RESUMO
RATIONALE: 5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes. OBJECTIVE: The effects of the 5-HT2C receptor agonist Ro-600175 ((αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats' performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen's Behav Brain Sci 17:105-172, 1994 general theory of schedule-controlled behaviour, 'mathematical principles of reinforcement'. METHOD: Rats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model's parameters, and the sensitivity of these effects to selective antagonists, were examined. RESULTS: Ro-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased δ (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist. CONCLUSIONS: The results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.
Assuntos
Receptor 5-HT2C de Serotonina/fisiologia , Reforço Psicológico , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Etilaminas/farmacologia , Fluorbenzenos/farmacologia , Alimentos , Indóis/farmacologia , Masculino , Motivação , Piperidinas/farmacologia , Ratos , Ratos Wistar , Tempo de Reação , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologiaRESUMO
Clozapine and some other atypical antipsychotics (e.g. quetiapine, olanzapine) have been found to exert a characteristic profile of action on operant behaviour maintained by progressive-ratio schedules, as revealed by Killeen's Mathematical Principles of Reinforcement model of schedule-controlled behaviour. These drugs increase the value of a parameter that expresses the 'incentive value' of the reinforcer (a) and a parameter that is inversely related to the organism's 'motor capacity' (δ). This experiment examined the effects of two further atypical antipsychotics, aripiprazole and amisulpride, on progressive-ratio schedule performance in rats; the effects of clozapine and a conventional antipsychotic, haloperidol, were also examined. In agreement with previous findings, clozapine (4, 8 mg kg⻹) increased a and δ, whereas haloperidol (0.05, 0.1 mg kg⻹) reduced a and increased δ. Aripiprazole (3,30 mg kg⻹) increased δ but did not affect a. Amisulpride (5, 50 mg kg⻹) had a delayed and protracted effect: δ was increased 3-6 hours after treatment; a was increased 1.5 hours, and reduced 12-24 hours after treatment. Interpretation based on Killeen's model suggests that aripiprazole does not share clozapine's ability to enhance reinforcer value. Amisulpride produced a short-lived enhancement, followed by a long-lasting reduction, of reinforcer value. Both drugs impaired motor performance.
Assuntos
Antipsicóticos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Antagonistas da Serotonina/farmacologia , Sulpirida/análogos & derivados , Amissulprida , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol , Comportamento Animal/efeitos dos fármacos , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Clozapina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Haloperidol/administração & dosagem , Haloperidol/efeitos adversos , Haloperidol/farmacologia , Cinética , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Esquema de Reforço , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/efeitos adversos , Sulpirida/administração & dosagem , Sulpirida/efeitos adversos , Sulpirida/farmacologiaRESUMO
Rats' ability to discriminate durations is disrupted by the monoamine-releasing agent D-amphetamine and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). It is unknown whether this effect is specific for temporal discrimination or reflects general disruption of stimulus control. This experiment addressed this question by comparing the effects of D-amphetamine and DOI on temporal discrimination and discrimination along a nontemporal dimension, light intensity. Twelve rats responded on a schedule in which a light (intensity 22 cd/m) was presented for t seconds (2.5-47.5 s), after which levers A and B were presented. Responses on A were reinforced when t was less than 25 s, and responses on B were reinforced when t was greater than 25 s. Twelve rats responded on a similar schedule in which a light of intensity i (3.6-128.5 cd/m) was presented for 25 s. Responses on A were reinforced when i was less than 22 cd/m, and responses on B were reinforced when i was greater than 22 cd/m. Logistic functions were fitted and psychophysical parameters estimated [T50, I50 (central tendency of temporal or light-intensity discrimination); Weber fraction (relative discriminative precision)]. D-Amphetamine (0.2-0.8 mg/kg) increased the Weber fraction for temporal and light-intensity discrimination; DOI (0.625-0.25 mg/kg) increased it for temporal discrimination only. Both drugs increased T50; neither altered I50. D-Amphetamine and DOI have similar effects on temporal discrimination but different effects on light-intensity discrimination. The increase in T50 may reflect the impairment of sustained attention during prolonged stimulus presentation.
Assuntos
Anfetaminas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Percepção Visual/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Limiar Diferencial/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Ratos , Ratos Wistar , Esquema de Reforço , Percepção do Tempo/efeitos dos fármacosRESUMO
Previous experiments using progressive-delay schedules showed that destruction of the nucleus accumbens core (AcbC) altered rats' choice between food reinforcers differing in size and delay. Application of a quantitative model of inter-temporal choice suggested that lesions of the AcbC increase the delay-dependent degradation of reinforcer value (delay discounting) without altering instantaneous reinforcer value. This experiment examined the effect of lesions of the AcbC on inter-temporal choice using an adjusting-delay schedule. Rats received excitotoxin-induced lesions of the AcbC or sham lesions. They were trained to press levers A and B for food-pellet reinforcers in an adjusting-delay schedule in which the delay to the larger reinforcer, d(B), varied in accordance with the rats' choices between the two levers. In two experimental conditions, the reinforcers associated with levers A and B were 1 vs. 4 and 2 vs. 4 pellets. The AcbC-lesioned group showed shorter indifference delays to reinforcer B (d(B(50))) than the sham-lesioned group under both conditions. In confirmation of a prediction derived from the model of inter-temporal choice, the ratio of the indifference delays from the two conditions did not differ between the groups. Analysis of the cyclical changes in d(B) by Fourier transform showed that the period of oscillation and power within the dominant frequency band did not differ between the groups, suggesting that the lesion did not disrupt the rats' ability to detect short-term changes in delay of reinforcement. The results are consistent with previous findings that indicate a role for the AcbC in delay discounting.
Assuntos
Comportamento de Escolha/fisiologia , Núcleo Accumbens/fisiologia , Esquema de Reforço , Algoritmos , Animais , Condicionamento Operante , Feminino , Análise de Fourier , Neurotoxinas/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Periodicidade , Ácido Quinolínico/toxicidade , Ratos , Reforço Psicológico , Fatores de TempoRESUMO
RATIONALE: Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D(2)-like dopamine receptor agonist quinpirole, and the D(1)-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D(1)-like and 5-HT(2A) receptor antagonists. It is not known whether d-amphetamine's effect requires an intact 5-hydroxytryptamine (5-HT) pathway. OBJECTIVE: The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. MATERIALS AND METHODS: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T(50), time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg(-1) i.p.), quinpirole (0.08 mg kg(-1) i.p.), and SKF-81297 (0.4 mg kg(-1) s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. RESULTS: Quinpirole and SKF-81297 reduced T(50) in both groups; d-amphetamine reduced T(50) only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. CONCLUSIONS: d-Amphetamine's effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT(2A) receptors, may play a 'permissive' role in dopamine release.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Dextroanfetamina/toxicidade , Tempo de Reação/efeitos dos fármacos , Serotonina/metabolismo , Animais , Benzazepinas/farmacologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Feminino , Ratos , Ratos WistarRESUMO
UNLABELLED: The subthalamic nucleus (STN), a major relay in the indirect striatofugal pathway, plays an important role in extrapyramidal motor control. Recent evidence indicates that it may also be involved in regulating the incentive value of food reinforcers. OBJECTIVE: To examine the effect of lesions of the STN on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes [Killeen PR. Mathematical principles of reinforcement. Behav Brain Sci 1994;17:105-72]. Rats with bilateral quinolinic acid-induced lesions of the STN (n=14) or sham lesions (n=14) were trained to press a lever for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions) it was two pellets; in Phase 3 (30 sessions) it was again one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio schedule performance. The motor parameter, delta, was significantly higher in the STN-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was significantly higher in the STN-lesioned group than in the sham-lesioned group, consistent with enhanced reinforcer value in the STN-lesioned group compared to the sham-lesioned group. In both groups, a was sensitive to changes in reinforcer size, being significantly greater under the two-pellet condition (Phase 2) than under the one-pellet condition (Phases 1 and 3). The results suggest that destruction of the STN impairs response capacity and enhances the incentive value of food reinforcers.
Assuntos
Desempenho Psicomotor/efeitos dos fármacos , Ácido Quinolínico/toxicidade , Reforço Psicológico , Núcleo Subtalâmico/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Feminino , Privação de Alimentos/fisiologia , Microinjeções/métodos , Desempenho Psicomotor/fisiologia , Ácido Quinolínico/administração & dosagem , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Esquema de Reforço , Recompensa , Núcleo Subtalâmico/patologia , Núcleo Subtalâmico/fisiopatologiaRESUMO
Previous experiments showed that destruction of the orbital prefrontal cortex (OPFC) or the nucleus accumbens core (AcbC) in rats altered choice between two delayed food reinforcers. Application of a quantitative model of inter-temporal choice suggested that lesions of either structure increased the delay-dependent degradation of reinforcer value (delay discounting); destruction of the OPFC (but not the AcbC) also increased the relative value of the larger reinforcer. This experiment examined the effect of disconnecting the OPFC from the AcbC on inter-temporal choice. Rats received excitotoxin-induced contralateral lesions of the OPFC and AcbC (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection+callosotomy) or sham lesions. They were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B50) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B50)vs. d(A)) were derived. The disconnection+callosotomy group showed a lower intercept of the indifference function (implying a higher rate of delay discounting) than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas the callosotomy group did not differ significantly from the sham-lesioned group. The results suggest that OPFC-AcbC connections are involved in delay discounting of food reinforcers, but provide no evidence for an involvement of OPFC-AcbC connections in regulating sensitivity to reinforcer size.
Assuntos
Comportamento de Escolha/fisiologia , Denervação , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal , Condicionamento Operante , Feminino , Privação de Alimentos , Lateralidade Funcional , Modelos Lineares , Vias Neurais/fisiologia , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Reforço Psicológico , Fatores de TempoRESUMO
RATIONALE: The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. OBJECTIVE: This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105-172). MATERIALS AND METHODS: Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r2 > 0.92). The motor parameter, delta, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. CONCLUSIONS: The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ácido Quinolínico/toxicidade , Animais , Peso Corporal/fisiologia , Sinais (Psicologia) , Interpretação Estatística de Dados , Feminino , Privação de Alimentos , Imuno-Histoquímica , Ratos , Ratos Wistar , Esquema de Reforço , Reforço Psicológico , Corrida/psicologiaRESUMO
RATIONALE: Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D(2)-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D(1)-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D(1)-like receptor stimulation. OBJECTIVE: The effects of a D(1)-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D(1)-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D(2)-like receptor antagonist haloperidol, were examined. MATERIALS AND METHODS: Rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T(50) [value of t corresponding to %B = 50] and the Weber fraction [(T(75)-T(25))/2T(50); T(25) and T(75) are values of t corresponding to %B = 25 and %B = 75] were compared among treatments. RESULTS: SKF-81297 (0.8 mg kg(-1)) reduced T(50); this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) but not by haloperidol (0.05, 0.1 mg kg(-1)). CONCLUSIONS: Stimulation of D(1)-like dopamine receptors affects performance in the free-operant psychophysical procedure.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Benzazepinas/farmacologia , Condicionamento Operante/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/fisiologia , Percepção do Tempo/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Feminino , Haloperidol/farmacologia , Psicometria , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/fisiologiaRESUMO
RATIONALE: There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. AIM: We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size. MATERIALS AND METHODS: Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after d(B). d(B) increased across blocks of trials, while d(A) was manipulated across phases of the experiment. Indifference delay d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d(B(50)) vs d(A)) derived. RESULTS: d(B(50)) increased linearly with d(A) (r(2) > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC. CONCLUSIONS: The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.
Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ácido Quinolínico/toxicidade , Algoritmos , Análise de Variância , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Imunoquímica , Modelos Anatômicos , Proteínas do Tecido Nervoso/análise , Proteínas Nucleares/análise , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Psicometria/métodos , Psicometria/normas , Ácido Quinolínico/administração & dosagem , Ratos , Ratos Wistar , Esquema de Reforço , Soluções/administração & dosagem , Soluções/química , Técnicas Estereotáxicas , Sacarose/administração & dosagem , Sacarose/química , Fatores de TempoRESUMO
RATIONALE: Operant timing behaviour is sensitive to dopaminergic manipulations. It has been proposed that this effect is mediated principally by D(2)-like dopamine receptors. However, we recently found that the effect of d-amphetamine on timing in the free-operant psychophysical procedure was mediated by D(1)-like dopamine receptors. It has not been established whether stimulation of D(2)-like receptors affects timing in this schedule. OBJECTIVE: To examine the effects of a D(2)-like receptor agonist quinpirole on second-range timing and the ability of dopamine receptor antagonists to reverse quinpirole's effects. MATERIALS AND METHODS: Rats responded on two levers (A and B) under a free-operant psychophysical schedule in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rates [percent responding on B (%B) vs time (t)] under each treatment; quantitative timing indices [T (50) (value of t when %B = 50) and Weber fraction] were compared among treatments. RESULTS: Quinpirole (0.04, 0.08 mg kg(-1)) reduced T (50). This effect was attenuated by D(2)-like receptor antagonists haloperidol (0.05, 0.1 mg kg(-1)), eticlopride (0.04, 0.08 mg kg(-1)) and sulpiride (30, 60 mg kg(-1)), but not by the D(3) receptor-preferring antagonist nafadotride (0.5, 1 mg kg(-1)), the D(4) receptor antagonist L-745870 (1, 3 mg kg(-1)) or the D(1)-like receptor antagonist SKF-83566 (0.015 mg kg(-1)). CONCLUSIONS: Results suggest that quinpirole reduced T (50) via an action at D(2) receptors. D(1)-like and D(2)-like receptors may mediate behaviourally similar but pharmacologically distinct effects on timing behaviour.