Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist.

The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine (HT)(1B) antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5-HT(1B) antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT(1B) agonist 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807). Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced vocalization paradigm in guinea pig pups, and in a suppressed responding procedure in pigeons and guinea pigs, but only a weak trend was noted in a suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was shown in a number of paradigms. In pigeons and guinea pigs responding under a differential reinforcement of low rates schedule of reinforcement (DRL), AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was shown to block escape failures in guinea pigs submitted to a learned helplessness paradigm. Taken together, these data suggest utility for 5-HT(1B) antagonists in the treatment of both anxiety and affective disorders.

The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist.

The pharmacological properties of the 5-hydroxytryptamine (HT)(1A) receptor agonist (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide (NAE-086) were examined with in vitro and in vivo techniques. Receptor binding studies demonstrated that NAE-086 was a high-affinity and selective 5-HT(1A) receptor ligand with a K(i) value of 4.5 nM in membranes from rat hippocampus. Of 32 other receptors examined NAE-086 had a modest affinity only for the 5-HT(7) receptor (K(i) = 240 nM). NAE-086 inhibited VIP-stimulated adenylyl cyclase activity in GH(4)ZD10 cells with 79% of the efficacy of 5-HT. This inhibition was blocked by the 5-HT(1A) receptor (and beta-adrenoceptor) antagonist (-)alprenolol. A minor metabolite of NAE-086 in rats, (R)-3,4-dihydro-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide had a similar receptor profile but had 17 times higher affinity for the 5-HT(1A) receptor (K(i) = 0.26 nM). In vivo, NAE-086 induced all the typical effects of a 5-HT(1A) receptor agonist in rats: it decreased 5-HT synthesis (5-HTP accumulation) and 5-HT turnover (measured as the ratio of 5-hydroxyindoleacetic acid/5-HT), increased corticosterone secretion, induced the 5-HT(1A) syndrome (flat body posture and forepaw treading), inhibited the cage-leaving response, and caused hypothermia. All the responses mediated by postsynaptic 5-HT(1A) receptors were attenuated after single or repeated treatment of the rats with NAE-086. Simultaneously with the development of the tolerance to 5-HT(1A) receptor-mediated responses, 5-HT(2A) receptor-mediated responses were enhanced, as judged from the increased number of spontaneous and/or agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced wet-dog shake responses. The significance of this behavioral effect in relation to clinical observations is discussed.

Varieties of impulsivity.

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 VII: the effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli.

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-HT(1A) agonist), RU24969 (primarily a 5-HT(1B) receptor agonist), DOI, (5-HT(2) agonist), WAY-100,635 (5-HT(1A) antagonist), ritanserin (5-HT(2) antagonist), and MDL-72222, (5-HT(3) 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-HT(1A) and 5-HT(2) 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 VI: the effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement.

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-HT(2) agonist, DOI, at a dose of 1.0 mg/kg. In contrast, the 5-HT(1A) 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-HT(1A): 0.01-0.1 mg/kg), ritanserin (5-HT(2): 0.1 and 0.3 mg/kg) and MDL-72222 (5-HT(3): 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-HT(1A), 5-HT(2) or 5-HT(3) receptors using selective antagonists does not affect self-control.

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 behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced fixed consecutive number schedule of reinforcement.

Spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) were trained under paced FCN schedules of reinforcement to complete a minimum number of consecutive responses on one lever, before responding on a second. The levers were retracted from the test chamber for a short period after each response to control the speed at which the rats could complete the sequence (paced FCN). Changes in the average chain length may reflect the influence of impulsivity on the execution of behavioral patterns. Although they quickly learned to press the levers, SHR rats performed poorly compared to the WKY rats when the chain length requirement was increased to FCN 6 and FCN 8. Eventually stable performance was obtained under paced FCN 6, although the SHR rats continued to have a consistently lower average chain length. Both strains of rats were treated with imipramine (10 mg/kg), chlordiazepoxide (3 and 10 mg/kg), d-amphetamine (0.4 and 0.8 mg/kg), haloperidol (0.05 and 0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), WAY-100635 (0.1 mg/kg), and DOI (0.3 and 1.0 mg/kg). The SHR rats were less sensitive to the effects of d-amphetamine, chlordiazepoxide, and DOI and slightly more sensitive to the effects of haloperidol. All of these drugs reduced the average chain length. There was no difference in the response of the two strains to imipramine and 8-OH-DPAT, both of which increased the average chain length. These results support the suggestion that SHR rats may more impulsive than WKY rats. The data with d-amphetamine and haloperidol support biochemical findings that these rats have a deficit in dopaminergic function, and the strain differences in response to chlordiazepoxide and DOI suggest that that there may be differences in GABAergic and 5-HT2-mediated neurotransmission relevant to regulating impulse control in the rat.

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

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 (1-10mg/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 discriminative stimulus effects of clomethiazole in the rat.

Rats were trained in a two-lever drug discrimination procedure using saline or clomethiazole (8 mg/kg, s.c. 15 min) as the training stimuli. A criterion of 9/10 days correct lever choice was adopted to select rats for substitution tests. The clomethiazole (CMZ) cue was not especially strong, and stable performance at this level was not achieved consistently. Nevertheless, in a series of substitution tests carried out in extinction, diazepam (3 mg/kg), chlordiazepoxide (10 mg/kg), phenobarbital (60 mg/kg), dizocilpine (0.1 mg/kg) and mianserin (3.0 mg/kg) were found to substitute for the training dose of CMZ. The first two of these produced a percentage choice of the drug lever equal to that produced by the training dose of CMZ (full generalization) whereas the latter three produced only partial generalization. Ethanol, muscimol, allopregnanolone, chlorpromazine and amitriptyline did not generalize to CMZ. CMZ is known to potentiate gamma-aminobutyric acid (GABAA) receptor function, a finding supported by the generalization to CMZ of the two benzodiazepines and phenobarbital. However, not all drugs acting at GABAA receptors generalized to CMZ. Although CMZ has no affinity for the N-methyl-D-aspartate (NMDA) receptor, it antagonizes a number of pharmacological responses mediated by NMDA receptors. The generalization in the drug discrimination procedure reported here support the suggestion that altering GABA activity can modulate NMDA-mediated responses. The lack of generalization after treatment with ethanol, chlorpromazine and amitriptyline suggests that the interoceptive cues are not mediated by a generalized sedation or drug-induced motor impairment.

The pharmacology of impulsive behaviour in rats III: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and ethanol on a paced fixed consecutive number schedule.

The behavioural trait of impulsivity may be made up of different components, including rapid decision making, intolerance to 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 could control the maximum rate of responding. The procedure was made up of two components based on an FCN 8 schedule of food reinforcement. In the Fast component, lever presses were spaced by a minimum of 2 s and in the Slow component by a minimum of 5 s. The average chain length was significantly shorter, and the rats were less efficient in the Slow component. Five drugs were tested on this baseline, imipramine (1.0-10.0 mg/kg), ethanol (300-3000 mg/kg administered PO), haloperidol (0.01-0.1 mg/kg), chlordiazepoxide ( 1.0-10.0 mg/kg) and d-amphetamine (0.2-0.8 mg/kg). All the drugs reduced responding at the highest dose, but imipramine was different from the others in that it increased the average number of responses in the chain and produced a shift in the chain length distribution to the right, possibly reflecting a reduction in impulsivity. The other four drugs reduced chain length at the highest dose, although in the case of ethanol this effect was very small and, unlike the other three drugs, did not result in a shift in the distribution to the left. The paced FCN procedure can differentiate the effects of different drugs on one aspect of impulsivity, and is likely to be a useful procedure for further study of this aspect of behaviour.

The pharmacology of impulsive behaviour in rats II: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and other drugs on fixed consecutive number schedules (FCN 8 and FCN 32).

The effects of drugs on one aspect of impulsive behaviour were evaluated using a schedule in which rats were trained to complete a fixed consecutive number of responses on one of two levers before pressing the second to obtain a reinforcer (FCN). Terminating the chain before completing the FCN resulted in the omission of the food, and can be considered an impulsive decision. Two groups of food-deprived rats were trained to press either 8 or 32 times on the left lever (FCN lever) of a two lever operant chamber before pressing the right lever (Reinforcement lever) to deliver a food pellet. Responding on the Reinforcement lever before completion of the sequence resulted in a short time-out and the rat had to begin the sequence again. After responding had stabilised, the rats were treated with a range of doses of a number of drugs. Impulsivity was assessed by several measures, including the mean chain length and the proportion of chains terminating in food delivery, and the distribution of chain lengths was analysed. The efficiency of the rats was similar under both FCN 8 and FCN 32, although it was more difficult to maintain a consistent baseline under FCN 32. Under the FCN 8 schedule, significant decreases in chain length were obtained with d-amphetamine (0.8-2.4 mg/kg), haloperidol (0.1 mg/kg), ethanol (1 and 3 g/kg) and chlordiazepoxide (10.0 mg/kg), and there were alterations in other measures consistent with an increase in impulsivity. Imipramine (1-10 mg/kg), citalopram (1-10 mg/kg) and metergoline (0.3-3.0 mg/kg) had no effect on mean chain length, although the first two drugs shifted the chain length distribution to the left. d-Amphetamine (0.4-1.2 mg/kg) and PCPA (100 mg/kg) reduced chain length and had other effects consistent with increased impulsivity under FCN 32 schedule, whereas imipramine had little, and citalopram no, effect. Taken generally, effect of the active drugs was relatively non-specific, including both a reduction in response rate and alterations in choice measures proposed to reflect an increase in impulsivity. Detailed analysis of the effect of amphetamine revealed that three processes were at work: chain shortening, an increased preference for the lever most closely associated with food delivery, and a gradual shift in the control over responding from the response sequence (pattern) to the individual lever press (act).

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

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.

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

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.

The effects of repeated treatment with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on the lever press responding of the rat under FI and DRL schedules of food reinforcement.

In general, the effects of 8-OH-DPAT on the body temperature of rats or in inducing the 5-HT syndrome show rapid tolerance. However, in contrast, the 8-OH-DPAT-induced increase in the activity of rats in a two-way active avoidance task only occurs after repeated administration, i.e. there is sensitisation. The present study was conducted to examine whether this developing hyperactivity may also be expressed as increased rates of lever press responding, and if so, under which conditions it occurs. Rats were trained to press levers under fixed interval 60-s (FI 60) or differential reinforcement of low rates 20-s or 72-s (DRL20, DRL72) schedules of food reinforcement. Groups of trained rats were then treated daily 5 min before testing with doses of 0.01, 0.1 and 1.0 mg/kg 8-OH-DPAT SC for 10-21 days. In all three procedures, in the first couple of days of drug treatment, 8-OH-DPAT generally suppressed lever pressing in a dose-dependent manner. Thereafter, tolerance to this effect was seen to a greater (DRL20, DRL72) or lesser (FI60) extent. Some evidence for stimulation of low rates of lever press responding was seen after 10 days treatment under FI60, but not in DRL20 or DRL72 during short 30 to 60 min long daytime tests although in the latter case, the rats responded to the stimulating effects of 0.8 mg/kg SC amphetamine administered once at the end of the experiment. However, when rats were allowed to respond under DRL72 testing for 12 h during the night, after 10 days treatment a clear stimulation of lever pressing was observed. This stimulation was not specific to lever pressing, however, since a stimulation of entries into the food tray and licking were also seen. From these results, it may be concluded that the stimulating effect of 8-OH-DPAT after repeated administration may be expressed as increased rates of lever pressing, but not under all conditions in which psychomotor stimulation by amphetamine is seen. The potential for 8-OH-DPAT and related compounds to stimulate motor responding in this way should be taken into account when interpreting the effects of these drugs in animal models of psychiatric disorders.

The effect of 5-HT1A receptor agonists on locomotor activity in the guinea-pig.

1. The present study examined the effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5-HT1A receptor, on the locomotor activity of guinea-pigs. The effects of these drugs were contrasted with those of the non-selective 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine (5-MeO-DMT) and the dopamine D2 antagonist, raclopride. 2. 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity. 3. The locomotor activity increasing effect of 1.0 mg kg-1 8-OH-DPAT was blocked by the selective 5-HT1A antagonist (S)-UH-301 (3.0 and 10.0 mg kg-1), but not by (-)-alprenolol (15.0 mg kg-1). Ipsapirone (30.0 mg kg-1) and raclopride (3.0 mg kg-1) antagonized 8-OH-DPAT-induced locomotor activity but only to a small extent. The 5-HT reuptake inhibitor, zimelidine (10.0 mg kg-1) had no effect. 4. The effect of the 5-HT1A agonists in the guinea-pig contrasts with the effects of 8-OH-DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8-OH-DPAT on habituated rats, which show a low baseline of activity. 5. These results support the suggestion that 5-HTIA agonists may have an intrinsic activating effect which may be masked by other effects of the drug (e.g. hypothermia, 5-HT syndrome). The rank ordering of the 5-HTIA agonists also suggests that the degree to which the drugs increase locomotor activity is related to their agonist efficacy at the postsynaptic 5-HTIA receptor.

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.

Effects of buspirone and ipsapirone on schedule induced polydipsia: comparison with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and raclopride.

In the present experiments, the effects of the azapirone anxiolytics, buspirone and ipsapirone, on excessive drinking induced by a FT-60 schedule of food delivery (schedule induced polydipsia, SIP) were investigated. Because buspirone is known to block dopamine receptors and both buspirone and ipsapirone act as agonists at the 5-HT1A receptor, their effects on polydipsia were compared to raclopride, an antagonist at D2 receptors, and 8-OH-DPAT, an agonist at the 5-HT1A receptor, thus providing information about the relative importance of the serotonergic and/or dopaminergic systems for the maintenance of polydipsia. The effects of all four drugs were investigated both acutely, and following repeated treatment. The doses employed were as follows: buspirone, 1.0, 3.0, and 10.0 mg/kg; raclopride, 0.05, 0.15, and 0.5 mg/kg; 8-OH-DPAT, 0.1, and 1.0 mg/kg and ipsapirone, 1.0, 3.0, 10.0 mg/kg. Administered acutely, the lowest doses of buspirone and raclopride did not alter drinking, whilst the low dose of 8-OH-DPAT significantly reduced polydipsia. These effects were reversed following repeated treatment over 16 successive days. Buspirone 1.0 mg/kg and 0.05 mg/kg raclopride reduced drinking, whilst tolerance developed to the effects of 0.1 mg/kg 8-OH-DPAT. Ipsapirone, at low doses, was without effect on drinking. At high doses, all four drugs reduced drinking both acutely and chronically. Repeated treatment with buspirone (3.0, and 10.0 mg/kg) reduced licking and panel entries, but induced a selective decrease in licking at the low dose (1.0 mg/kg). Similar effects were seen following raclopride treatment, although the effects were less selective. 8-OH-DPAT and ipsapirone, in contrast reduced licking only at the highest dose, and both drugs increased panel entries as testing continued. The effects of buspirone resembled those of raclopride whereas the effects of ipsapirone resembled those of 8-OH-DPAT. Buspirone appears to act as a dopamine antagonist in this test. The effects of the drugs suggest that SIP depends upon motivational and performance factors which may be more sensitive to drug manipulation than potential underlying psychological factors such as anxiety or stress.

Effects of repeated treatment with 5-HT1A agonists on active avoidance responding in the rat.

The behavioural effects of the serotonin 1A receptor (5-HT1A) agonist anxiolytics are generally examined after acute administration. The present study examined the effects of these substances during repeated treatment in the two-way active avoidance (Conditioned Avoidance Response, CAR) procedure. Previously it has been found that the prototypical 5-HT1A receptor agonist, 8-OH-DPAT, increases avoidance, apparently by increasing general activity, after repeated administration but not on acute administration. In the present study, it was demonstrated that this increase in activity can be blocked by the 5-HT1A receptor antagonists (-)alprenolol (also beta adrenergic antagonist) and (S)-UH-301, but not by the non-selective 5-HT antagonist metergoline. The relatively full 5-HT1A agonist, flesinoxan, and the partial 5-HT1A agonist, ipsapirone, had qualitatively similar effects to 8-OH-DPAT, although the effect of ipsapirone was clearly smaller in magnitude. Buspirone, the 5-HT1A partial agonist/dopamine D2 antagonist, markedly decreased activity, and thus avoidance of the shocks, in a manner similar to the antipsychotic drug, haloperidol. However, when the hypothermic effects of these compounds were investigated after acute administration, buspirone induced a strong hypothermic response in rats, like 8-OH-DPAT, whereas haloperidol had no effect. With the exception of buspirone, the effectiveness of these compounds in increasing activity in the CAR test appears to be related to their agonist efficacy at the 5-HT1A receptor. Similarities between the effects of these compounds and previously reported results with serotonin-depleting agents (Tenen 1967; Breese et al. 1974) suggest that the net effect of 5-HT1A agonists after repeated administration is to produce a functional reduction in 5-HT activity. The activity suppressing action of buspirone indicates that the dopamine antagonist activity of buspirone predominates in this procedure.

Caffeine and nicotine improve visual tracking by rats: a comparison with amphetamine, cocaine and apomorphine.

Psychomotor stimulant drugs such as caffeine, nicotine, amphetamine and cocaine, have been shown to improve vigilance in man under conditions of fatigue. Nicotine has also been shown to improve performance in some cognitive tests in patients with Alzheimer's disease. In rodents these drugs increase activity which may confound "performance enhancing effects" in rodent models. However, improvements have been found in a number of tests that do not seem to be directly dependent upon an enhancement of locomotor activation. In one example, Evenden and Robbins (1985) reported consistent improvements in a visual tracking test following amphetamine. The present study was undertaken to determine whether these performance enhancing effects of amphetamine could also be obtained with cocaine and apomorphine, which both have psychomotor stimulant effects through their actions as, respectively, indirect and direct dopamine agonists, and by caffeine and nicotine, which do not have a direct dopaminergic mechanism of action. The results of the study indicate that all five drugs improved tracking performance at one or more doses. The most consistent effects were obtained with amphetamine which, like cocaine and nicotine, improved tracking at a dose which did not produce other changes in behaviour. Taking into account previous studies (Evenden and Robbins 1983, 1985), these results were interpreted as indicating that psychomotor stimulant drugs produce a general activation of behaviour. At all but the highest doses of such drugs, the form of behaviour that is observed depends upon the environment.(ABSTRACT TRUNCATED AT 250 WORDS)