Biomedical subjects

S C Fowler

Publications and source records attributed to S C Fowler.

At least 37 records · Page 2Linked to original sources

PubMed1997

Quantifying operant behavior deficits in rats with bilateral 6-hydroxydopamine lesions of the ventrolateral striatum.

The present study examined the effects of bilateral 6-hydroxydopamine lesions in the ventrolateral striatum on the operant behavior of rats. Use of the specially modified operant chambers allowed the measurement of forelimb response force and duration as well as the time intervals between selected behavior in the press-consume-press sequence. More specifically, four time intervals between separate behavioral events were measured: 1) the time from the end of forelimb response to entry of muzzle into the reinforcement well, 2) the time from muzzle entry to the first tongue lick of the water reinforcer; 3) the time from the last lick to muzzle withdrawal from the reinforcement well, and 4) the time from muzzle withdrawal to the beginning of the next forelimb operant response. As determined by neurochemical (HPLC) analysis, the lesioned group exhibited dopamine levels that were 35% of the control group. The operant behavioral deficits were most profoundly appeared in the first week of postoperative test. Behaviorally, the lesioned group exhibited longer forelimb response durations (bradykinesia), and decrements were seen in both the number of muzzle entries and the number of recorded licks during reward consumption. Furthermore, the lesion significantly increased the average latency to switch from the forelimb response to the entry of the muzzle into the reward well. The latency from well entry to the first tongue extension to the reward was also increased by the lesion. These data support the view that the rodent neostriatum is important in the control of behavioral sequences for psychomotor function and at the same time demonstrate the utility of new quantitative behavioral methods for investigating such functions.

Animals↗

PubMed1997

Scopolamine reversal of tremor produced by low doses of physostigmine in rats: evidence for a cholinergic mechanism.

In order to provide evidence for the involvement of cholinergic mechanisms in a low-dose physostigmine-induced tremor, a novel technique for measuring forelimb tremor in rats was used. Rats that were administered physostigmine (0.05 and 0.1 mg/kg, s.c.), scopolamine (0.1 and 0.2 mg/kg, s.c.), and combinations of the two drugs, pressed a force-sensing operandum while a computer measured force output and performed Fourier analyses on resulting force-time waveforms. When given alone, both drugs decreased task engagement but mutually antagonized this effect when given together. Physostigmine increased tremors as well as peak force. Scopolamine decreased tremor and force when administered alone and reversed physostigmine-induced increases in force and tremor. Physostigmine's low-dose induction of increased tremor during rats' skilled forelimb use appears to have a prominent cholinergic component.

Animals↗

PubMed1997

Subchronic effects of clozapine and haloperidol on rats' forelimb force and duration during a press-while-licking task.

In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug's suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine's marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine's effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs.

Animals↗

PubMed1997

Similarities and differences between the subchronic and withdrawal effects of clozapine and olanzapine on forelimb force steadiness.

The purpose of this study was to compare the subchronic, low-dose effects of clozapine with those of olanzapine in a learned behavioral task previously shown to distinguish between clozapine and haloperidol with acute and subchronic treatment regimes. Rats were trained to use a single forelimb to press a force-recording operandum and simultaneously to lick water from a dipper that remained available while forelimb force exceeded a modest lower limit. Analysis of the resulting forcetime recordings provided measures of task engagement (time on task-analogous to response rate), lick rhythm, tremor, ballistic (maximum force) and tonic (hold force) forelimb force measures, as well as the durations of the individual responses. In a between-groups dosing design, five separate groups of rats received vehicle, clozapine 1.0 or 5.0 mg/kg, olanzapine 0.5 or 1.0 mg/kg daily for 27 days. A 7-day withdrawal period followed. On days 22 and 26 of antipsychotic drug treatment, all rats additionally received 0.3 mg/kg trihexyphenidyl or 1.0 mg/kg quipazine, respectively. The effects of olanzapine and clozapine were similar in that both drugs reduced time on task, increased response duration, and slowed lick rhythm. The two drugs differed in that clozapine reduced the force and tremor measures but olanzapine did not. Both tolerance and withdrawal effects, as reflected by the tremor measure, were observed for clozapine but not for olanzapine. Trihexyphenidyl further increased the duration of responses already lengthened by clozapine; in contrast, trihexyphenidyl decreased the duration lengthening effect of olanzapine. Taken together, the results indicated that olanzapine did not have the antitremor and hypotonic effects displayed by clozapine, and olanzapine did not induce tolerance and withdrawal phenomena as clozapine did.

Animals↗

PubMed1996

Similarity of clozapine's and olanzapine's acute effects on rats' lapping behavior.

As a way of further comparing the behavioral effects of clozapine and olanzapine, dose ranges of these drugs were studied in a task emphasizing fine motor detail of rats' tongue movements during lapping behavior. Rats lapped drops of tap water from a force-sensing disk. From this behavior four variables were derived: peak-force of tongue strikes, duration of tongue contact, number of separate tongue contacts in 2 min, and the rhythm of the lapping behavior as quantified by Fourier analysis. Both clozapine (0.5-4.0 mg/kg, IP, 45 min) and olanzapine (0.25-2.0 mg/kg, IP, 45 min) dose dependently reduced all four measures of behavior. With respect to lick rhythm, a behavioral marker which clearly distinguishes haloperidol from clozapine in this behavioral paradigm, olanzapine was about twice as potent as clozapine, with the two drugs having parallel dose-effect functions. Within-session decrements in behavior previously reported for haloperidol in the lick task were not produced by clozapine nor by olanzapine. Taken together, these data strengthen the idea that the behavioral effects of clozapine and olanzapine are strikingly similar, and thereby emphasize the potential of olanzapine as an atypical anti-psychotic agent.

Animals↗

PubMed1996

An update of Fowler and Das: anticholinergic reversal of haloperidol-induced, within-session decrements in rats' lapping behavior.

Dopamine receptor-blocking neuroleptics produce progressive decrements in response output during behavioral test sessions. If these response decrements reflect Parkinson-like motor effects of neuroleptic treatment, then within-session decrements should be ameliorated by concurrent anticholinergic treatment. To investigate this question, new within-session data analyses were performed on previously published data that addressed haloperidol-scopolamine influences across the entire session (Fowler and Das, 1994). The peak force and duration of individual licks were recorded for 36 rats along with the number of licks emitted in each daily 2-min session. The effects on this behavior of vehicle and three doses of haloperidol (0.06, 0.12, and 0.24 mg/kg, IP, 45 min before sessions) were evaluated alone and in combination with vehicle and two doses of scopolamine HCl (0.1 and 0.2 mg/kg, SC, 60 min before sessions). Despite the brief sessions, haloperidol produced pronounced within-session decrements, and pretreatment with scopolamine reversed the haloperidol-induced within-session decrements in lick emission. Scopolamine by itself produced within-session increments in all three measures of lapping behavior. The results support the idea that within-session decrements in licking behavior are Parkinson-like and diminish confidence in hedonic interpretations of neuroleptic-induced within-session decrements.

Animals↗

PubMed1995

Acute and subchronic effects of clozapine on licking in rats: tolerance to disruptive effects on number of licks, but no tolerance to rhythm slowing.

In order to assess the effects of the atypical neuroleptic clozapine on orolingual competence in rats, tongue function was measured by quantitating the rhythm of tongue movements after acute (1.0, 3.0, 6.0 mg/kg) or subchronic intraperitoneal treatment (1.5, 3.0, 4.5 mg/kg, each dose for at least 7 days) with the drug. Thirsty rats were trained to lick water from a force-sensing disk by thrusting the tongue through a 12-mm-diameter hole to strike the horizontal disk located 5 mm below the hole. Number of licks in 2 min and rhythm of tongue movements (as determined by Fourier analysis of the force-time signal) were each dose dependently reduced in the acute dose-effect phase of the study. In the subchronic study number of licks exhibited tolerance, but the slowing of lick rhythm did not show tolerance. An acute dose range of the serotonin antagonist ritanserin (0.5, 1.0, 2.0, 4.0 mg/kg) was also studied in the same rats. Ritanserin had no effect on any of the measures of orolingual function. The clozapine result was replicated in a second study using younger, drug naive rats. The results for clozapine were contrasted with previous reports indicating that haloperidol has little effect on lick rhythm. Additional discussion evaluated the possible contribution of neurotransmitter receptors on motor neurons of the hypoglossal nucleus to the observed rhythm slowing induced by clozapine.

Animals↗

PubMed1995

Caffeine and time of day effects on a force discrimination task in humans.

The effects of caffeine (0 mg/kg, 1 mg/kg, 3 mg/kg) and time of day (TOD) on human performance were studied using a multiple forceband discrimination task (MFDT) and subjective ratings. Self-rated measures of energy level were affected by TOD and caffeine, while mood was affected by TOD. Energy level decreased throughout the day and was offset by caffeine which increased energy level independent of TOD. Self-reported anxiety was not affected by TOD or caffeine. Mood was affected by TOD in a complex cubic trend with late morning and late evening peaks 12 h apart. MFDT performance was affected by TOD, caffeine dosage, and their interaction. Trend analyses showed varying patterns of TOD effects across peak force variability, response latency, response duration, and correct responding. Results support and extend previous findings of TOD influences on the MFDT and support the utility of multicomponent proprioceptive tasks for examining drug effects on performance.

Adult↗

PubMed1995

Effects of chronic haloperidol on reaction time and errors in a sustained attention task: partial reversal by anticholinergics and by amphetamine.

The attentional and motor-disruptive effects of low doses of haloperidol were studied in a sustained attention task performed by rats. Five separate groups (n = 7 or 8) of rats were trained to react to a 0.125-sec visual stimulus by executing a nose-poke response within 3 sec of stimulus presentation. Each group of rats received its own dose (0.0, 0.02, 0.04, 0.08 or 0.12 mg/kg) of haloperidol daily for 3 months, and from the 1st week onward dose-effects on reaction time were quite stable across time. Haloperidol treatment disrupted the sustained attention task performance by decreasing the number of behavior-initiated stimulus presentations, decreasing the number of reinforcers earned, increasing the proportion of errors of omission and increasing reaction time to the target stimulus. Testing of challenge drugs began after 23 days of haloperidol treatment. Scopolamine (0.1 and 0.2 mg/kg), benztropine (1.0, 3.0 and 6.0 mg/kg) and d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) ameliorated haloperidol-induced reaction time slowing, whereas only benztropine and amphetamine lessened haloperidol-induced errors of omission. The 2.0-mg/kg dose of amphetamine by itself produced a significant increase in errors of omission without affecting reaction time. Haloperidol effectively normalized this amphetamine-induced disruption in attention. The results are consistent with a dopaminergic involvement in the expression of both attention and motor processes.

Adrenergic Agents↗

PubMed1994

Microcatalepsy and disruption of forelimb usage during operant behavior: differences between dopamine D1 (SCH-23390) and D2 (raclopride) antagonists.

In an experiment designed to distinguish between the behavioral consequences of treatment with SCH-23390, a D1 dopamine receptor blocker, and raclopride, a D2 antagonist, rats were trained to perform a water-reinforced forelimb operant response. Response rate and the duration of each forelimb contact with the operandum were recorded. In addition, the durations of the rat's visits to the reward well were detected by a photobeam which was blocked by the rat's muzzle as it remained at the reward well. In a between-groups dosing design, separate groups of rats (11-13 rats/group) received SCH-23390 (0, 0.01, 0.02, 0.04, 0.08, 0.12 mg/kg, IP, 30 min) or raclopride (0. 0.05, 0.1, 0.2, 0.4, 0.8 mg/kg, IP, 30 min) for 21 consecutive days. Quantitative analyses indicated that for comparable amounts of operant rate reduction, raclopride had a significantly greater tendency than SCH-23390 to increase the duration of operant responses and to increase the maximum muzzle entry duration (i.e., to induce microcatalepsy). The results support the idea that at relatively low doses D2 antagonism is more likely than D1 antagonism to produce effects identified preclinically with extrapyramidal side effects.

Animals↗

PubMed1994

Unlike haloperidol, clozapine slows and dampens rats' forelimb force oscillations and decreases force output in a press-while-licking behavioral task.

In order to detect putative differences in the behavioral effects of clozapine and haloperidol, rats were trained to use a single forelimb to exert continuous pressure on a force-sensing operandum. Behavior was maintained by presenting a water-filled dipper for consumption only as long as the force remained above a specified level (the water fountain task). Effects of clozapine (2.0, 4.0, 8.0 mg/kg) and haloperidol (0.02, 0.04, 0.08, 0.12 mg/kg) on the forelimb force oscillations manifested during the operandum pressing episodes were analyzed with power spectral analysis and other quantitative methods. All rats exhibited force oscillations with a fundamental frequency near 7 Hz. Clozapine shifted the frequency to lower values (i.e., oscillation slowing), while haloperidol shifted oscilations to slightly higher frequencies. Moreover, clozapine reduced power in the region of the spectrum above 5 Hz. In contrast, haloperidol tended to increase power in these regions. Time domain analyses of the force-time waveforms indicated that haloperidol increased force emission during the hold phase of the forelimb response, and clozapine decreased this measure. The results are congruent with the high extrapyramidal side effects of haloperidol and the lack of such effects of clozapine in the clinic. In addition, clozapine may have antitremor effects in rats as it does in humans.

Animals↗

PubMed1994

Haloperidol-induced decrements in force and duration of rats' tongue movements during licking are attenuated by concomitant anticholinergic treatment.

To investigate the hypothesis that haloperidol's impairment of tongue protrusion in rats is Parkinson-like, the effects of centrally active scopolamine hydrochloride (0.1 or 0.2 mg/kg, SC) were evaluated in 36 rats that were also administered haloperidol (0.06, 0.12, or 0.24 mg/kg, IP). Rats were trained to lick water from a force-sensing disk, and the peak force and duration of each tongue contact were recorded along with the number of licks emitted in a 2-min session. Scopolamine hydrochloride significantly reversed haloperidol-induced deficits observed for peak force, duration, and number of licks. When given alone, scopolamine hydrochloride decreased peak force and duration. Fourier methods showed that the basic rhythm of licking was slowed by scopolamine hydrochloride but not by haloperidol. Taken together, the data suggest that central nervous system dopaminergic-cholinergic interactions importantly modulate tongue dynamics in the rat in a manner consistent with such interactions in neuroleptic-treated human patients.

Animals↗

PubMed1993

Effects of variation in chronic dose of cocaine on contingent tolerance as assessed in a milk-drinking task.

Tolerance to the suppressive effects of cocaine on milk drinking by rats was studied using a contingent tolerance experimental design. Three separate groups (n = 6) of rats received 8.0, 16.0, or 32.0 mg/kg cocaine daily 15 min before a 15-min period of access to sweetened condensed milk for 20 days. Three additional groups of six rats each received the same chronic doses 15 min after access to milk. Milk, water, and food intake as well as body weight were measured daily. Tolerance effects were assessed by comparing initial acute dose-effect determinations with a probe dose-effect redetermination in which all rats again received doses of cocaine pre-session after having experienced the differential pre- or post-session chronic treatment. Behavioral tolerance on the milk intake measure was observed for the 8.0 mg/kg and 16.0 mg/kg doses, but not for the 32.0 mg/kg chronic treatment, even though the latter group exhibited evidence of tolerance in the water intake measure. Chronic treatment with 8.0 and 16.0 mg/kg produced different outcomes in that chronic exposure to 16.0 mg/kg in the presence of milk resulted in generalization of tolerance to both a lower (8.0 mg/kg) and a higher dose (32.0 mg/kg), but the group receiving 8.0 mg/kg did not exhibit generalization of tolerance to higher doses. Modest sensitization effects were observed in the rats treated post-session with either 8.0 or 16.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Raclopride, but not SCH 23,390, induces maldirected jumping in rats trained to perform a run-climb-run behavioral task.

In order to explore further the putative differential behavioral consequences of D1 dopamine and D2 dopamine receptor antagonism, SCH 23,390 (0.01-0.12 mg/kg) and raclopride (0.12-1.0 mg/kg) were administered to two separate groups of rats that had been trained in an eight-trial-per-day format to run down an alleyway, climb a vertical rope, and run across a horizontal board to access sweetened milk. Although both drugs dose-dependently reduced the speed of task completion, only raclopride produced vigorous, maldirected jumping behavior in the floor segment of the apparatus. The number of such jumps increased with dose. This raclopride-specific jumping phenomenon may provide a new behavioral arena for investigating the functional differences between D1 and D2 receptor antagonism.

Animals↗

PubMed1993

In a drug discrimination procedure isolation-reared rats generalize to lower doses of cocaine and amphetamine than rats reared in an enriched environment.

Rats with different behavioral histories, defined by rearing and housing in either an enriched condition (EC) or an isolation condition (IC), were trained in a two-lever operant procedure to discriminate 5.0 mg/kg cocaine from saline. In cocaine dose-generalization tests, the IC rats exhibited an ED50 (1.01 mg/kg) significantly lower than the EC rats (ED50: 1.55 mg/kg). The cocaine-appropriate responding was emitted when the rats were treated with d-amphetamine, and for the d-amphetamine test doses the ED50 (0.19 mg/kg) was again significantly lower for the IC rats compared to the ECs (ED50: 0.33 mg/kg). These data suggest that IC rats are more sensitive to the stimulus properties of indirect dopaminergic agonists than EC rats and highlight the importance of environmental variables in governing an organism's response to the stimulus properties of abused drugs.

Animals↗

PubMed1993

Effects of haloperidol on a run-climb-run behavioral task: distance climbed does not alter within-session decrements.

Effects of haloperidol (0.04-0.32 mg/kg) were assessed in 10 hungry rats trained in a 10-trials-per-day format to run down an alleyway, climb a vertical rope, and run across a horizontal board to obtain sweetened milk. Rope lengths of 0.59 m and 1.32 m defined low- and high-effort requirements, respectively. Haloperidol produced substantial within-session decrements on Trials 2-10, but the drug did not affect rope-climbing speed more than horizontal running speed. Drug-induced within-session decrements were similar for both low- and high-effort requirements. After treatment with the 0.16-mg/kg dose, force-time waveforms of the climbing behavior documented instances of arrest of movement on the rope, but no bradykinesia of individual locomotor acts was discerned. Results suggest that haloperidol may produce associative deficits as well as disruptions of motor processes.

Animals↗

PubMed1992

Time of day effects on a human force discrimination task.

Although numerous studies have demonstrated reliable relationships between various human performance measures and time of day, disagreement exists concerning the shape of these relationships and their dependence on task variables. Most perceptual-motor tasks emphasize responsiveness to exteroceptive stimuli. We used a multiple force-band discrimination task that requires responsiveness to both exteroceptive and proprioceptive information. Results for a response duration measure showed a quadratic time of day trend similar to previously reported performance tasks. Response latency to the force emission cue and number of correct inband force emissions showed cubic time of day trends not typically reported in the time of day and performance literature. These results have implications for time-of-day effects on real world perceptual performance.

Body Temperature↗

PubMed1992

Low doses of haloperidol interfere with rat tongue extensions during licking: a quantitative analysis.

Orolingual dyskinetic effects of haloperidol were studied in rats trained to lick drops of water from a force-sensing disk. Haloperidol dose-dependently decreased force of tongue protrusion, decreased lick duration, increased interlick interval, and decreased number of licks. Fourier methods showed that haloperidol, in doses as low as 0.06 mg/kg, slowed the lick oscillations from an average of 5.250 Hz to 5.096 Hz (p = .014). Lick force was modulated by water drop delivery, but this effect was not influenced by haloperidol, which suggests no interference of the drug with sensory regulation of licking. The drug-induced deficits in tongue force may be manifestations of either postural alterations (pseudoparkinsonism) or orobuccolingual dyskinesias or both. Orolingual motor impairments may account for some of the neuroleptic-engendered behavioral decrements that have previously been explained in terms of reward, motivational deficits, or both.

Animals↗