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Impulsivity as a confounding factor in certain animal tests of cognitive function
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COGNITIVE BRAIN RESEARCH
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Cognitive Brain Research 3 (1996) 243-250
Impulsivity as a confounding factor in certain animal tests of cognitive function J.-C. Bizot a,*, M.-H. Thi6bot b a Service de Pharmacologie, DGA / ETCA / CEB, BP 3, 91710 Vert-le-Petit, France b INSERM U288, D~partement de Pharmacologie, Facult~ de Mddecine Piti~-Salp~tribre, 91 boulevard de l'H~pital, 75634 Paris C~dex 13, France
Accepted 18 December1995
Abstract Performance in cognitive tasks which require the subject to wait and/or to process a large amount of information can be disrupted by an increase in impulsive-like behaviour. Accordingly, a decrease in impulsive-like behaviour can improve performance in such tasks. Conversely, impulsive-like behaviour may improve performance in cognitive tasks where simple and fast responses and/or only little information processing is required. Thus, impulsivity constitutes a confounding factor in studies of cognitive function. Impulsive-like behaviour may be modified by serotonergic (5-HT) activity, with underactivity in 5-HT neurotransmission increasing impulsivity and vice versa. Drug- or lesion-induced alteration in 5-HT neurotransmission may, therefore, constitute suitable tools to investigate the role of impulsivity in animal tests of cognitive function. Benzodiazepines also increase impulsive-like behaviour, possibly by decreasing 5-HT neurotransmission. Hence, the effects of modulation of 5-HT systems and of the benzodiazepine-binding site on performance in animals tests of cognitive function will be discussed. It is predicted that the effects of manipulations of serotonergic activity or of benzodiazepine administration depend upon the nature of the response required, and that these effects may be mediated through changes in impulse control. Keywords: Animal model; Benzodiazepine; Cognition; Impulsivity;5-HT; Memory
1. Introduction Impulsivity is characterized by a subject's inability to reflect or to wait for a stimulus before acting [1,27,37,81,115]. Thus, the performance of any cognitive function requiring reflection can be disrupted by impulsivity. Conversely, in cognitive tasks where rapid decisions and fast responses are necessary for success, an increase in impulsivity may improve function. Animal models of impulsive-like behaviour are usually based on choice procedures in which the amount, delay and rate of reinforcement (reward or punishment) are primary determinants of the behaviour. As in man, alterations in impulsivity (essentially induced by drugs or brain lesions) can interfere with cognitive experiments in animals. Variations in impulsivity can confound animal studies dealing with cognitive function. Impulsivity is a feature of a number of pathological
* Corresponding author. 0926-6410/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PII S0926-6410(96)00010-9
behaviours, such as bulimia, kleptomania, suicide or violent acts. It has been linked to a reduction of serotoninergic (5-HT) neurotransmission ([54], see for review [6,17] and [106]). Animal studies indicate that, among other effects, benzodiazepines (BZP) decrease 5-HT function [55,92,105,114] and, therefore, might increase impulsivity [25,32,106]. Compounds which increase 5-HT neurotransmission, such as antidepressants and more specifically 5-HT uptake inhibitors, exert beneficial therapeutic effects in certain diseases such as bulimia nervosa or obsessivecompulsive disorder [33,56,106], perhaps by improving impulse control.
2. Impulsivity: animal data Few studies have focused upon impulsivity in animals. Since behaviour is considered to be impulsive when it sacrifices long-term considerations for short-term gain [1,27,37,81,115] most animal models of impulsivity measure choice between several alternatives where the amount,
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rate and delay of reinforcement are varied. According to Herrnstein [37], tolerance to delay of reward is an index of impulsivity. We will briefly review these models and their sensitivity to modifications of 5-HT neurotransmission and to the effects of BZP (see [111] for review). In the model of waiting capacity in a T-maze, described extensively elsewhere [110], a rat has to choose between a small reward delivered immediately and a large but delayed reward. Since tolerance to delay of reward can be considered as an index of impulsivity, drugs that increase or decrease impulsivity, should respectively reduce or enhance the percentage of choice of the large-but-delayed reward. All BZP studied in this model decreased the number of choices of the large-but-delayed reward [110]. p-Chlorophenylalanine (p-CPA), an antagonist of 5-HT synthesis [52], produced the same effect [62]. Conversely, 5-HT reuptake inhibitors increased the number of choices of the large-but-delayed reward [9,110]. In an operant schedule where rats were trained to withold responding on a lever to obtain a reward of free pellets which are delivered at a decreasing rate, or respond on a FR 48 schedule of reinforcement in order to gain one food pellet and to reinitiate free pellet distribution, drugs that decrease impulsivity should increase the interval during which the animal refrains from pressing the lever in order to obtain free rewards. Indeed, 5-HT uptake inhibitors studied in this model increased the mean waiting time tolerated for free pellets [9]. In the Differential Reinforcement of Low rates of responding (DRL) schedule, a response is reinforced only when it is emitted after a fixed time interval has elapsed since the previous response. Responses occurring earlier than the minimum time reinitiate the interval (for more details, see the references cited below). Drugs that increase impulsivity, should increase the number of non-reinforced responses whereas drugs that decrease impulsivity should induce the opposite effect. With the exception of several studies in which the time interval requirement was particularly long (DRL 72 s) [45,85,118], BZP increase the number of non-reinforced responses and response bursts [15,69,78,86,91,93-95]. In keeping with the 5-HT hypothesis of impulsivity, destruction of 5-HT neurons originating from dorsal and median raphe nuclei by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which dramatically decreases brain 5-HT levels, induced disruption of either acquisition or performance of a DRL 15-s schedule [124]. Conversely, an increased number of reinforcements and a decreased number of responses in DRL 72 s were observed following administration of 5-HT reuptake inhibitors [61,70,71,84,102,118] or 5-hydroxytryptophan (5-HTP), a 5-HT precursor, which increase both central and peripheral 5-HT neurotransmission [61,85]. Go-no go procedures consist of the successive presentation of go trials, during which the animal has to make a conditioned response in order to obtain a positive reinforcement, and no go trials, during which the animal has to
refrain from making this response for a minimum time, in order to be reinforced. In some studies, no go trials merely consist of an extinction period, during which the conditioned response is not reinforced [21,22]. Go and no go trials can be signalled by stimuli (go-no go discrimination task [116]) or can alternate (go-no go alternation task [36]). BZP have been shown to disrupt ability to refrain from responding during no go trials [21,23,43,116]. However, in one study [36] with chlordiazepoxide this effect was not observed. In a schedule fairly similar to the go-no go procedures, rewards were delivered to rats when a lever press was emitted only during periods signalled by a light, while such periods were delayed when a press was emitted during the light-off period [31]. This task was disrupted by moderate doses of chlordiazepoxide, which increased the number of presses during light-off periods, an effect interpreted by the authors as disinhibition [31 ], but which could also indicate impulsive behaviour.
3. Animal models of cognition: effects of BZP and treatments which alter 5-HT neurotransmission Many animal models of cognition have been proposed and most of them are devoted to the study of learning and memory. Impulsivity could be a critical factor in a number of these models, particularly where the timing of a response is essential for success, in situations where animals are required to inhibit their behaviour or, conversely, in situations where they have to act rapidly. We will review such situations and examine the effects of drugs acting on impulsivity such as BZP and other drugs that reduce or increase 5-HT neurotransmission. 3.1. Extinction schedules
In extinction schedules, animals previously trained to emit conditioned responses are no longer reinforced [7,8,109]. Resistance to extinction is thought due to a learning impairment. However, inability to refrain from responding during extinction could also be explained by increased impulsivity. Certain pharmacological results are in support of such an hypothesis since resistance to extinction of operant responding has been demonstrated in rats [103,109] and pigs [24] treated with BZP or in rats subjected to 5-HT depletion with p-CPA [7]. Conversely, the 5-HT agonist, quipazine, but not the 5-HT uptake blocker fluoxetine, accelerated extinction [8]. 3.2. Reaction time schedules
Reaction time paradigms are not strictly cognitive tests. Nevertheless, they have been considered important in studies on information processing (see [63]) and drugs that alter attentional processes modify reaction time (see below). In reaction time schedules, the animal has a limited
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time to respond after presentation of a conditioned stimulus in order to obtain a positive reinforcement [26,38,39,60] or to avoid punishment [63,64]. Such schedules are sensitive to both stimulant and sedative drugs. For instance, amphetamine reduced reaction time in rats trained to release a lever to avoid a foot-shock [64]. d-Methamphetamine decreased auditory reaction time (and less consistently visual reaction time) in baboons trained to release a lever to obtain food pellets [39]. Conversely, two drugs that reduce attention processes, pentobarbital [38], and ethanol [63], increased reaction time in baboons and rats, respectively. A drug that increases impulsivity could make the animal less able to wait for the conditioned stimulus and could, therefore, increase the number of responses in anticipation of the conditioned stimulus. On the basis of signal detection theory, a number of authors have considered these responses to be false alarms [26,39,60,90]. Further, increases in impulsivity could also increase the number of responses emitted during presentation of the conditioned stimulus, but before the animal has detected it. When these responses are taken into account, calculation of the reaction time may be artificially decreased. Since false alarms do not appear to be enhanced by dmethamphetamine, the reported reduction in reaction time induced by this compound [39] cannot be explained by an increase of impulsivity. Some drugs considered to increase impulsivity, such as BZP, can increase the number of false alarms. This may be the case for chlordiazepoxide (but not midazolam) in rats subjected to a simple reaction time paradigm requiring the animal to respond to a rarely occurring and unpredictable brief visual stimulus in order to obtain food pellets [26]. The rate of false alarms was also reported to be slightly, although not significantly, increased by diazepam and triazolam in baboons subjected to auditory and visual reaction time tasks [60]. However, this effect was not associated with a decrease, but rather an increase in reaction time [26,60]. Therefore, our hypothesis that false alarms are an index of impulsivity and is a confounding factor in simple reaction time schedules remains to be proved. However, it cannot be excluded that a pro-impulsive effect of BZP, resulting in an increased number of false alarms and a decreased reaction time, would be masked by their sedative effects.
3.2.1. Five-choice serial reaction time schedule The five-choice serial reaction time task is designed to measure selective attention [46]. In this schedule, rats are trained to detect and respond, within a limited time, to brief flashes of light presented randomly in one of five locations [16,18,19,46]. Premature responses, i.e. responses emitted during intertrial intervals, have been considered by some authors to be an index of impulsivity [18,19]. As hypothesized above for the simple reaction time schedule, some premature responses could be emitted during presentation of the stimuli, but before they have been detected by the animal. In this case, they are not recorded as
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premature responses, but statistically, 80% of them would be incorrect and 20% would be correct, regardless of the overall performance level. In other words, they would decrease accuracy (i.e. the number of correct responses divided by the total number of responses during the stimulus presentation). The mean response time would, therefore, be decreased to a greater extent for incorrect responses than for correct responses, d-Fenfluramine, which releases 5-HT from nerve endings and blocks 5-HT uptake, but not a sedative drug such as haloperidol, decreased premature responses in the five-choice reaction time task [16]. p-Chloroamphetamine (p-PCA), which depletes 5-HT neurons, increased these responses [104]. These data are consistent with the proposal that premature responses can be considered as an index of impulsivity. However, p-CPA, also thought to increase impulsivity, reduced the number of premature responses [46]. One possible explanation of this discrepant result is that an increase in premature responses may occur independently of increased impulsivity. For instance, amphetamine has been shown to increase premature responses in a five-choice serial reaction time task at doses which did not disrupt accuracy [18,19]. Response time was decreased but for correct responses only in one study [19] and for both correct and incorrect responses in the other [18]. Conversely, scopolamine, an antagonist of muscarinic receptors, thought to disrupt cognitive processes [44] decreased premature responses [46]. Since there is no evidence, to our knowledge, that amphetamine or scopolamine may alter impulsivity, we can hypothesize that paradoxically, vigilance and premature responses covary; both are increased by amphetamine and decreased by scopolamine.
3.3. Delayed matching and delayed non-matching schedules Delayed matching or delayed non-matching schedules are designed to measure short-term memory. In the schedules frequently used in monkeys [10,41,101] or pigeons [89], a sample stimulus (a light of a given color, or a geometric symbol) is presented to the animal. A first response (sample response), allows the animal to terminate sample presentation and to initiate a delay at the end of which two stimuli are presented, one of which is identical to the sample stimulus. The animal is reinforced if it makes a response (choice response) corresponding to the matching stimulus in delayed matching to sample (DMTS) schedules or to the non-matching stimulus in delayed non-matching to sample (DNMTS) schedules. The delayed matching to position tasks (DMTP) [20] and delayed nonmatching to position tasks (DNMTP) [47], frequently used in rats, are very similar to DMTS and DNMTS. They involve two retractable levers of an operant chamber, to provide a position sample to which the animal must respond for subsequent matching to the position response. A
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variable delay can be inserted between presentation of the sample and choice stimuli. This delay can be used to distinguish alterations in attentional processes (alteration of performance regardless of the delay) from alterations in short-term memory (delay-dependent alteration of performance). In such schedules, Reading and Dunnett [83] suggested that disinhibition could mimic a mnemonic deficit. Increased impulsivity could possibly interfere with response accuracy, due to a reduction in the latency to emit the choice response. A disruption of the ability to wait can also result in a reduction in the latency to emit the sample response which terminates sample presentation, thereby reducing the duration during which the sample can be memorized. Premature responses, when they are possible (as in most of the DMTS and DNMTS schedules in pigeons and primates), could also be considered to be an index of impulsivity. In DMTP and DNMTP tasks, levers are retracted during the delay, but other responses such as nose pokes into the food tray, could nevertheless reflect the animal's impulsivity. Some results clearly support the hypothesis of impulsivity as an important confounding factor in delay tasks. In a titrating matching to sample schedule in pigeons (a DMTS in which the length of the delay changes as a function of the animal's performance), Wenger et al. [123] showed that diazepam disrupted matching performances and noted a decrease (although not statistically significant) in the mean latency of the sample response for all of the five animals treated with diazepam (1 mg/kg). In a delayed pair comparison task in pigeons (a task similar to DMTS), chlordiazepoxide increased the number of responses during the delay which disrupted performance. However, a decreased choice latency and an increase in activity during the delay does not necessarily imply a disruption of performance, as indicated by the results reported with ZK 95962 (a partial agonist of BZP receptors) in a DMTP task in rats. On the other hand, alterations of performance in delayed matching schedules frequently reported with drugs claimed to affect impulsivity (i.e. BZP and p-CPA) are associated with a reduction, rather than an increase, in premature responses [20] and lengthening of response times [10,20,41,47,89,101]. This suggests that sedation a n d / o r non-specific motor effects, rather than impulsivity are involved in the observed deterioration of behaviour. The fact that the BZP receptor partial agonist, ZK 95962, and the complete BZP agonist, lorazepam, respectively decrease and increase the choice latency in DMTP tasks [20] supports this hypothesis, since partial BZP agonists are less sedative than complete BZP agonists [34]. 3.4. A v o i d a n c e schedules
Avoidance tests have been used extensively to study the effects of drugs or brain lesions on learning and memory.
They can be schematically divided into two types: passive and active avoidance. In passive avoidance tests, the animal (usually a rat or a mouse) is trained during a learning session to stay in one place, i.e. a lit compartment or platform, in order to avoid a punishment, generally an electric foot-shock, delivered in another place (a dark compartment connected with the lit one, or a grid floor below the platform). In the one-trial passive avoidance procedure, the animal is removed from the apparatus after having received the punishment. In other passive avoidance procedures, the trial is repeated several times, or shocks delivered repeatedly until the animal returns to the safe place (multiple-trial passive avoidance). Latency to move from the safe place to the punished place is assessed during a test-session performed after an interval of several hours or days. Amnesic or promnesic drugs decrease and increase this latency, respectively. In active avoidance procedures, animals are trained to go from one place to another (to change compartment in most procedures) to avoid a punishment, generally an electric foot-shock. In one-way active avoidance procedures, the animal is placed in the 'punished' place and, after a fixed delay, the punishment is delivered until the animal moves to the 'safe' place. Punishment is not delivered when an avoidance response is emitted, i.e. when the animal runs from the punished to the safe place during the delay. The trial is repeated several times or until the number of avoidance responses reaches a fixed criterion level. In the two-way active avoidance procedure, performed in a shuttle-box, a punishment is delivered after presentation of a conditioned stimulus (a light or sound or both) when the animal fails to escape from one compartment to the other during this presentation. Crossing from one compartment to the other during punishment interrupts this punishment. Since impulsive subjects are liable to make rapid decision and to respond quickly without thinking [27], we can hypothesize that in passive avoidance, an increase in impulsivity would make the animal less able to remain passively in one place. Such impairment in the animal's ability to inhibit an active response would be unfavourable for passive avoidance acquisition. Inversely, a decrease in impulsivity would be favourable to acquisition or restitution of a passive response. In active avoidance procedures, impulsive behaviour would promote active motor responses, and would, therefore, be helpful to learn or restore an active avoidance response. Conversely, a decrease in impulsivity would be unfavourable for learning and response restoration. When BZP are administered before the learning session in passive avoidance tasks, they always exert an amnesic effect: the latency to return into the punished place during the test session is decreased [4,13,14,48,49,67,68,79,80,112,113,119,121,122]. An amnesic effect of BZP administered before the test session has been reported by some authors [ 121 ], but not by others [14,68,79]. Conversely, when administered at moderate doses, BZP exert beneficial effects on active avoidance
J.-C. Bizot, M.-H. Thi£bot / Cognitive Brain Research 3 (1996) 243-250
acquisition or restitution [72,88,96-99]. Therefore, an increase of impulsivity by BZP could partially explain why these compounds act in an opposite way on passive avoidance acquisition and on active avoidance acquisition. Effects of treatments that reduce 5-HT transmission on passive avoidance acquisition are more equivocal. PCA disrupted passive avoidance acquisition in male rats, but not in females [35]. In some studies, p-CPA did not modify passive avoidance acquisition when administered alone [28,87] but aggravated mecamylamine-induced amnesia [87], and in others, p-CPA improved passive avoidance learning [11,82]. There are also discrepancies between results on the effects of 5-HT neurotransmission decrements on active avoidance acquisition. 5-HT depletion induced by p - C P A facilitated active avoidance acquisition in some studies [11,108,117], but not in others [29,53]. Depletion of 5-HT neurons with PCA could produce either an improvement [120] or a disruption [73] of active avoidance acquisition. Electrolytic lesions of raphe nuclei facilitated 2-way active avoidance acquisition [53,57,58] but disrupted 1-way active avoidance acquisition [40,53,59,107], and raphe lesions with 5,7-DHT had no effect on 1-way avoidance learning [59]. Therefore, 5-HT depletions induce different effects such as increase of activity level [53,107], increase of pain sensitivity [108] or increase of reactivity to novel environnment [107] that could influence performance in avoidance tasks. For instance, a large number of factors such as the extent or the localisation of the 5-HT depletion, the shock intensity, the strains or the sex of the animals or their housing conditions can influence avoidance performance [53,59,87,100,117]. Therefore, the hypothesis that an increase of impulsivity by 5-HT neurotransmission decrement could be partly responsible for alterations in acquisition of avoidance schedules seems plausible, but further experiments are required for this to be confirmed. Treatments that increase 5-HT neurotransmission such as 5-HT inhibitors or 5-HT agonists [2,3] administered before the retention test have memory enhancing effects in passive avoidance tasks. Furthermore, 5-HT uptake inhibitors or 5-HT releasing agents administered before the learning session antagonised the amnesic-like effect induced by bulbectomy [12,50] or by scopolamine [66]. A promnesic effect of 5-HT mimetics could be at least partly due to an improvement of the processes involved in memory consolidation, as observed when drugs were administered after the acquisition session [30,42]. Conversely, disruption of active avoidance acquisition were found following injections of 5-HT uptake inhibitors in some studies [5,50,65], but not in others [74,75], and following administration of 5-HT releasing agents [65,74-77] or 5-HTP [51]. Therefore, drugs that increase 5-HT neurotransmission have clearly opposite effects upon passive avoidance (a memory-enhancing effect) and active avoidance (a memory-disrupting effect). A decrease of impulsivity could partly account for such effects.
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4. Conclusion For those cognitive tasks which require the inhibition of behaviour or which require the processing of a large amount of information before responding, a decrease in impulsivity can be beneficial by improving the animal's ability to wait or to take the time necessary to collect relevant information. Conversely, in situations which require the processing of little information and the responses necessary are simple but must be rapid, increases or decreases in impulsivity could improve or disrupt performance, respectively. Drugs that modify 5-HT neurotransmission have predictable effects upon the performance of some cognitive tasks which depend upon the nature of the responses required. It is suggested the effects of these drugs in these circumstances are mediated through changes in impulsivity. Perhaps the clearest evidence in favour of this hypothesis can be found when considering the differential effects of modulators of 5-HT neurotransmission upon the performance of passive and active avoidance tasks. There are many other cognitive tasks where the response(s) required may be sensitive to changes in impulsivity. The potential confounding influence of this factor for the interpretation of data from such tasks cannot be ignored.
Acknowledgements We are grateful to T. Steckler for his comments on the manuscript. Particular thanks are due to G.D. D'Mello for his invaluable comments, suggestions and criticisms on the manuscipt and for his assistance with the translation into English.
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,/1~!
COGNITIVE BRAIN RESEARCH
i+'++! ELSEVIER
Cognitive Brain Research 3 (1996) 243-250
Impulsivity as a confounding factor in certain animal tests of cognitive function J.-C. Bizot a,*, M.-H. Thi6bot b a Service de Pharmacologie, DGA / ETCA / CEB, BP 3, 91710 Vert-le-Petit, France b INSERM U288, D~partement de Pharmacologie, Facult~ de Mddecine Piti~-Salp~tribre, 91 boulevard de l'H~pital, 75634 Paris C~dex 13, France
Accepted 18 December1995
Abstract Performance in cognitive tasks which require the subject to wait and/or to process a large amount of information can be disrupted by an increase in impulsive-like behaviour. Accordingly, a decrease in impulsive-like behaviour can improve performance in such tasks. Conversely, impulsive-like behaviour may improve performance in cognitive tasks where simple and fast responses and/or only little information processing is required. Thus, impulsivity constitutes a confounding factor in studies of cognitive function. Impulsive-like behaviour may be modified by serotonergic (5-HT) activity, with underactivity in 5-HT neurotransmission increasing impulsivity and vice versa. Drug- or lesion-induced alteration in 5-HT neurotransmission may, therefore, constitute suitable tools to investigate the role of impulsivity in animal tests of cognitive function. Benzodiazepines also increase impulsive-like behaviour, possibly by decreasing 5-HT neurotransmission. Hence, the effects of modulation of 5-HT systems and of the benzodiazepine-binding site on performance in animals tests of cognitive function will be discussed. It is predicted that the effects of manipulations of serotonergic activity or of benzodiazepine administration depend upon the nature of the response required, and that these effects may be mediated through changes in impulse control. Keywords: Animal model; Benzodiazepine; Cognition; Impulsivity;5-HT; Memory
1. Introduction Impulsivity is characterized by a subject's inability to reflect or to wait for a stimulus before acting [1,27,37,81,115]. Thus, the performance of any cognitive function requiring reflection can be disrupted by impulsivity. Conversely, in cognitive tasks where rapid decisions and fast responses are necessary for success, an increase in impulsivity may improve function. Animal models of impulsive-like behaviour are usually based on choice procedures in which the amount, delay and rate of reinforcement (reward or punishment) are primary determinants of the behaviour. As in man, alterations in impulsivity (essentially induced by drugs or brain lesions) can interfere with cognitive experiments in animals. Variations in impulsivity can confound animal studies dealing with cognitive function. Impulsivity is a feature of a number of pathological
* Corresponding author. 0926-6410/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PII S0926-6410(96)00010-9
behaviours, such as bulimia, kleptomania, suicide or violent acts. It has been linked to a reduction of serotoninergic (5-HT) neurotransmission ([54], see for review [6,17] and [106]). Animal studies indicate that, among other effects, benzodiazepines (BZP) decrease 5-HT function [55,92,105,114] and, therefore, might increase impulsivity [25,32,106]. Compounds which increase 5-HT neurotransmission, such as antidepressants and more specifically 5-HT uptake inhibitors, exert beneficial therapeutic effects in certain diseases such as bulimia nervosa or obsessivecompulsive disorder [33,56,106], perhaps by improving impulse control.
2. Impulsivity: animal data Few studies have focused upon impulsivity in animals. Since behaviour is considered to be impulsive when it sacrifices long-term considerations for short-term gain [1,27,37,81,115] most animal models of impulsivity measure choice between several alternatives where the amount,
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rate and delay of reinforcement are varied. According to Herrnstein [37], tolerance to delay of reward is an index of impulsivity. We will briefly review these models and their sensitivity to modifications of 5-HT neurotransmission and to the effects of BZP (see [111] for review). In the model of waiting capacity in a T-maze, described extensively elsewhere [110], a rat has to choose between a small reward delivered immediately and a large but delayed reward. Since tolerance to delay of reward can be considered as an index of impulsivity, drugs that increase or decrease impulsivity, should respectively reduce or enhance the percentage of choice of the large-but-delayed reward. All BZP studied in this model decreased the number of choices of the large-but-delayed reward [110]. p-Chlorophenylalanine (p-CPA), an antagonist of 5-HT synthesis [52], produced the same effect [62]. Conversely, 5-HT reuptake inhibitors increased the number of choices of the large-but-delayed reward [9,110]. In an operant schedule where rats were trained to withold responding on a lever to obtain a reward of free pellets which are delivered at a decreasing rate, or respond on a FR 48 schedule of reinforcement in order to gain one food pellet and to reinitiate free pellet distribution, drugs that decrease impulsivity should increase the interval during which the animal refrains from pressing the lever in order to obtain free rewards. Indeed, 5-HT uptake inhibitors studied in this model increased the mean waiting time tolerated for free pellets [9]. In the Differential Reinforcement of Low rates of responding (DRL) schedule, a response is reinforced only when it is emitted after a fixed time interval has elapsed since the previous response. Responses occurring earlier than the minimum time reinitiate the interval (for more details, see the references cited below). Drugs that increase impulsivity, should increase the number of non-reinforced responses whereas drugs that decrease impulsivity should induce the opposite effect. With the exception of several studies in which the time interval requirement was particularly long (DRL 72 s) [45,85,118], BZP increase the number of non-reinforced responses and response bursts [15,69,78,86,91,93-95]. In keeping with the 5-HT hypothesis of impulsivity, destruction of 5-HT neurons originating from dorsal and median raphe nuclei by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which dramatically decreases brain 5-HT levels, induced disruption of either acquisition or performance of a DRL 15-s schedule [124]. Conversely, an increased number of reinforcements and a decreased number of responses in DRL 72 s were observed following administration of 5-HT reuptake inhibitors [61,70,71,84,102,118] or 5-hydroxytryptophan (5-HTP), a 5-HT precursor, which increase both central and peripheral 5-HT neurotransmission [61,85]. Go-no go procedures consist of the successive presentation of go trials, during which the animal has to make a conditioned response in order to obtain a positive reinforcement, and no go trials, during which the animal has to
refrain from making this response for a minimum time, in order to be reinforced. In some studies, no go trials merely consist of an extinction period, during which the conditioned response is not reinforced [21,22]. Go and no go trials can be signalled by stimuli (go-no go discrimination task [116]) or can alternate (go-no go alternation task [36]). BZP have been shown to disrupt ability to refrain from responding during no go trials [21,23,43,116]. However, in one study [36] with chlordiazepoxide this effect was not observed. In a schedule fairly similar to the go-no go procedures, rewards were delivered to rats when a lever press was emitted only during periods signalled by a light, while such periods were delayed when a press was emitted during the light-off period [31]. This task was disrupted by moderate doses of chlordiazepoxide, which increased the number of presses during light-off periods, an effect interpreted by the authors as disinhibition [31 ], but which could also indicate impulsive behaviour.
3. Animal models of cognition: effects of BZP and treatments which alter 5-HT neurotransmission Many animal models of cognition have been proposed and most of them are devoted to the study of learning and memory. Impulsivity could be a critical factor in a number of these models, particularly where the timing of a response is essential for success, in situations where animals are required to inhibit their behaviour or, conversely, in situations where they have to act rapidly. We will review such situations and examine the effects of drugs acting on impulsivity such as BZP and other drugs that reduce or increase 5-HT neurotransmission. 3.1. Extinction schedules
In extinction schedules, animals previously trained to emit conditioned responses are no longer reinforced [7,8,109]. Resistance to extinction is thought due to a learning impairment. However, inability to refrain from responding during extinction could also be explained by increased impulsivity. Certain pharmacological results are in support of such an hypothesis since resistance to extinction of operant responding has been demonstrated in rats [103,109] and pigs [24] treated with BZP or in rats subjected to 5-HT depletion with p-CPA [7]. Conversely, the 5-HT agonist, quipazine, but not the 5-HT uptake blocker fluoxetine, accelerated extinction [8]. 3.2. Reaction time schedules
Reaction time paradigms are not strictly cognitive tests. Nevertheless, they have been considered important in studies on information processing (see [63]) and drugs that alter attentional processes modify reaction time (see below). In reaction time schedules, the animal has a limited
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time to respond after presentation of a conditioned stimulus in order to obtain a positive reinforcement [26,38,39,60] or to avoid punishment [63,64]. Such schedules are sensitive to both stimulant and sedative drugs. For instance, amphetamine reduced reaction time in rats trained to release a lever to avoid a foot-shock [64]. d-Methamphetamine decreased auditory reaction time (and less consistently visual reaction time) in baboons trained to release a lever to obtain food pellets [39]. Conversely, two drugs that reduce attention processes, pentobarbital [38], and ethanol [63], increased reaction time in baboons and rats, respectively. A drug that increases impulsivity could make the animal less able to wait for the conditioned stimulus and could, therefore, increase the number of responses in anticipation of the conditioned stimulus. On the basis of signal detection theory, a number of authors have considered these responses to be false alarms [26,39,60,90]. Further, increases in impulsivity could also increase the number of responses emitted during presentation of the conditioned stimulus, but before the animal has detected it. When these responses are taken into account, calculation of the reaction time may be artificially decreased. Since false alarms do not appear to be enhanced by dmethamphetamine, the reported reduction in reaction time induced by this compound [39] cannot be explained by an increase of impulsivity. Some drugs considered to increase impulsivity, such as BZP, can increase the number of false alarms. This may be the case for chlordiazepoxide (but not midazolam) in rats subjected to a simple reaction time paradigm requiring the animal to respond to a rarely occurring and unpredictable brief visual stimulus in order to obtain food pellets [26]. The rate of false alarms was also reported to be slightly, although not significantly, increased by diazepam and triazolam in baboons subjected to auditory and visual reaction time tasks [60]. However, this effect was not associated with a decrease, but rather an increase in reaction time [26,60]. Therefore, our hypothesis that false alarms are an index of impulsivity and is a confounding factor in simple reaction time schedules remains to be proved. However, it cannot be excluded that a pro-impulsive effect of BZP, resulting in an increased number of false alarms and a decreased reaction time, would be masked by their sedative effects.
3.2.1. Five-choice serial reaction time schedule The five-choice serial reaction time task is designed to measure selective attention [46]. In this schedule, rats are trained to detect and respond, within a limited time, to brief flashes of light presented randomly in one of five locations [16,18,19,46]. Premature responses, i.e. responses emitted during intertrial intervals, have been considered by some authors to be an index of impulsivity [18,19]. As hypothesized above for the simple reaction time schedule, some premature responses could be emitted during presentation of the stimuli, but before they have been detected by the animal. In this case, they are not recorded as
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premature responses, but statistically, 80% of them would be incorrect and 20% would be correct, regardless of the overall performance level. In other words, they would decrease accuracy (i.e. the number of correct responses divided by the total number of responses during the stimulus presentation). The mean response time would, therefore, be decreased to a greater extent for incorrect responses than for correct responses, d-Fenfluramine, which releases 5-HT from nerve endings and blocks 5-HT uptake, but not a sedative drug such as haloperidol, decreased premature responses in the five-choice reaction time task [16]. p-Chloroamphetamine (p-PCA), which depletes 5-HT neurons, increased these responses [104]. These data are consistent with the proposal that premature responses can be considered as an index of impulsivity. However, p-CPA, also thought to increase impulsivity, reduced the number of premature responses [46]. One possible explanation of this discrepant result is that an increase in premature responses may occur independently of increased impulsivity. For instance, amphetamine has been shown to increase premature responses in a five-choice serial reaction time task at doses which did not disrupt accuracy [18,19]. Response time was decreased but for correct responses only in one study [19] and for both correct and incorrect responses in the other [18]. Conversely, scopolamine, an antagonist of muscarinic receptors, thought to disrupt cognitive processes [44] decreased premature responses [46]. Since there is no evidence, to our knowledge, that amphetamine or scopolamine may alter impulsivity, we can hypothesize that paradoxically, vigilance and premature responses covary; both are increased by amphetamine and decreased by scopolamine.
3.3. Delayed matching and delayed non-matching schedules Delayed matching or delayed non-matching schedules are designed to measure short-term memory. In the schedules frequently used in monkeys [10,41,101] or pigeons [89], a sample stimulus (a light of a given color, or a geometric symbol) is presented to the animal. A first response (sample response), allows the animal to terminate sample presentation and to initiate a delay at the end of which two stimuli are presented, one of which is identical to the sample stimulus. The animal is reinforced if it makes a response (choice response) corresponding to the matching stimulus in delayed matching to sample (DMTS) schedules or to the non-matching stimulus in delayed non-matching to sample (DNMTS) schedules. The delayed matching to position tasks (DMTP) [20] and delayed nonmatching to position tasks (DNMTP) [47], frequently used in rats, are very similar to DMTS and DNMTS. They involve two retractable levers of an operant chamber, to provide a position sample to which the animal must respond for subsequent matching to the position response. A
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variable delay can be inserted between presentation of the sample and choice stimuli. This delay can be used to distinguish alterations in attentional processes (alteration of performance regardless of the delay) from alterations in short-term memory (delay-dependent alteration of performance). In such schedules, Reading and Dunnett [83] suggested that disinhibition could mimic a mnemonic deficit. Increased impulsivity could possibly interfere with response accuracy, due to a reduction in the latency to emit the choice response. A disruption of the ability to wait can also result in a reduction in the latency to emit the sample response which terminates sample presentation, thereby reducing the duration during which the sample can be memorized. Premature responses, when they are possible (as in most of the DMTS and DNMTS schedules in pigeons and primates), could also be considered to be an index of impulsivity. In DMTP and DNMTP tasks, levers are retracted during the delay, but other responses such as nose pokes into the food tray, could nevertheless reflect the animal's impulsivity. Some results clearly support the hypothesis of impulsivity as an important confounding factor in delay tasks. In a titrating matching to sample schedule in pigeons (a DMTS in which the length of the delay changes as a function of the animal's performance), Wenger et al. [123] showed that diazepam disrupted matching performances and noted a decrease (although not statistically significant) in the mean latency of the sample response for all of the five animals treated with diazepam (1 mg/kg). In a delayed pair comparison task in pigeons (a task similar to DMTS), chlordiazepoxide increased the number of responses during the delay which disrupted performance. However, a decreased choice latency and an increase in activity during the delay does not necessarily imply a disruption of performance, as indicated by the results reported with ZK 95962 (a partial agonist of BZP receptors) in a DMTP task in rats. On the other hand, alterations of performance in delayed matching schedules frequently reported with drugs claimed to affect impulsivity (i.e. BZP and p-CPA) are associated with a reduction, rather than an increase, in premature responses [20] and lengthening of response times [10,20,41,47,89,101]. This suggests that sedation a n d / o r non-specific motor effects, rather than impulsivity are involved in the observed deterioration of behaviour. The fact that the BZP receptor partial agonist, ZK 95962, and the complete BZP agonist, lorazepam, respectively decrease and increase the choice latency in DMTP tasks [20] supports this hypothesis, since partial BZP agonists are less sedative than complete BZP agonists [34]. 3.4. A v o i d a n c e schedules
Avoidance tests have been used extensively to study the effects of drugs or brain lesions on learning and memory.
They can be schematically divided into two types: passive and active avoidance. In passive avoidance tests, the animal (usually a rat or a mouse) is trained during a learning session to stay in one place, i.e. a lit compartment or platform, in order to avoid a punishment, generally an electric foot-shock, delivered in another place (a dark compartment connected with the lit one, or a grid floor below the platform). In the one-trial passive avoidance procedure, the animal is removed from the apparatus after having received the punishment. In other passive avoidance procedures, the trial is repeated several times, or shocks delivered repeatedly until the animal returns to the safe place (multiple-trial passive avoidance). Latency to move from the safe place to the punished place is assessed during a test-session performed after an interval of several hours or days. Amnesic or promnesic drugs decrease and increase this latency, respectively. In active avoidance procedures, animals are trained to go from one place to another (to change compartment in most procedures) to avoid a punishment, generally an electric foot-shock. In one-way active avoidance procedures, the animal is placed in the 'punished' place and, after a fixed delay, the punishment is delivered until the animal moves to the 'safe' place. Punishment is not delivered when an avoidance response is emitted, i.e. when the animal runs from the punished to the safe place during the delay. The trial is repeated several times or until the number of avoidance responses reaches a fixed criterion level. In the two-way active avoidance procedure, performed in a shuttle-box, a punishment is delivered after presentation of a conditioned stimulus (a light or sound or both) when the animal fails to escape from one compartment to the other during this presentation. Crossing from one compartment to the other during punishment interrupts this punishment. Since impulsive subjects are liable to make rapid decision and to respond quickly without thinking [27], we can hypothesize that in passive avoidance, an increase in impulsivity would make the animal less able to remain passively in one place. Such impairment in the animal's ability to inhibit an active response would be unfavourable for passive avoidance acquisition. Inversely, a decrease in impulsivity would be favourable to acquisition or restitution of a passive response. In active avoidance procedures, impulsive behaviour would promote active motor responses, and would, therefore, be helpful to learn or restore an active avoidance response. Conversely, a decrease in impulsivity would be unfavourable for learning and response restoration. When BZP are administered before the learning session in passive avoidance tasks, they always exert an amnesic effect: the latency to return into the punished place during the test session is decreased [4,13,14,48,49,67,68,79,80,112,113,119,121,122]. An amnesic effect of BZP administered before the test session has been reported by some authors [ 121 ], but not by others [14,68,79]. Conversely, when administered at moderate doses, BZP exert beneficial effects on active avoidance
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acquisition or restitution [72,88,96-99]. Therefore, an increase of impulsivity by BZP could partially explain why these compounds act in an opposite way on passive avoidance acquisition and on active avoidance acquisition. Effects of treatments that reduce 5-HT transmission on passive avoidance acquisition are more equivocal. PCA disrupted passive avoidance acquisition in male rats, but not in females [35]. In some studies, p-CPA did not modify passive avoidance acquisition when administered alone [28,87] but aggravated mecamylamine-induced amnesia [87], and in others, p-CPA improved passive avoidance learning [11,82]. There are also discrepancies between results on the effects of 5-HT neurotransmission decrements on active avoidance acquisition. 5-HT depletion induced by p - C P A facilitated active avoidance acquisition in some studies [11,108,117], but not in others [29,53]. Depletion of 5-HT neurons with PCA could produce either an improvement [120] or a disruption [73] of active avoidance acquisition. Electrolytic lesions of raphe nuclei facilitated 2-way active avoidance acquisition [53,57,58] but disrupted 1-way active avoidance acquisition [40,53,59,107], and raphe lesions with 5,7-DHT had no effect on 1-way avoidance learning [59]. Therefore, 5-HT depletions induce different effects such as increase of activity level [53,107], increase of pain sensitivity [108] or increase of reactivity to novel environnment [107] that could influence performance in avoidance tasks. For instance, a large number of factors such as the extent or the localisation of the 5-HT depletion, the shock intensity, the strains or the sex of the animals or their housing conditions can influence avoidance performance [53,59,87,100,117]. Therefore, the hypothesis that an increase of impulsivity by 5-HT neurotransmission decrement could be partly responsible for alterations in acquisition of avoidance schedules seems plausible, but further experiments are required for this to be confirmed. Treatments that increase 5-HT neurotransmission such as 5-HT inhibitors or 5-HT agonists [2,3] administered before the retention test have memory enhancing effects in passive avoidance tasks. Furthermore, 5-HT uptake inhibitors or 5-HT releasing agents administered before the learning session antagonised the amnesic-like effect induced by bulbectomy [12,50] or by scopolamine [66]. A promnesic effect of 5-HT mimetics could be at least partly due to an improvement of the processes involved in memory consolidation, as observed when drugs were administered after the acquisition session [30,42]. Conversely, disruption of active avoidance acquisition were found following injections of 5-HT uptake inhibitors in some studies [5,50,65], but not in others [74,75], and following administration of 5-HT releasing agents [65,74-77] or 5-HTP [51]. Therefore, drugs that increase 5-HT neurotransmission have clearly opposite effects upon passive avoidance (a memory-enhancing effect) and active avoidance (a memory-disrupting effect). A decrease of impulsivity could partly account for such effects.
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4. Conclusion For those cognitive tasks which require the inhibition of behaviour or which require the processing of a large amount of information before responding, a decrease in impulsivity can be beneficial by improving the animal's ability to wait or to take the time necessary to collect relevant information. Conversely, in situations which require the processing of little information and the responses necessary are simple but must be rapid, increases or decreases in impulsivity could improve or disrupt performance, respectively. Drugs that modify 5-HT neurotransmission have predictable effects upon the performance of some cognitive tasks which depend upon the nature of the responses required. It is suggested the effects of these drugs in these circumstances are mediated through changes in impulsivity. Perhaps the clearest evidence in favour of this hypothesis can be found when considering the differential effects of modulators of 5-HT neurotransmission upon the performance of passive and active avoidance tasks. There are many other cognitive tasks where the response(s) required may be sensitive to changes in impulsivity. The potential confounding influence of this factor for the interpretation of data from such tasks cannot be ignored.
Acknowledgements We are grateful to T. Steckler for his comments on the manuscript. Particular thanks are due to G.D. D'Mello for his invaluable comments, suggestions and criticisms on the manuscipt and for his assistance with the translation into English.
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