RESUMEN
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.
Asunto(s)
Benzopiranos/farmacología , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , 5-Hidroxitriptófano/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Benzopiranos/efectos adversos , Corticosterona/metabolismo , AMP Cíclico/metabolismo , Dihidroxifenilalanina/metabolismo , Dopamina/metabolismo , Interacciones Farmacológicas , Ácido Hidroxiindolacético/metabolismo , Hipotermia/inducido químicamente , Masculino , Erección Peniana/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Salivación/efectos de los fármacos , Serotonina/metabolismo , Tritio , Células Tumorales Cultivadas , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
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.
Asunto(s)
Conducta Impulsiva/diagnóstico , Animales , Humanos , Conducta Impulsiva/tratamiento farmacológico , Conducta Impulsiva/psicología , Determinación de la Personalidad , Escalas de Valoración Psiquiátrica , Serotoninérgicos/uso terapéuticoRESUMEN
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.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Conducta Impulsiva/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Estimulación Luminosa/métodos , RatasRESUMEN
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.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Conducta Impulsiva/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetaminas/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
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.
Asunto(s)
Conducta Impulsiva , Aprendizaje/efectos de los fármacos , Psicotrópicos/farmacología , Anfetamina/farmacología , Animales , Clordiazepóxido/farmacología , Etanol/farmacología , Haloperidol/farmacología , Imipramina/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Análisis y Desempeño de TareasRESUMEN
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).
Asunto(s)
Conducta Impulsiva , Aprendizaje/efectos de los fármacos , Psicotrópicos/farmacología , Anfetamina/farmacología , Animales , Clordiazepóxido/farmacología , Citalopram/farmacología , Etanol/farmacología , Haloperidol/farmacología , Imipramina/farmacología , Masculino , Metergolina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Conducta Impulsiva/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Citalopram/farmacología , Indoles/farmacología , Masculino , Metergolina/farmacología , Ratas , Refuerzo en Psicología , Ritanserina/farmacología , Tropanos/farmacología , p-Cloroanfetamina/farmacologíaRESUMEN
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.
Asunto(s)
Fármacos del Sistema Nervioso Central/uso terapéutico , Conducta Impulsiva/tratamiento farmacológico , Psicotrópicos/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Animales , Masculino , Metergolina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Factores de TiempoRESUMEN
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.
Asunto(s)
Actividad Motora/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Interacciones Farmacológicas , Cobayas , Masculino , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Zimeldina/farmacologíaRESUMEN
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)
Asunto(s)
Cafeína/farmacología , Nicotina/farmacología , Desempeño Psicomotor/efectos de los fármacos , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Cocaína/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Buspirona/farmacología , Condicionamiento Operante/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Pirimidinas/farmacología , Salicilamidas/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Antagonistas de Dopamina/farmacología , Masculino , Racloprida , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
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.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Electrochoque , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacologíaRESUMEN
The anticholinergic, scopolamine, consistently disrupts one-trial passive avoidance conditioning but the effects of such drugs on one-trial conditioned taste aversion (CTA) are variable and contradictory. In the present study, treatment of rats with scopolamine impaired the suppression of sucrose intake by post-ingestion administration of lithium chloride (LiCl) in a two-bottle choice test. A similar effect was obtained by using N-methyl scopolamine which penetrates the brain only to a limited degree on acute administration. The blockade of CTA could be prevented in three ways: (i) by exposing the rats to sucrose only on the training day, (ii) by pre-exposing the rats to both sucrose and scopolamine, and (iii) by using a less palatable sucrose/ascorbate mixture. The results demonstrate that the effect of scopolamine on taste aversion is not mediated by the central nervous system, and can be modified by altering the novelty and relative salience of the taste conditioned stimulus. These experiments suggest that conditioned associations between taste and LiCl, and scopolamine and LiCl may underlie the blockade of CTA by scopolamine.
Asunto(s)
Amnesia/inducido químicamente , Reacción de Prevención/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Parasimpatolíticos/farmacología , Derivados de Escopolamina/farmacología , Escopolamina/farmacología , Gusto/efectos de los fármacos , Amnesia/psicología , Animales , Ácido Ascórbico/farmacología , Cloruros/farmacología , Litio/farmacología , Cloruro de Litio , Masculino , N-Metilescopolamina , Neostigmina/farmacología , Fisostigmina/farmacología , Ratas , Ratas Endogámicas , Sacarosa/farmacologíaRESUMEN
8-OH-DPAT, a selective 5-HT1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Reacción de Prevención/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Discriminación en Psicología/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrochoque , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
In general, chlordiazepoxide (CDP) and amphetamine reduce high rates of responding and increase low rates (rate-dependent effect). However, unlike CDP, amphetamine does not typically increase low rates resulting from suppression of responding by noxious stimuli. In the present experiment, key pecking by pigeons was reinforced under a random ratio schedule of food presentation. This responding was then suppressed by stimuli correlated with electric shocks of varying intensity (2 or 4 mA) or reduced by the omission of the food (extinction). Treatment with CDP (0.3-10.0 mg/kg) and morphine (0.3-10.0 mg/kg) increased the rate of suppressed responding: lower rates being increased to a proportionately greater extent than high rates. d-Amphetamine (0.1-1.0 mg/kg) further reduced the rate of suppressed responding: the lower rates being reduced proportionately more than the higher rates. Thus the effects of all three drugs depended upon the control rates of responding, but the effects of amphetamine were the inverse of those of CDP, and morphine. The effects of amphetamine on low, suppressed or punished response rates are therefore not an exception to the generality of rate-dependency, but a different aspect of the same principle - "inverse rate-dependency".
Asunto(s)
Anfetamina/farmacología , Clordiazepóxido/farmacología , Condicionamiento Operante/efectos de los fármacos , Electrochoque , Morfina/farmacología , Animales , Columbidae , Masculino , Refuerzo en PsicologíaRESUMEN
The effect of the purine agonist N-ethylcarboxamido-adenosine (NECA) on apomorphine-induced rotation was investigated in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Intrastriatal administration of NECA on the denervated side caused a dose-dependent inhibition of contralateral rotation. This inhibition was prevented by prior intrastriatal injection of theophylline. The adenosine A1 receptor antagonist 8-cyclopentyltheophylline was ineffective at concentrations which block this receptor, but effective in preventing the action of NECA at concentrations which block the adenosine A2 receptor. In the absence of apomorphine, NECA had no effect on behaviour. It is concluded that A2 receptor activation counteracts apomorphine effects in the striatum. Since the A2 receptor may be localized to striatal cholinergic neurones, the possible role of these neurones in purine-induced behaviours is discussed.
Asunto(s)
Apomorfina/farmacología , Cuerpo Estriado/metabolismo , Dopamina/fisiología , Receptores Purinérgicos/metabolismo , Conducta Estereotipada/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Animales , Química Encefálica/efectos de los fármacos , Cuerpo Estriado/fisiología , Desnervación , Relación Dosis-Respuesta a Droga , Hidroxidopaminas/farmacología , Oxidopamina , Ratas , Sustancia Negra/fisiología , Simpatectomía Química , Teofilina/análogos & derivados , Teofilina/farmacologíaRESUMEN
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Actividad Motora/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Tetrahidronaftalenos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Habituación Psicofisiológica/efectos de los fármacos , Masculino , Ratas , Ratas EndogámicasRESUMEN
Patients with dementia of the Alzheimer type (DAT) received two tests of visual selective attention, together with tests of spatial and visual recognition memory and visuospatial conditional learning previously used to show deficits early in the course of DAT. One set of attentional tests compared visual discrimination learning along intra- and extra-dimensional shifts, using a "total change" design. In the 12 DAT patients capable of attempting the extra-dimensional shift (subgroup 1), performance was equivalent to that of controls. This subgroup was also unimpaired at simple and compound discrimination learning and reversal and an intra-dimensional shift. They were as accurate as controls on a visual search task requiring matching of stimuli on two dimensions with variable numbers of alternatives, but were significantly impaired in the tests of recognition memory and learning. By contrast, the other 13 patients showed marked impairments in the attentional tasks. This subgroup was also significantly worse than subgroup 1 in performance on the visual recognition and conditional learning tasks, and showed greater severity on most of the clinical ratings of dementia. The sparing of attentional shifting in patients early in the course of DAT is contrasted with the impairments previously described in patients with Parkinson's disease with only mild or absent memory loss. The implications of this double dissociation of deficits for understanding the neural bases of the cognitive deficits in these two neurodegenerative diseases are discussed and their significance for the staging of DAT is considered.
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Enfermedad de Alzheimer/psicología , Atención , Recuerdo Mental , Reconocimiento Visual de Modelos , Anciano , Enfermedad de Alzheimer/clasificación , Enfermedad de Alzheimer/diagnóstico , Nivel de Alerta , Aprendizaje Discriminativo , Femenino , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Orientación , Aprendizaje por Asociación de Pares , Desempeño PsicomotorRESUMEN
Rats received infusions of ibotenic acid into the substantia innominata, in the region of the nucleus basalis of Meynert (nbM), before and after training on simple (simultaneous) and conditional visual discriminations. The ibotenate infusions reduced cortical choline acetyltransferase (ChAT) levels by about 20%, destroyed many ChAT-immunoreactive neurons in the nbM, but also caused the loss of many neurons in the substantia innominata and adjacent areas. These lesions did not impair the acquisition and performance of a simple visual discrimination, but did impair reversal of the discrimination and the performance of a conditional visual discrimination. However, the degree of impairment was unrelated to the degree of cortical ChAT loss. Ibotenic acid lesions to the dorsal globus pallidus also impaired reversal of discrimination but left acquisition and performance unaffected. Striatal dopamine depletion produced by 6-hydroxydopamine (6-OHDA) infusions into the mid-ventral caudate nucleus impaired performance of the simultaneous visual discrimination. Cortical noradrenaline depletion produced by 6-OHDA lesions of the dorsal noradrenergic bundle either alone or in combination with ibotenic acid lesions of the substantia innominata had no effect on acquisition of the discrimination. It is concluded that ibotenic acid lesions of the substantia innominata or to the dorsal globus pallidus affect learning and performance of conditional visual discrimination performance and impair reversal learning without affecting the capacity to discriminate visual events. These results are compared to those following cortical noradrenaline depletion or striatal dopamine loss.
Asunto(s)
Ganglios Basales/fisiología , Aprendizaje Discriminativo/fisiología , Globo Pálido/fisiología , Memoria/fisiología , Recuerdo Mental/fisiología , Aprendizaje Inverso/fisiología , Sustancia Innominada/fisiología , Percepción Visual/fisiología , Animales , Atención/fisiología , Mapeo Encefálico , Corteza Cerebral/fisiología , Colina O-Acetiltransferasa/fisiología , Masculino , Vías Nerviosas/fisiología , Norepinefrina/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas EndogámicasRESUMEN
Groups of patients with Parkinson's disease, either medicated, or unmedicated and early in the course, together with age- and IQ-matched control subjects were tested in two paradigms measuring different aspects of selective attention. The first set of tests compared visual discrimination learning following intra- and extra-dimensional shifts, using a "total change" design in which each shift was made in the presence of novel exemplars of the compound stimuli used as discriminanda. The second test consisted of a visual search task in which the number of alternatives was varied. The results of the first experiment showed a selective deficit in both groups of Parkinsonian subjects in their ability to perform an extra-dimensional shift. In the visual search task, the patients were less accurate, but responded with equivalent choice reaction times to those of controls. The results are discussed in terms of the nature of the attentional dysfunction that occurs in Parkinson's disease.