John Evenden

Varieties of impulsivity

Abstract The concept of impulsivity covers a wide range of ”actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes”. As such it plays an important role in normal behaviour, as well as, in a pathological form, in many kinds of mental illness such as mania, personality disorders, substance abuse disorders and attention deficit/hyperactivity disorder. Although evidence from psychological studies of human personality suggests that impulsivity may be made up of several independent factors, this has not made a major impact on biological studies of impulsivity. This may be because there is little unanimity as to which these factors are. The present review summarises evidence for varieties of impulsivity from several different areas of research: human psychology, psychiatry and animal behaviour. Recently, a series of psychopharmacological studies has been carried out by the present author and colleagues using methods proposed to measure selectively different aspects of impulsivity. The results of these studies suggest that several neurochemical mechanisms can influence impulsivity, and that impulsive behaviour has no unique neurobiological basis. Consideration of impulsivity as the result of several different, independent factors which interact to modulate behaviour may provide better insight into the pathology than current hypotheses based on serotonergic underactivity.

The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement

Abstract Impulsive behaviour is an important component of many psychiatric syndromes. It is often expressed as aggressive or violent behaviour, but may also be non-violent. One important factor which might lead to aggression or violence is an inability to tolerate a delay of gratification, leading to frustration and aggressive outbursts. In animals and in man, tolerance to delay of gratification can be studied using delay of reinforcement (also known as self-control) procedures. Experiments with delay of reinforcement in rats show that serotonergic mechanisms may be involved in this form of impulsive behaviour, which seems to support clinical findings in this area. The present experiment examined the effects of a series of psychoactive drugs on delays of reinforcement using a steady state operant procedure involving lever-pressing by rats. Rats were trained to choose between one food pellet delivered immediately and three or five pellets delivered after varying delays which increased during the course of the session. Using this procedure the rats remained sensitive to within- and between-session variations in delay of reinforcement even after long periods of testing. It was used to demonstrate an increase in impulsivity (after d-amphetamine) and a reduction in impulsivity (after diazepam and metergoline), indicated by shifts in the choice/delay function. The other drugs tested, imipramine, citalopram, haloperidol and carbamazepine, had no consistent effects although tested at doses which are active in other procedures. This method has proved to be a useful way of examining the effects of drugs on choice of delay of reinforcement in the rat. Although the behavioural basis of tolerance to delay of reinforcement (self-control) has received considerable attention, little is yet known about the biological basis. The present data indicate that the procedure described here can be used to elucidate the pharmacological basis of this aspect of impulsive behaviour.

Impulsivity: a discussion of clinical and experimental findings.

Impulsivity can often be an important clinical problem in psychiatry and neurology. In psychiatry, the manifestation of impulsive behaviour in syndromes such as personality disorders, attention deficit hyperactivity disorder and in substance abuse may be different, and this has led to conflicting definitions. There has also been a tendency to concentrate on the nature of the behavioural manifestation (problems with the law, aggression, drug use, behavioural problems in school) rather than shared psychological processes, and to ignore the fact that impulsivity can also have positive aspects. In a normal population, the personality trait of impulsivity has been analysed using personality inventory questionnaires. Analysis of these data lead to the suggestion that impulsivity as commonly defined and understood may be made up of several independent factors, which may have separate biological bases. These self-rating questionnaires have been complemented by objective tests that are now often computerized, and which have been used in man (e.g. with criminal offenders, children, or patients who have undergone brain surgery). Some of these tests, such as the differential reinforcement of low rates procedure or the delay of reinforcement procedure, have also been used to study impulsivity in animals. Analysis of the behavioural principles of these tests suggests that they too may reflect different aspects of impulsivity. Many different biological systems have been proposed to contribute to the neurobiological basis of impulsivity. The serotonergic neurotransmitter system has recently received the most attention, with evidence of its involvement coming from animal studies as well as from studies in psychiatric patients. The frontal lobes have been proposed to play an important role in regulating impulsivity, although it unclear how specific this is. None of this biological knowledge has yet led to reliable pharmacotherapy for excessive impulsivity and, as yet, there is little understanding of the mechanisms by which those drugs, which have been found empirically to have some efficacy (e.g. the psychomotor stimulants in attention deficit hyperactivity disorder), exert their therapeutic effect. By bringing together knowledge from different areas of research it is hoped that a cross fertilization will be achieved, which will lead to a sharpening of concepts, an improvement in methodology and the stimulation of biological studies.

The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement

Abstract Rationale: Tolerance to delay of reinforcement has been proposed as an important facet of self-control in both animals and man. Poor self-control, leading to impulsive behaviour, can be a major problem if it reaches pathological levels. Objectives: The effects of five serotonergic drugs were compared to those of ethanol on a procedure for measuring tolerance to delay of reinforcement in rats in order to elucidate further the role of the serotonin systems in the regulation of impulsive behaviour. Methods: Rats were trained to choose between a single food pellet (small reinforcer) delivered immediately or five food pellets (large reinforcer) delivered after programmed delays. At the start of each session, there was no delay between the response and delivery of the large reinforcer, but this was increased stepwise during the session to delays of 10, 20, 40 and 60 s. Results: The rats showed consistent preference for the larger reinforcer when it was not delayed but showed a shift in preference as the session continued, so that they preferred the small reinforcer when the large was delayed by 40 or 60 s. Ethanol at a dose of 1.0 g/kg produced a significance increase in preference for the small, immediate reinforcer throughout the session, although there were marked individual differences in the size of the effect. A similar, but somewhat smaller effect was seen with the 5-HT2 agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT1A agonist, 8-OH-DPAT (0.3 mg/kg) reduced preference for the large reinforcer at the start of the session, and reduced preference for the small reinforcer at the end of the session, i.e. produced a regression to indifference. Lower doses of these three drugs, and treatment with the 5-HT receptor subtype selective antagonists WAY-100635 (5-HT1A: 0.01–0.1 mg/kg), ritanserin (5-HT2: 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT3: 1.0 and 3.0 mg/kg) had no significant effects on reinforcer choice. Conclusion: These data show that ethanol and DOI increase preference for the immediate reinforcer, which can be construed as evidence of an increase in impulsive behaviour (reduction in self control), whereas selective blockade of the 5-HT1A, 5-HT2 or 5-HT3 receptors using selective antagonists does not affect self-control.

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on locomotor activity and rearing of mice and rats

The effects of 8-OH-DPAT on locomotor activity have not yet been clearly defined. Tricklebank et al. (1984) and Dourish et al. (1985) provide evidence that 8-OH-DPAT increases activity, whereas Mittman and Geyer (1989), Hillegaart et al. (1989) and Carli et al. (1989) suggest that it is reduced by the drug. In the present study, the effects of 8-OH-DPAT on locomotor activity and rearing were examined in habituated and unhabituated mice and rats. The effects of the drug were followed for up to 2 h in the mouse and up to 4 h in the rat. In unhabituated mice and rats, doses of 0.1 mg/kg or more of 8-OH-DPAT blocked activity during the period post-injection when control levels of activity were highest. However, after about 60 min in mice and 150 min in the rat a marked hyperactivity was observed, which was followed by a period of increased rearing. In habituated mice this biphasic effect on locomotor activity was also observed, but there was no increase in rearing. In habituated rats there was no decrease in locomotor activity, rather a biphasic increase was observed. The effects of 8-OH-DPAT on locomotor activity immediately post-injection are interpreted as being a result of the stereotyped, uncoordinated “ambulation” which forms a part of the 5-HT syndrome, and which results in a level of activity intermediate between that of unhabituated and habituated rats. The mechanism by which 8-OH-DPAT produces elevated locomotor activity and increased rearing seen 60 min or more post-injection is not yet known, but may be a result of brain concentrations of the drug falling to a low, but still effective level.

The pharmacology of impulsive behaviour in rats VII: the effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli

Abstract Rationale: The serotonergic systems have been implicated in the pathological impulsive behaviour on the basis of both clinical and preclinical data. However, impulsivity is probably made up of several independent factors, and the involvement of the diverse regulatory mechanisms of the serotonergic systems has not been widely studied. Objective: The influence of a range of serotonergic agents on impulsivity was examined using a procedure designed to test the dimension of impulsivity termed ”reflection-impulsivity” in rats. Methods: An operant procedure was used in which the need to wait before responding was made explicit by using a signal which increased in predictive value the longer the subject waited before responding. First, the rats learned that a light signal indicated the availability of a food reinforcer if one of two levers was pressed. In the test procedure, on each trial, when the light was turned on it was only 50% likely to indicate the ”correct” lever. After a brief interval it was turned off and on again, this time with a slightly higher probability (>50%) of indicating the correct lever. Over a period of a few seconds the probability that the light indicated the correct lever increased to almost 100%. Thus a quick response to the light would result in many errors, whereas a slow response could always result in food delivery. Once trained the rats were treated with a series of drugs: citalopram, (selective serotonin reuptake inhibitor), p-chloramphetamine (PCA, serotonin releaser), 8-OH-DPAT (5-HT1A agonist), RU24969 (primarily a 5-HT1B receptor agonist), DOI, (5-HT2 agonist), WAY-100,635 (5-HT1A antagonist), ritanserin (5-HT2 antagonist), and MDL-72222, (5-HT3 antagonist). Results: Of the test compounds, PCA, DOI and 8-OH-DPAT increased reaction times, whereas ritanserin reduced them. Citalopram and WAY-100,635 had no significant effects, RU-24969 appeared to disrupt responding, and MDL-72222 reduced premature responses and the number of short reaction times. Conclusions: Since agonists at the 5-HT1A and 5-HT2 receptors both reduced impulsivity in this procedure, these data suggest that serotonin may promote ”reflection” in this procedure via stimulation of these receptor subtypes.

The pharmacology of impulsive behaviour in rats V: the effects of drugs on responding under a discrimination task using unreliable visual stimuli

Abstract Impulsivity is widely considered to be multifactorial. One factor, frequently termed “reflection-impulsivity”, refers to the need to give time to information analysis and reflection before making a response. In most reaction time tasks employed for non-human subjects, responding is expected immediately after a specific stimulus has been presented. In the present experiment, the need to wait before responding was made explicit by using a signal which increased in predictive value the longer the subject (a rat) waited before responding. First, the rats learned that a light signal indicated the availability of a food reinforcer if one of two levers was pressed. In the test procedure, on each trial, when the light was turned on it was only 50% likely to indicate the “correct” lever. After a brief interval it was turned off and on again, this time with a slightly higher probability (>50%) of indicating the correct lever. Over a period of a few seconds the probability that the light indicated the correct lever increased to almost 100%. Thus a quick response to the light would result in many errors, whereas a slow response could always result in food delivery. Once trained the rats were treated with a series of drugs: haloperidol (0.01–0.1 mg/kg), chlordiazepoxide (1–10 mg/kg), ethanol (100–1000 mg/kg), d-amphetamine (0.4–1.2 mg/kg), metergoline (0.3–3.0 mg/kg), imipramine, desipramine and clomipramine (all 1, 3 and 10 mg/kg), as well as being given additional food just prior to testing. Ethanol and clomipramine had no effects on behaviour in the dose range tested. Amphetamine did not affect accuracy and had no effect on reaction time. The other drugs all reduced the number of short reaction times and thereby increased overall accuracy. Additional feeding, chlordiazepoxide and haloperidol also increased selectively the accuracy of responses made with short reaction times. These results can be interpreted by supposing that desipramine and imipramine specifically reduced impulsivity whereas additional feeding, chlordiazepoxide, haloperidol increased the response criterion. The pharmacological specificity of the tricyclics suggests that stimulation principally of the noradrenergic system (via desipramine), but not necessarily the serotonergic (clomipramine) or dopaminergic (amphetamine) improves performance in this procedure.

The pharmacology of impulsive behaviour in rats IV: the effects of selective serotonergic agents on a paced fixed consecutive number schedule

Abstract An impulsive cognitive style may affect behaviour in several different ways, including rapid decision making, intolerance of the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter can control the maximum rate of responding. The procedure was made up of two components. In both, the schedule requirement was FCN 8, but in the Fast component lever presses were spaced by a minimum of 2.5 s and in the Slow component by a minimum of 5 s. Alterations in impulsivity were inferred from changes in the mean chain length and the distribution of chain lengths. The 5-HT1A agonist, 8-OH-DPAT (0.03–0.3 mg/kg), increased chain lengths within a narrow dose range, whereas the 5-HT1A antagonist, WAY 100 635 (0.03–0.3 mg/kg), reduced chain lengths. The 5-HT2 agonist, DOI (0.1–1.0 mg/kg), markedly reduced chain lengths, whereas the 5-HT2 antagonist, ritanserin (0.03–0.3 mg/kg), had no effect. The 5-HT1A/1b agonist, RU 24969 (0.03–0.3 mg/kg), reduced chain lengths. The 5-HT releaser, p-chloramphetamine (0.1–1.0 mg/kg), had a weak, biphasic effect, slightly reducing the number of short chains at the lowest dose tested and slightly increasing this number at the highest dose. Other drugs tested, citalopram (1.0–10.0 mg/kg), metergoline (0.3–3.0 mg/kg) and MDL-72222 (0.1–3.0 mg/kg), had no significant effects. These results suggest that stimulation of 5-HT1A receptors reduces impulsivity, whereas stimulation of 5-HT2 receptors increases it. These data are in agreement with previous results using the DRL-72 schedule, and indicate that there is no simple role for serotonin in the control of impulsivity.

Preclinical findings with new antipsychotic agents: what makes them atypical?

Many early antipsychotics such as haloperidol, while effective in treating the symptoms of schizophrenia, cause detrimental side effects and moreover induce nonspecific sedation in many patients. Newer drugs such as remoxipride are as effective as the classical antipsychotics but induce fewer debilitating side effects. These clinical properties are reflected to some extent in their preclinical pharmacology, with drugs such as remoxipride having effects on various preclinical behavioural and biochemical models that are quite different to those exerted by drugs such as haloperidol. This article reports some new behavioural data and discusses the various mechanisms that can underlie the effect of new atypical antipsychotics.

The non-competitive NMDA receptor antagonist (+)MK-801 counteracts the long-lasting attenuation of the hypothermic response induced by acute doses of 8-OH-DPAT in the rat ☆

The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothermic response, induced by a challenge dose of 8-OH-DPAT, were examined in rats. Acute doses of 8-OH-DPAT (1.0 or 0.5 mg/kg, s.c.) significantly attenuated the hypothermic response induced by 8-OH-DPAT (0.05 mg/kg, s.c.). The response to 8-OH-DPAT was almost abolished between 4 hr and 4 days and the attenuation of the response lasted for 21 days. On day 28 the response had returned to the control level. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine [(+)MK-801], blocked this long-lasting attenuation of the 8-OH-DPAT-induced hypothermic response. Given on its own, (+)MK-801 did not reduce body temperature, at the doses used in the experiments but the drug did block the acute effects of 8-OH-DPAT, at the same doses which blocked the attenuation of the hypothermic response. The present data suggest that stimulation of glutamate NMDA receptors may underlie the long-lasting effect of acute injections of 8-OH-DPAT.