaluated: (1) number of avoidances: mouse crossed during the light signal; (2) number of non responses: mouse did not cross to the other compartment; and (3) response latency: time of response to avoid or escape. The number of crossings during the adaptation period and ITIs were also recorded as activity measures. In order to evaluate the effects of bupropion on learning and memory, each mouse underwent thirty trials during each of the four daily acquisition sessions (acquisition phase: days 1–4), and a further thirty trials in the performance session (retention phase: day 5). 2.4. Statistical analysis Analysis of variance (ANOVA) of repeated measures was performed for each of the measures obtained (avoidances, nonresponses, response latency, adaptation and ITI crossings). Post-hoc comparisons were conducted when appropriate using the Tukey HSD test. One-way ANOVAs were also performed to evaluate data on the performance day (day 5). In all cases, a p < 0.05 was considered as significant. 3. Results 3.1. Acquisition phase With respect to active avoidance acquisition (days 1–4), the ANOVA revealed that treatment had a significant effect on the number of avoidances [F(3, 56) = 4.27, p < 0.009, p2 0.186]. Post-hoc tests indicated that mice administered 20 or 10 mg/kg of bupropion showed significantly more avoidance responses (p < 0.052 and p < 0.033, respectively) than the control group. The factor Session [F(3, 168) = 235, p < 0.001, p2 0.808] and Session × Treatment [F(9, 168) = 3.79, p < 0.001, p2 0.169] also reached statistical significance (see Fig. 2). ANOVAs conducted independently for each session indicated that the Treatment factor reached statistical significance in session 1 [F(3, 56) = 8.52, p < 0.001 p2 0.314], session 2 [F(3,56) = 2.9, p < 0.042 p2 0.135] and session 4 [F(3, 56) = 4.63, p < 0.006, p2 0.199] (see Fig. 2). In session 1, mice treated with
10 mg/kg displayed more avoidances than those receiving 40 mg/kg or the vehicle (p < 0.001 and p < 0.027, respectively). In session 2, comparisons failed to detect statistically significant differences between groups (data are not shown). In session 4, mice receiving 10 and 20 mg/kg exhibited more avoidances than controls (p < 0.043 and p < 0.020, respectively). The ANOVA of response latency revealed that the factors Treatment [F(3,56) = 3.88, p < 0.014, p2 0.172] and Session [F(3,168) = 31.67, p < 0.001, p2 0.361] were significant. In session 3, animals treated with 10 and 20 mg/kg of bupropion displayed shorter response latencies than vehicle-treated mice (p < 0.024 and p < 0.005, respectively). In session 4, mice receiving 20 and 40 mg/kg exhibited shorter response latencies than controls (p < 0.027 and p < 0.033, respectively) (see Fig. 3). The number of crossings during the adaptation period along acquisition sessions (1–4 days) was also evaluated. Results showed that there were no differences between groups in the number of adaptation crossings, although the Session factor [F(1,168) = 10.07, p < 0.001, p2 0.152] reached statistical significance. A separate analysis for each experimental session indicated significant differences in session 3 [F(3,56) = 2.93, p < 0.041, p2 0.136]. In this session, mice treated with 40 mg/kg of bupropion displayed a significantly lower number of adaptation crossings than those treated with 20 mg/kg (p < 0.025). No significant differences were found in the interaction Session × Treatment. In relation with the number of crossings during ITIs, there was a trend towards a significant effect of Treatment in the number of crossings during ITIs [F(3,56) = 2.60, p < 0.061, p2 0.123]. The Session factor [F(3,168) = 31.1, p < 0.001, p2 0.357] and the interaction Session × Treatment [F(9,168) = 2.35, p < 0.016, p2 0.112] also reached statistical significance. Treatment was statistically significant in sessions 3 [F(3,56) = 4.97, p < 0.004, p2 0.210] and 4 [F(3,56) = 2.73, p < 0.052, p2 0.128], during both of which mice treated with 20 mg/kg of bupropion crossed more times than vehicle-treated animals (p < 0.003 and p < 0.029, respectively). 3.2. Retention phase As previously mentioned, effects on performance were also evaluated in session 5, during which half the mice in each bupropion-treated group continued to receive their corresponding
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Fig. 3. Mean (±) SEM of response latency shown by mice receiving different pharmacological treatments in the acquisition phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion and BUP-40: 40 mg/kg of bupropion during acquisition training sessions (days 1-4) in a two-way shuttle box. *BUP-20 and BUP-40 vs. VEH, p < 0.05. +BUP-10 and BUP-20 vs. VEH, p < 0.05.
dose while the other half received saline, and while in the vehicletreated group different sub-groups of mice were challenged with each dose of bupropion. Although no statistically significant differences were observed between experimental groups, data showed that bupropion-treated groups during the acquisition phase when they were treated with saline in the retention phase increased the number of avoidances and decreased the response latencies. Similarly, mice that received saline during the acquisition phase when administered bupropion augmented the number of avoidances and reduced response latencies in the retention phase. ANOVA did not reveal a main effect of Treatment for any measure obtained (number of avoidances, non-responses; response latency, ITI and adaptation crossings) (see Fig. 4). 4. Discussion Regarding the effects of bupropion on acquisition phase in a two-way active avoidance task (sessions 1–4), when the low and intermediate doses (10 and 20 mg/kg) were administered, an increased number of avoidances was observed. Response latency confirmed this improvement, since this parameter also decreased during sessions. In session 3, animals treated with 10 and 20 mg/kg of bupropion exhibited shorter response latencies than controls. In session 4, mice treated with 20 and 40 mg/kg showed shorter response latencies than controls. These results, which suggest an enhancement in acquisition of avoidance learning within some bupropion groups, confirm those of previous studies with this drug that indicated an improvement of other learning tasks, such as retrieval of inhibitory avoidance (Barros et al., 2002), lever-press avoidance active task (Jiao et al., 2014), conditioned place preference (Ortmann, 1985), conditioned emotional response (Lipina and Roder, 2010; Carmack et al., 2014), or novel object recognition (Kruk-Słomka et al., 2014). Moreover, present data agree with previous observations showing that bupropion reverses reserpineinduced impairment in a conditioned avoidance task (Nakagawa et al., 1997) and reverses nicotine withdrawal-associated deficits in contextual fear conditioning by enhancing retrieval processes (Portugal and Gould, 2007). These later authors also reported an impairment in the acquisition and expression of contextual memories with higher doses of bupropion, observing that mice treated
with 20 and 40 mg/kg of bupropion displayed deficits in contextual and cued fear conditioning (Portugal and Gould, 2007). Given that previous data on the behavioural effects of bupropion in active avoidance tasks are limited (Jiao et al., 2014), we consider that present results add new information about the ability of bupropion to induce beneficial changes in the control of emotional responses. Considering that the active avoidance task is a relatively complex form of learning in which the animals have to learn a particular behavior in order to avoid the application of a stressor as a footshock, the performance displayed by animals treated with bupropion during sessions (jointly with the increase in the number of avoidances and the decrease in response latency observed here) suggests that this drug may improve the control of emotional responses. When interpreting current findings, it must be taken into account, as previously suggested (Vaglenova et al., 2004), that the behavior displayed by the animals in the active avoidance model contains elements of anxiety, fear or emotionality. Although there are relatively few studies that have examined bupropion effects on anxiety, present data agree with previous observations showing that this drug has an anxiolytic-like profile (Biała and Kruk, 2009; Carrasco et al., 2006; Joshi et al., 2005) in the plus-maze task, a classical model of anxiety. However, the findings obtained in other studies suggest that the actions of this drug on anxiety are modulated by different factors, such as age of the animals when exposed to the drug, nature of the stress procedure, housing conditions or baseline anxiety level (Carrasco et al., 2013; Gómez et al., 2008a,b; Hayashi et al., 2010). The increase in the number of avoidances is usually interpreted as the optimal response for mice in the active avoidance task, and our findings indicate that mice treated with bupropion (10 and 20 mg/kg) displayed a more active coping style than control group. As we can observe in Fig. 2, during the first acquisition day the group treated with 40 mg/kg of bupropion decreased the number of avoidance responses, in contrast with the group treated with 10 mg/kg of bupropion. It can be suggested during the first acquisition day mice receiving the highest dose of bupropion increased motor activity and reduced the control of active avoidance responses. Although locomotor activity was not assessed directly in the present experiment, we must take into account than along the adaptation period, during which mice could explore the apparatus for 3 min before
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Fig. 4. Mean (±) SEM of number of avoidances shown by mice receiving different pharmacological treatments in the retention phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion, and BUP-40: 40 mg/kg.
each session (both in the acquisition and retention phases), no significant differences between groups were observed in the number of crossings, suggesting that this indirect measure of locomotion was unaffected by treatment with bupropion neither during learning nor during the retention of the task. Bearing in mind the total number of avoidance responses and response latency of each group, our results suggest a general improvement in learning in groups treated with bupropion. An interesting result was also observed in the retention phase. Comparing the performance of the ten experimental groups evaluated in the current study, our findings indicate that all animals displayed a good retention. In this phase, half of the mice in each bupropion-treated group continued with their dose of bupropion and the other half began to receive saline. In addition, the twentyfour animals included in the control group were subdivided into four groups (treated with 10, 20, 40 mg/kg of bupropion or vehicle). The results obtained indicated no significant differences in performance between groups during the retention of the active avoidance task. In fact, animals treated with bupropion seem to display similar emotional memory in comparison to control groups. This lack of a clear influence of the antidepressant bupropion on performance could be related to a possible ceiling effect due to the high number of avoidances reached in some bupropion-treated groups on the last acquisition day. Therefore, bupropion seems not to improve significantly retention of the active avoidance task in “expert” mice. There is some evidence to suggest that bupropion effects may depend of the mnemonic performance level of animals, since this drug attenuates the nicotine-induced memory improvement in the novel object recognition test, whereas prevented scopolamine-induced memory impairment (Kruk-Słomka et al., 2014). In addition, in the elevated plus-maze, although usually applied as a model of anxiety in rodent, some studies have been performed in order to evaluate changes in memory, indicating that in this apparatus bupropion modulates memory-related responses induced by nicotine (Biała and Kruk, 2009; Kruk et al., 2011). The cognitive effects of bupropion have been addressed directly by few preclinical studies. Data about behavioral effects of this drug on the active avoidance task, an animal paradigm that requires the control of emotional responses, are limited (Ilango et al., 2014). Results obtained in the current study suggest that bupropion can induce changes in the emotional and motivational circuitries,
which influence the learning process of the avoidance response. Therefore, our data suggest that this drug may have therapeutic potential for the treatment of different cognitive disorders as previously reported (Kruk-Słomka et al., 2014). It might be of interest to further explore the ability of bupropion to improve the acquisition of effective coping strategies in emotional situations applying different learning and memory paradigms in rodents. Current findings can contribute to the development of new behavioral and pharmacological treatments of cognitive alterations in mental and neurodegenerative disorders. 5. Conclusions Our data show that bupropion can modulate the acquisition process during active avoidance conditioning. This drug induces an improvement of the control of emotional responses, a factor which is essential to the development of more effective coping strategies in stress situations. Furthermore, present study also suggests that the beneficial effects of bupropion on emotional memory could be influenced by the mnemonic performance level of each animal, since this drug did not enhance retention of the two-way active avoidance conditioning task in “expert” rodents. Our findings extend present knowledge concerning main mechanisms involved in the active avoidance response and the potential use of bupropion as a cognitive enhancer. Further studies will be required to determine the implications and possible therapeutic applications of the cognitive effects of bupropion. References Arias, H.R., 2009. Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? Int. J. Biochem. Cell Biol. 41, 2098–2108, http:// dx.doi.org/10.1016/j.biocel.2009.05.015. Barros, D.M., Izquierdo, L.A., Medina, J.H., Izquierdo, I., 2002. Bupropion and sertraline enhance retrieval of recent and remote long-term memory in rats. Behav. Pharmacol. 13, 215–220. Biała, G., Kruk, M., 2009. Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze. Pharmacol. Rep. 61, 236–244. Booij, L., Van der Does, A.J., Riedel, W.J., 2003. Monoamine depletion in psychiatric and healthy populations: review. Mol. Psychiatry 8, 951–973. Carmack, S.A., Howell, K.K., Rasaei, K., Reas, E.T., Anagnostaras, S.G., 2014. Animal model of methylphenidate’s long-term memory-enhancing effects. Learn. Mem. 21, 82–89, http://dx.doi.org/10.1101/lm.033613.113.
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Behavioural Processes journal homepage: www.elsevier.com/locate/behavproc
Differential effects of bupropion on acquisition and performance of an active avoidance task in male mice M.C. Gómez, R. Redolat, M.C. Carrasco ∗ Departamento Psicobiología, Facultad de Psicología, Universitat de València, Blasco Iba˜ nez, 21, Valencia 46010, Spain
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Article history: Received 10 June 2015 Received in revised form 4 December 2015 Accepted 8 December 2015 Available online 10 December 2015 Keywords: Active avoidance Bupropion Mice Learning Memory
a b s t r a c t Bupropion is an antidepressant drug that is known to aid smoking cessation, although little experimental evidence exists about its actions on active avoidance learning tasks. Our aim was to evaluate the effects of this drug on two-way active avoidance conditioning. In this study, NMRI mice received bupropion (10, 20 and 40 mg/kg) or saline before a daily training session (learning phase, days 1–4) in the active avoidance task. Performance was evaluated on the fifth day (retention phase): in each bupropion-treated group half of the mice continued with the same dose of bupropion, and the other half received saline. Among the vehicle-treated mice, different sub-groups were challenged with different doses of bupropion. Results indicated that mice treated with 10 and 20 mg/kg bupropion exhibited more number of avoidances during acquisition. The response latency confirmed this learning improvement, since this parameter decreased after bupropion administration. No differences between groups were observed in the retention phase. In conclusion, our data show that bupropion influences the learning process during active avoidance conditioning, suggesting that this drug can improve the control of emotional responses. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Bupropion is an antidepressant that has shown to be effective in the treatment of tobacco dependence (Hughes et al., 2014) and it is included in the seven first-line pharmacological agents for smoking cessation (Hudmon et al., 2010). In addition, bupropion is a candidate for treatment of psychostimulant drug abuse (Castells et al., 2010; Schindler et al., 2011), cannabis addiction (Penetar et al., 2012), pathological gambling (Dannon et al., 2005), or excessive online game playing (Han and Renshaw, 2012). The treatment with naltrexone plus bupropion may also be useful for overweight and obesity (Greenway et al., 2010; Yanovski and Yanovski, 2015). Cognitive effects of bupropion have been reported in children and adults with attention deficit hyperactivity disorder (ADHD) (Clay et al., 1988; Wilens et al., 2005) and in patients with major depression (Herrera-Guzmán et al., 2008; Gorlyn et al., 2015), suggesting that bupropion treatment could improve neuropsychological functioning in these patients. However, some
Abbreviations: ADHD, attention deficit hyperactivity disorder; BUP, bupropion; IP, intraperitoneally; ITI, intertrial interval; nAChRs, nicotinic cholinergic receptors; NE, norepinephrine; US, unconditioned stimulus; VEH, vehicle. ∗ Corresponding author. Fax: +34 963864668. E-mail addresses: [email protected] (M.C. Gómez), [email protected] (R. Redolat), [email protected] (M.C. Carrasco). http://dx.doi.org/10.1016/j.beproc.2015.12.003 0376-6357/© 2015 Elsevier B.V. All rights reserved.
inconsistencies regarding cognitive effects of this drug have been reported. For example, acute treatment with the antidepressants bupropion and sertraline had no detectable effects on the retrieval of emotionally arousing material learned one week prior to testing in healthy adult subjects (Carvalho et al., 2006). In contrast, bupropion improves cognitive performance after overnight smoking abstinence in healthy adult smokers (Perkins et al., 2013a). The neuropharmacological actions of bupropion indicate that this agent has an atypical antidepressant profile sharing some similarities with traditional psychostimulants (Dwoskin et al., 2006). The drug is a relatively weak dopamine-uptake inhibitor which also inhibits firing of locus coeruleus norepinephrine (NE) neurons at high concentrations (Cooper et al., 1994). Bupropion also inhibits the function of the dopamine and NE transporters (Dwoskin et al., 2009). The effectiveness of bupropion (and/or its hydroxy metabolites) in the treatment of nicotine dependence has been related to its effects on mood, which are mediated by enhancement of noradrenergic and dopaminergic signals, as well as to its effects on NE transporters and on members of the diverse family of nicotinic cholinergic receptors (nAChRs) (Damaj et al., 2004). It has been reported that bupropion acts as a non-competitive nicotinic receptor antagonist (Arias, 2009; Slemmer et al., 2000), which could contribute to their efficacy as an antidepressant and as a smoking cessation agent (Dowskin et al., 2006). However, the mechanisms
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by which it increases abstinence rates in smokers are not clear (Perkins et al., 2013b; Wright and Rodgers, 2013). Monoamine neurotransmitter systems are involved in the regulation of mood and cognition (Booij et al., 2003; Hamon and Blier, 2013), suggesting that monoamine-elevating medications may be useful for emotional and cognitive improvement. There is, for example, evidence of the positive effects of antidepressant treatment on synaptic plasticity in cortical and subcortical brain circuits related with mood disorders and memory (Castrén and Hen, 2013; Sairanen et al., 2007). In animal models, bupropion has been found to induce place preference (Ortmann, 1985; Rauhut et al., 2008), to improve performance in a novel object recognition task (Kruk-Słomka et al., 2014), to disrupt latent inhibition measured in a conditioned emotional response (Lipina and Roder, 2010), to facilitate extinction of avoidance responses in a lever-press avoidance task in animals with innate vulnerability to anxiety (Jiao et al., 2014). Bupropion also improves the retrieval of an inhibitory avoidance response (Barros et al., 2002) and reverses the reserpine-induced impairment in conditioned avoidance response when administered at 40 mg/kg (Nakagawa et al., 1997), although this drug failed to alter the conditioned place preference induced by nicotine (Rauhut et al., 2008). However, the administration of a low dose of bupropion (5 mg/kg) reverses nicotine withdrawal-associated deficits in contextual fear conditioning, whereas high doses (20 or 40 mg/kg) induce deficits in contextual and cued fear conditioning (Portugal and Gould, 2007). In a Pavlovian fear learning task, Carmack et al., (2014) have recently reported that bupropion induced long-term memory-enhancing effects. This cognitive improvement was similar to that observed for animals treated with the psychostimulant methylphenidate, an agent used as a cognitive enhancer for a diversity of disorders, in particular as treatment for ADHD (Carmack et al., 2014). Despite of these findings obtained in animal models, limited work has evaluated effects of bupropion on learning and memory tasks. Specifically, its direct actions on an active avoidance conditioning using a two-way shuttle box model have not been previously studied. Therefore, our aim was to evaluate the effects of varying doses of bupropion on acquisition and performance in a two-way active avoidance task. Preclinical previous research has been reported memory-enhancing effects of bupropion using different animal models, however, no study has yet examined whether the two-way active avoidance conditioning can be improved with bupropion treatment in mice. This animal model is based on the acquisition of a relatively complex learning task that requires the control of emotional responses. Recent evidence indicates that during the active avoidance response both emotional and motivational circuitries contribute to the acquisition of the task: the amygdala plays a central role in the emotional circuitry whereas different midbrain dopaminergic structures integrate the motivational circuitry (Ilango et al., 2014). The two-way active avoidance conditioning task can be useful for gathering information about the behavioral responses displayed by the animal both during the acquisition and the retention phases. These data could provide information regarding differential effects of the drug on learning and emotional memory.
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Fig. 1. Experimental design, including the acquisition and retention phases of the study. In the retention phase, half of the mice in each bupropion-treated group continued with their dose of bupropion and the other half began to receive saline.
forms well in different learning paradigms (Ghaderi et al., 2015; Moragrega et al., 2005). All procedures complied with the “principles of laboratory animal care” and international guidelines (EU Directive 2010/63/EU) for the care and treatment of animals. 2.2. Drugs Bupropion hydrochloride (Sigma–Aldrich, Madrid, Spain) was dissolved in physiological saline. During acquisition phase (1–4 days), bupropion (40, 20, 10 mg/kg) or the vehicle was administered intraperitoneally 30 min before each daily shuttle box training session. In the performance session or retention phase (5 day), half of the mice in each bupropion-treated group (n = 12) continued with their dose of bupropion and the other half began to receive saline. This treatment challenge was performed in order to differentiate effects of drug on performance and acquisition. In this session, the control group (n = 24) was subdivided into four groups which received 10, 20, 40 mg/kg of bupropion or vehicle (see experimental design in Fig. 1). The doses employed in the current research were selected on the basis of previous studies about the effects of bupropion in NMRI mice (Carrasco et al., 2004, 2013; Gomez et al., 2009a,b; Redolat et al., 2005a,b) and are in the range of doses habitually used to assess behavioral effects of bupropion in rodents (Biała and Kruk, 2009; Lipina and Roder, 2010; Randall et al., 2014). 2.3. Apparatus and procedure
2. Material and methods 2.1. Animals Sixty male NMRI mice (Charles River, Barcelona, Spain) weighing 26–28 g were used for the experiment. The animals were housed five per cage under standard laboratory conditions, with food and water ad libitum, and exposed to a reversed 12:12 h light/dark cycle (lights off at 8:00 h). NMRI mice were selected since this strain per-
Mice were trained in an automated two-way shuttle-box (45 × 24.5 × 19 cm) (Shuttle Scan, Model SC-II, OMNITECH, Columbus, OH) which was placed in a sound-attenuating box in order to avoid disturbances. A light (6 w) was used as conditioned stimulus, preceding by 10 s the onset of the unconditioned stimulus (US) and overlapping it for 10 s. The US consisted of an electric shock (0.3 mA) applied to the grid floor, which was formed by stainless steel bars. The box was divided into two compartments with a white
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Fig. 2. Mean (±) SEM of number of avoidances shown by mice receiving different pharmacological treatments in the acquisition phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion and BUP-40: 40 mg/kg of bupropion during acquisition training sessions (days 1–4) in a two-way shuttle box. * BUP-10 vs. BUP-40 and VEH, p < 0.05. +BUP-10 and BUP-20 vs. VEH, p < 0.05.
plexiglas barrier. During the adaptation period (3 min) mice could explore the apparatus. The intertrial interval (ITI) varied between 20 and 40 s, during which the mice could move freely between compartments. The following behavioral parameters were evaluated: (1) number of avoidances: mouse crossed during the light signal; (2) number of non responses: mouse did not cross to the other compartment; and (3) response latency: time of response to avoid or escape. The number of crossings during the adaptation period and ITIs were also recorded as activity measures. In order to evaluate the effects of bupropion on learning and memory, each mouse underwent thirty trials during each of the four daily acquisition sessions (acquisition phase: days 1–4), and a further thirty trials in the performance session (retention phase: day 5). 2.4. Statistical analysis Analysis of variance (ANOVA) of repeated measures was performed for each of the measures obtained (avoidances, nonresponses, response latency, adaptation and ITI crossings). Post-hoc comparisons were conducted when appropriate using the Tukey HSD test. One-way ANOVAs were also performed to evaluate data on the performance day (day 5). In all cases, a p < 0.05 was considered as significant. 3. Results 3.1. Acquisition phase With respect to active avoidance acquisition (days 1–4), the ANOVA revealed that treatment had a significant effect on the number of avoidances [F(3, 56) = 4.27, p < 0.009, p2 0.186]. Post-hoc tests indicated that mice administered 20 or 10 mg/kg of bupropion showed significantly more avoidance responses (p < 0.052 and p < 0.033, respectively) than the control group. The factor Session [F(3, 168) = 235, p < 0.001, p2 0.808] and Session × Treatment [F(9, 168) = 3.79, p < 0.001, p2 0.169] also reached statistical significance (see Fig. 2). ANOVAs conducted independently for each session indicated that the Treatment factor reached statistical significance in session 1 [F(3, 56) = 8.52, p < 0.001 p2 0.314], session 2 [F(3,56) = 2.9, p < 0.042 p2 0.135] and session 4 [F(3, 56) = 4.63, p < 0.006, p2 0.199] (see Fig. 2). In session 1, mice treated with
10 mg/kg displayed more avoidances than those receiving 40 mg/kg or the vehicle (p < 0.001 and p < 0.027, respectively). In session 2, comparisons failed to detect statistically significant differences between groups (data are not shown). In session 4, mice receiving 10 and 20 mg/kg exhibited more avoidances than controls (p < 0.043 and p < 0.020, respectively). The ANOVA of response latency revealed that the factors Treatment [F(3,56) = 3.88, p < 0.014, p2 0.172] and Session [F(3,168) = 31.67, p < 0.001, p2 0.361] were significant. In session 3, animals treated with 10 and 20 mg/kg of bupropion displayed shorter response latencies than vehicle-treated mice (p < 0.024 and p < 0.005, respectively). In session 4, mice receiving 20 and 40 mg/kg exhibited shorter response latencies than controls (p < 0.027 and p < 0.033, respectively) (see Fig. 3). The number of crossings during the adaptation period along acquisition sessions (1–4 days) was also evaluated. Results showed that there were no differences between groups in the number of adaptation crossings, although the Session factor [F(1,168) = 10.07, p < 0.001, p2 0.152] reached statistical significance. A separate analysis for each experimental session indicated significant differences in session 3 [F(3,56) = 2.93, p < 0.041, p2 0.136]. In this session, mice treated with 40 mg/kg of bupropion displayed a significantly lower number of adaptation crossings than those treated with 20 mg/kg (p < 0.025). No significant differences were found in the interaction Session × Treatment. In relation with the number of crossings during ITIs, there was a trend towards a significant effect of Treatment in the number of crossings during ITIs [F(3,56) = 2.60, p < 0.061, p2 0.123]. The Session factor [F(3,168) = 31.1, p < 0.001, p2 0.357] and the interaction Session × Treatment [F(9,168) = 2.35, p < 0.016, p2 0.112] also reached statistical significance. Treatment was statistically significant in sessions 3 [F(3,56) = 4.97, p < 0.004, p2 0.210] and 4 [F(3,56) = 2.73, p < 0.052, p2 0.128], during both of which mice treated with 20 mg/kg of bupropion crossed more times than vehicle-treated animals (p < 0.003 and p < 0.029, respectively). 3.2. Retention phase As previously mentioned, effects on performance were also evaluated in session 5, during which half the mice in each bupropion-treated group continued to receive their corresponding
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Fig. 3. Mean (±) SEM of response latency shown by mice receiving different pharmacological treatments in the acquisition phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion and BUP-40: 40 mg/kg of bupropion during acquisition training sessions (days 1-4) in a two-way shuttle box. *BUP-20 and BUP-40 vs. VEH, p < 0.05. +BUP-10 and BUP-20 vs. VEH, p < 0.05.
dose while the other half received saline, and while in the vehicletreated group different sub-groups of mice were challenged with each dose of bupropion. Although no statistically significant differences were observed between experimental groups, data showed that bupropion-treated groups during the acquisition phase when they were treated with saline in the retention phase increased the number of avoidances and decreased the response latencies. Similarly, mice that received saline during the acquisition phase when administered bupropion augmented the number of avoidances and reduced response latencies in the retention phase. ANOVA did not reveal a main effect of Treatment for any measure obtained (number of avoidances, non-responses; response latency, ITI and adaptation crossings) (see Fig. 4). 4. Discussion Regarding the effects of bupropion on acquisition phase in a two-way active avoidance task (sessions 1–4), when the low and intermediate doses (10 and 20 mg/kg) were administered, an increased number of avoidances was observed. Response latency confirmed this improvement, since this parameter also decreased during sessions. In session 3, animals treated with 10 and 20 mg/kg of bupropion exhibited shorter response latencies than controls. In session 4, mice treated with 20 and 40 mg/kg showed shorter response latencies than controls. These results, which suggest an enhancement in acquisition of avoidance learning within some bupropion groups, confirm those of previous studies with this drug that indicated an improvement of other learning tasks, such as retrieval of inhibitory avoidance (Barros et al., 2002), lever-press avoidance active task (Jiao et al., 2014), conditioned place preference (Ortmann, 1985), conditioned emotional response (Lipina and Roder, 2010; Carmack et al., 2014), or novel object recognition (Kruk-Słomka et al., 2014). Moreover, present data agree with previous observations showing that bupropion reverses reserpineinduced impairment in a conditioned avoidance task (Nakagawa et al., 1997) and reverses nicotine withdrawal-associated deficits in contextual fear conditioning by enhancing retrieval processes (Portugal and Gould, 2007). These later authors also reported an impairment in the acquisition and expression of contextual memories with higher doses of bupropion, observing that mice treated
with 20 and 40 mg/kg of bupropion displayed deficits in contextual and cued fear conditioning (Portugal and Gould, 2007). Given that previous data on the behavioural effects of bupropion in active avoidance tasks are limited (Jiao et al., 2014), we consider that present results add new information about the ability of bupropion to induce beneficial changes in the control of emotional responses. Considering that the active avoidance task is a relatively complex form of learning in which the animals have to learn a particular behavior in order to avoid the application of a stressor as a footshock, the performance displayed by animals treated with bupropion during sessions (jointly with the increase in the number of avoidances and the decrease in response latency observed here) suggests that this drug may improve the control of emotional responses. When interpreting current findings, it must be taken into account, as previously suggested (Vaglenova et al., 2004), that the behavior displayed by the animals in the active avoidance model contains elements of anxiety, fear or emotionality. Although there are relatively few studies that have examined bupropion effects on anxiety, present data agree with previous observations showing that this drug has an anxiolytic-like profile (Biała and Kruk, 2009; Carrasco et al., 2006; Joshi et al., 2005) in the plus-maze task, a classical model of anxiety. However, the findings obtained in other studies suggest that the actions of this drug on anxiety are modulated by different factors, such as age of the animals when exposed to the drug, nature of the stress procedure, housing conditions or baseline anxiety level (Carrasco et al., 2013; Gómez et al., 2008a,b; Hayashi et al., 2010). The increase in the number of avoidances is usually interpreted as the optimal response for mice in the active avoidance task, and our findings indicate that mice treated with bupropion (10 and 20 mg/kg) displayed a more active coping style than control group. As we can observe in Fig. 2, during the first acquisition day the group treated with 40 mg/kg of bupropion decreased the number of avoidance responses, in contrast with the group treated with 10 mg/kg of bupropion. It can be suggested during the first acquisition day mice receiving the highest dose of bupropion increased motor activity and reduced the control of active avoidance responses. Although locomotor activity was not assessed directly in the present experiment, we must take into account than along the adaptation period, during which mice could explore the apparatus for 3 min before
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Fig. 4. Mean (±) SEM of number of avoidances shown by mice receiving different pharmacological treatments in the retention phase. VEH: physiological saline, BUP-10: 10 mg/kg of bupropion, BUP-20: 20 mg/kg of bupropion, and BUP-40: 40 mg/kg.
each session (both in the acquisition and retention phases), no significant differences between groups were observed in the number of crossings, suggesting that this indirect measure of locomotion was unaffected by treatment with bupropion neither during learning nor during the retention of the task. Bearing in mind the total number of avoidance responses and response latency of each group, our results suggest a general improvement in learning in groups treated with bupropion. An interesting result was also observed in the retention phase. Comparing the performance of the ten experimental groups evaluated in the current study, our findings indicate that all animals displayed a good retention. In this phase, half of the mice in each bupropion-treated group continued with their dose of bupropion and the other half began to receive saline. In addition, the twentyfour animals included in the control group were subdivided into four groups (treated with 10, 20, 40 mg/kg of bupropion or vehicle). The results obtained indicated no significant differences in performance between groups during the retention of the active avoidance task. In fact, animals treated with bupropion seem to display similar emotional memory in comparison to control groups. This lack of a clear influence of the antidepressant bupropion on performance could be related to a possible ceiling effect due to the high number of avoidances reached in some bupropion-treated groups on the last acquisition day. Therefore, bupropion seems not to improve significantly retention of the active avoidance task in “expert” mice. There is some evidence to suggest that bupropion effects may depend of the mnemonic performance level of animals, since this drug attenuates the nicotine-induced memory improvement in the novel object recognition test, whereas prevented scopolamine-induced memory impairment (Kruk-Słomka et al., 2014). In addition, in the elevated plus-maze, although usually applied as a model of anxiety in rodent, some studies have been performed in order to evaluate changes in memory, indicating that in this apparatus bupropion modulates memory-related responses induced by nicotine (Biała and Kruk, 2009; Kruk et al., 2011). The cognitive effects of bupropion have been addressed directly by few preclinical studies. Data about behavioral effects of this drug on the active avoidance task, an animal paradigm that requires the control of emotional responses, are limited (Ilango et al., 2014). Results obtained in the current study suggest that bupropion can induce changes in the emotional and motivational circuitries,
which influence the learning process of the avoidance response. Therefore, our data suggest that this drug may have therapeutic potential for the treatment of different cognitive disorders as previously reported (Kruk-Słomka et al., 2014). It might be of interest to further explore the ability of bupropion to improve the acquisition of effective coping strategies in emotional situations applying different learning and memory paradigms in rodents. Current findings can contribute to the development of new behavioral and pharmacological treatments of cognitive alterations in mental and neurodegenerative disorders. 5. Conclusions Our data show that bupropion can modulate the acquisition process during active avoidance conditioning. This drug induces an improvement of the control of emotional responses, a factor which is essential to the development of more effective coping strategies in stress situations. Furthermore, present study also suggests that the beneficial effects of bupropion on emotional memory could be influenced by the mnemonic performance level of each animal, since this drug did not enhance retention of the two-way active avoidance conditioning task in “expert” rodents. Our findings extend present knowledge concerning main mechanisms involved in the active avoidance response and the potential use of bupropion as a cognitive enhancer. Further studies will be required to determine the implications and possible therapeutic applications of the cognitive effects of bupropion. References Arias, H.R., 2009. Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? Int. J. Biochem. Cell Biol. 41, 2098–2108, http:// dx.doi.org/10.1016/j.biocel.2009.05.015. Barros, D.M., Izquierdo, L.A., Medina, J.H., Izquierdo, I., 2002. Bupropion and sertraline enhance retrieval of recent and remote long-term memory in rats. Behav. Pharmacol. 13, 215–220. Biała, G., Kruk, M., 2009. Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze. Pharmacol. Rep. 61, 236–244. Booij, L., Van der Does, A.J., Riedel, W.J., 2003. Monoamine depletion in psychiatric and healthy populations: review. Mol. Psychiatry 8, 951–973. Carmack, S.A., Howell, K.K., Rasaei, K., Reas, E.T., Anagnostaras, S.G., 2014. Animal model of methylphenidate’s long-term memory-enhancing effects. Learn. Mem. 21, 82–89, http://dx.doi.org/10.1101/lm.033613.113.
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