J L Evenden1. 1. Preclinical Research and Development, Astra Arcus, Södertälje, Sweden.
Abstract
RATIONALE: The serotonergic systems have been implicated in the pathological impulsive behaviour on the basis of both clinical and preclinical data. However, impulsivity is probably made up of several independent factors, and the involvement of the diverse regulatory mechanisms of the serotonergic systems has not been widely studied. OBJECTIVE: The influence of a range of serotonergic agents on impulsivity was examined using a procedure designed to test the dimension of impulsivity termed "reflection-impulsivity" in rats. METHODS: An operant procedure was used in which the need to wait before responding was made explicit by using a signal which increased in predictive value the longer the subject waited before responding. First, the rats learned that a light signal indicated the availability of a food reinforcer if one of two levers was pressed. In the test procedure, on each trial, when the light was turned on it was only 50% likely to indicate the "correct" lever. After a brief interval it was turned off and on again, this time with a slightly higher probability (>50%) of indicating the correct lever. Over a period of a few seconds the probability that the light indicated the correct lever increased to almost 100%. Thus a quick response to the light would result in many errors, whereas a slow response could always result in food delivery. Once trained the rats were treated with a series of drugs: citalopram, (selective serotonin reuptake inhibitor), p-chloramphetamine (PCA, serotonin releaser), 8-OH-DPAT (5-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.
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.
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