Response Duration Differentiation Research Articles

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.

Long-Term Deficits Following Cerebral Hypoxia–Ischemia in Four-Week-Old Rats: Correspondence between Behavioral, Histological, and Magnetic Resonance Imaging Assessments

We examined whether following a hypoxic–ischemic insult in young animals there are long-lasting functional deficits that correlate either to histological tissue damage or to potential compensatory plasticity changes. Four-week-old rats were subjected to an episode of cerebral hypoxia–ischemia (right carotid artery occlusion + 30 min of hypoxia) or a sham operation. In hypoxic–ischemic animals there were gross neurological deficits 1, 24, and 48 h postinsult with recovery by 1 week. Behavioral deficits were observed in both the acquisition and the performance of a response duration differentiation test and a fine motor control test (staircase test) 3 months after the hypoxia–ischemia. Functional magnetic resonance imaging studies demonstrated less activation in the sensory–motor cortex of hypoxic–ischemic animals in response to left vs right forepaw stimulation 4 months postinsult. Histological assessment delineated striatal, cortical, and hippocampal damage in the hypoxic–ischemic hemisphere and a reduction in cortical thickness, bilaterally. GFAP immunoreactivity was increased in injured striatum and cortex. Neurofilament heavy chain (NF200) immunoreactivity was normally most intense in white matter and decreased in areas of ipsilateral cortical damage. Synaptophysin immunoreactivity was reduced around areas of infarction and somewhat increased in adjacent undamaged striatum and in layer IV of parietal cortex. The histological damage or chronic degenerative changes could account for much of the variance in functional outcome detected with sensitive behavioral tests so that overall the compensatory or plasticity changes evident within the juvenile brain are rather modest.

Disruption of acquisition and performance of operant response-duration differentiation by unilateral nigrostriatal lesions

Response duration differentiation (RDD), an operant schedule requiring fine motor timing and control, was assessed as a possible baseline for study of the long-term consequences of nigrostriatal lesions and as a possible baseline to test the therapeutic efficacy of candidate palliative, neuroprotective and neurorestorative drugs. Rats were subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of striatum, medial forebrain bundle (mfb), or were sham lesioned, and their ability to acquire the operant task was studied in a single overnight session. In a second set of studies, rats that had been well trained in the RDD task were sham lesioned or were given unilateral 6-OHDA lesions of the mfb, and behavior under this baseline was studied for more than 30 weeks. Lesions of both striatum and of mfb resulted in impaired acquisition of RDD responding, with the relatively greater effect by the mfb lesion. In rats previously trained under the RDD schedule, mfb lesions produced marked disruptions in RDD performance, which did not fully recover. L-DOPA administration decreased the variability of the response durations, primarily by decreasing the proportion of short-duration lever presses.

Characteristics and species generality of the antidepressant effect upon response duration differentiation

Characteristics and species generality of the antidepressant effect upon response duration differentiation

AntIdepressant-like effects of 5-hydroxytryptamine1A receptor agonists on operant responding under a response duration differentiation schedule

A response duration differentiation schedule, where rats depress a lever for between 1.0 and 1.3 s to obtain a food reward, provides a useful measure for detecting antidepressant activity. It is known that 5-hydroxytryptamine1A (5-HT1A) receptor agonists exhibit antidepressant-like activity in multiple animal models of depression, however, compounds selective for this receptor have not been tested in this model to date. Thus, the present study sought to determine the effect of the full 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial 5-HT1A agonist, buspirone, on responding in the response duration differentiation task. The effects of these drugs were compared to the effects of the non-specific serotonergic agonist, lysergic acid diethylamide (LSD); the phenothiazine, chlorpromazine; the atypical antidepressant, trazodone; and the non-selective 5-HT1A antagonists, propranolol and alprenolol. It was found that propranolol, trazodone, and both the full (8-OH-DPAT) and partial (buspirone) 5-HT1A agonists produced increases in the mean response duration, which is typical of antidepressant activity. By contrast, with the exception of propranolol, compounds lacking antidepressant efficacy (e.g. chlorpromazine, LSD and alprenolol), failed to produce increases in mean response durations. Further, the effects of 8-OH-DPAT were inhibited by pretreatment with the 5-HT1A antagonist, (-)-alprenolol (3.0 and 30.0 mg/kg i.p.). The results of this study provide further support for the suggestion that 5-HT1A agonists may be useful for the treatment of clinical depression and that these effects are specifically mediated by 5-HT1A receptors.

Drug effects on response-duration differentiation IV: Effects of trimethyltin

Trimethyltin (TMT) is a toxicological agent that produces damage in a number of limbic structures, resulting in concomitant disruptions of behavior. The purpose of the present study was to determine the utility of response-duration differentiation (RDD) responding as a behavioral baseline for studying the behavioral consequences of TMT administration. Under the RDD schedule, responses of a restricted duration (1-1.3 s) were reinforced, and disruption of this performance may represent effects upon fine motor control, timing behavior, or both. Two doses of TMT (4 mg/kg) were administered 1 week apart, and behavior under the schedule was studied daily for 6 weeks thereafter in a group of four rats. Additionally, the effects of diazepam (0.1-3mg/kg) administered prior to and following TMT administration were compared. TMT produced disruptions in accuracy of responding and increases in rates of responding in the weeks following its administration. Behavior had generally recovered by 6 weeks after the first TMT administration. Diazepam flattened the relative frequency distributions of response durations at lower doses in the TMT-treated rat. These data show that RDD responding is sensitive to the effects of TMT, and TMT treatment can result in alterations in the effects of diazepam.

Effects of drugs on response duration differentiation III. Acute variation of reinforced duration

Rats trained to hold a lever down for at least 1.0 s but less than 1.3 s could differentiate the reinforced response duration on about 50% of the trials. The response duration frequency distribution was a normal distribution with a peak near the minimum reinforced response duration. Dose-effect curves were determined for the effects of phencyclidine (PCP) and methamphetamine. Subsequently, rats continued to be trained for 3 days a week with responses between 1.0 and 1.3 s reinforced, but on days when injections were given either the maximum reinforced duration was increased to 2.3 s, or the minimum reinforced duration was lowered to 0.5. When the maximum duration was increased to 2.3 s, the percentage of reinforced responses increased to 60% and when the minimum reinforced duration was decreased to 0.5 s, the percentage of reinforced responses increased to 89%. Despite the increased percentage of reinforced responses when the time window was widened, the effects of PCP and methamphetamine were not changed. These data suggest that the effects of drugs on response duration differentiation are not greatly influence by transient changes in reinforcement frequency.

Production de durée chez la personne âgée : comparaison avec le jeune adulte

Summary : Response duration differentiation in elderly people : a comparison with young adults. Two groups of elderly retiree subjects (65-69 years, N = 16 and 70-80 years, N = 14) matched for sex, education and past professional activities were compared with 20-year-olds (N = 22) on a duration production task (button press) with minimal instructions (« press the button »). Response durations lasting for 4 to 6 seconds were followed by the feedback « GOOD » on a computer screen. « MEDIUM » followed presses lasting for 2.5 to 4 and 6 to 7.5. seconds ; « POOR » followed more extreme durations. Subjects were requested to produce as many « GOOD » feedbacks as possible. Each trial was followed by the question « What do you have to do to obtain "GOOD" on the screen ? ». No striking difference could be found between 20- and 65-69-year-olds. However, the 70-80-year-olds produced fewer correct response durations and time-related rules, such as « You must press for x seconds ». An analysis of the evolution of behavior over successive quarters of the 40-trial session further showed that the oldest subjects acquired response timing and discovered the accurate response rule only towards the end of the session significant correlation between the number of correct response durations and timing rules was found for each group The oldest subjects were thus able to emit accurate non-verbal and verbal behavior their overall deficiency resulting from much slower acquisition rate than at 20 or 65-69 years Results were discussed in relationship to timing and problem solving

TEMPORAL DIFFERENTIATION OF RESPONSE DURATION IN CHILDREN OF DIFFERENT AGES: DEVELOPMENTAL CHANGES IN RELATIONS BETWEEN VERBAL AND NONVERBAL BEHAVIOR

Children aged 4.5, 7, or 11 years received an experimental session in which a contingency was placed on button-press duration. Each discrete trial was followed by a brief verbal probe asking a question about the contingency requirement. Other groups of children received an identical task followed by a postexperimental interview. Level of adaptation to the duration contingency tended to increase with age in subjects receiving posttrial verbal probes, but not for those who were interviewed. Eleven-year-olds in the verbal probe condition showed a strong correlation between accurate temporal differentiation and number of verbalizations relating to response duration or timing. The younger subjects, with one exception, showed no association between timing-related verbalizations (which were almost totally absent) and response duration differentiation. This developmental difference occurred even though the younger subjects verbalized after almost every trial. The results suggest that although 11-year-old children apparently produce rule-governed behavior under verbal control as adults do, the behavior of younger children may be controlled directly by reinforcement contingencies even when their verbal repertoires are highly developed.

Response Feedback and Response Duration Differentiation in the Albino Rat

Twelve male albino rats were reinforced for lever press durations of 0.5, 1.0, 1.5, 2.0 and 2.5 seconds. Half of the subjects (F) received an auditory feedback after non-reinforced responses. The 6 other (Controls, C) worked without feedback. F rats emitted on the average higher mean response durations and earned more reinforcements than C subjects. The standard deviation and coefficient of variation of their response duration distributions were significantly lower than those of group C. These results tend to show that feedback stimulus following non-reinforced responses improve the accuracy of performance in the response duration differentiation schedule.

Effects of prior experience on differential learning under amphetamine.

Differential learning of operant behavior under non-drug and amphetamine states was explained with a "drug-behavior-reinforcement interaction" process. When a drug affects the relationship between ongoing behavior and existing reinforcement contingencies, the sets of behavioral patterns subjected to the process of reinforcement or non-reinforcement under a drug may differ from the patterns under non-drug conditions. If, following sufficient training, the drug conditions are then changed, persistence of these behavioral patterns may result in a difference from those patterns produced if acquisition occurs solely under non-drug conditions. To investigate this process, groups of rats were given varying amounts of non-drug acquisition training on a response-duration differentiation task before being given extended training under 0.75 mg/kg d-amphetamine. All groups were then tested under non-drug conditions. Amphetamine significantly enhanced performance, and this enhancement transferred to subsequent non-drug conditions. However, if non-drug training occurred before drug training, this enhancement was greatly attenuated. Furthermore, only those behavioral components under which amphetamine led to an increase in reinforcement rate showed enhancement in the non-drug state. The results, which supported the present position, were discussed in relation to a "stimulus generalization decrement" explanation of differential learning under amphetamine.

Response differentiation: A psychophysical method for response produced stimuli

Twenty-four rats were reinforced for releasing a lever between t and t + .20 sec after pressing it. Response duration differentiation performance decreased monotonically as t was increased in length from .10 sec to 1.60 sec. A response analogue of Weber’s ratio was constant throughout the middle range of duration bandwidth requirements and increased at the ex tremely short bandwidth—a response-differentiation finding analogous to Weber’s law of stimulus discrimination. This finding was interpreted as support for the conceptualization that response differentiation represents a special instance of response discrimination or discrimination based on response-produced stimuli.

Response duration differentiation during fixed ratio responding

Eight albino rats were trained to pull a plunger for water reinforcements that were delivered on several fixed ratios from FR-4 to FR-32. The mean durations of the nonreinforced responses in the FR chain were significantly longer than mean reinforced durations. This differentiation also proved to be labile to exteroceptive stimulus cues.