Stephen C. Fowler

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.

Deficits in contralateral and ipsilateral forepaw motor control following unilateral motor cortical ablations in rats

Two force transducers which were interfaced with a minicomputer were used as operant manipulanda to assess changes in peak force and rate of response produced by unilateral motor cortical lesions in rats. Spatial arrangement of the manipulanda permitted a subject to respond on Transducer I exclusively with his left forepaw and on Transducer II exclusively with his right. Permanent deficits as measured by both force and rate of response were observed for the limb contralateral to the lesion. In the forelimb ipsilateral to the lesion rate of response was severely depressed immediately following the lesion and, although there was marked recovery during the 10-12 days following surgery, post-lesion rates never attained pre-lesion levels.

Effects of haloperidol on the biophysical characteristics of operant responding: Implications for motor and reinforcement processes

Food-deprived rats were reinforced with sweetened condensed milk for pressing a force-sensing operandum on a continuous reinforcement basis. Force was continuously recorded (every 0.00195 sec) during each response, and measures derived from the resulting force-time waveforms served as the basis for evaluating neuroleptic challenge in the form of haloperidol (0.04, 0.08, 0.16 mg/kg). Significant dose-related drug effects included a decrease in response rate, an increase in mean emitted peak force, and an increase in overall response duration. Additional quantitative analyses revealed that the drug-induced increase in response duration resulted primarily from a slowing in the animals paw removal from the force-sensing operandum. The findings are analogous to deficits in Parkinsons disease and suggest a behavioral mechanism that might account for much of the rate attenuating effects of neuroleptics. Implications for motor and reward interpretations of the actions of dopamine antagonists are also discussed.

Use of operant response duration to distinguish the effects of haloperidol from nonreward

Prior experimentation, making exclusive use of operant response rate, has offered conflicting evidence regarding the role of reinforcement and motor effects in neuroleptic-induced changes in operant responding. In the present work, response rate and response duration were recorded for 12 rats responding under a fixed-ratio 10 schedule of food reinforcement. On six consecutive days separate groups of animals were given haloperidol or saline-with-extinction. Although both drug treatment and extinction produced elevated durations compared to pre-treatment baseline, the haloperidol group exhibited response durations that were significantly higher than those of the no-drug-extinction group. In view of these results, and since prior work has shown that response duration provides information which is nonredundant with response rate, it is suggested that response duration may be a valuable tool in future work attempting to partial out the motivational and motor effects of neuroleptics on operant responding.

Drug effects upon force and duration of response during fixed-ratio performance in rats ☆

Abstract Rats responded on a tandem FR24CRF CRF CRF CRF schedule of water reinforcement by paw-pressing a silent, isometric, force-sensing manipulandum. Oral dose ranges of d-amphetamine, chlordiazepoxide, chlorpromazine, and dantrolene were evaluated for their effects on this schedule-controlled behavior. Peak force, duration and interresponse time (IRT) of individual responses were recorded with a laboratory computer system. Conjoint examination of these three dependent variables revealed that the intensitive measures of response (i.e., peak force and duration) provided information about drug effects that could not be detected with the conventional IRT measure alone. More specifically, peak force was elevated by d-amphetamine at 1.6 mg/kg during the FR component, but IRT was unaffected at this dose. At 3.2 mg/kg, d-amphetamine decreased peak force and lengthened IRT during the FR component. Chlordiazepoxide increased peak force up to the highest dose examined (27.0 mg/kg), whereas dantrolene decreased peak force. Chlorpromazine did not affect peak force but did increase response duration. Higher doses of chlordiazepoxide, chlorpromazine, and dantrolene lengthened IRT during the FR component. For all three dependent variables drug effects were generally less pronounced or altogether undetected in the CRF component. The results are discussed in relation to explanatory principles such as rate-dependency and stereotyped behaviors.

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 withd-amphetamine, and for thed-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 organisms response to the stimulus properties of abused drugs.

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 rats visits to the reward well were detected by a photobeam which was blocked by the rats 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.

Haloperidol produces within-session increments in operant response duration in rats

On the basis of previously reported observations that haloperidol induces within-session decrements in operant response rate in rats, it was suspected that other measures of operant behavior may also display within-session changes after treatment with this neuroleptic. Accordingly, haloperidol (0.02, 0.04, 0.08, 0.16 mg/kg) was administered to six rats trained on a fixed-ratio 20 schedule of liquid food reinforcement, and response duration was recorded as a measure of drug effects independent of response rate. Significant within-session decrements in response rate and increments in response duration were observed as responding ensued. At the 0.08 mg/kg dose, 300% increases in response duration were seen during the last third of the responses made in a session. The progressive slowing of individual motor acts were interpreted as neuroleptic-induced Parkinsonism in the rat, and within-session decrements in response rate were likewise seen as a manifestation of the same pharmacological effects that increased response duration.

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 oscillations 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.

Effects of pimozide, across doses and within sessions, on discriminated lever release performance in rats

By using either water or food reinforcement, rats were trained to perform a discriminated lever release task (DLR), which required the rat to hold an operant lever in the closed position through one of five randomly presented foreperiods (2–6 s) and to release the lever within 0.5 s of the onset of a light discriminative stimulus. The procedure is analogous to the method used in human reaction time studies, except that here the procedure was free-operant, not fixed-trial. The effects of pimozide (0.12, 0.25, and 0.50 mg/kg) on this behavior were evaluated in terms of numbers of total responses, reinforced responses (successful releases), anticipatory responses, and extended responses (holding too long). Significant dose-dependent decreases in total responses and in reinforced responses were seen as supporting the hypothesis of a deficit in response initiation, which is often invoked to account for neuroleptic-induced reductions in discriminated active avoidance. Pimozide also increased the proportion of extended responses, suggesting that the drug affected the nature of responding as well as the tendency to respond. In the DLR task, pimozide produced substantial within-session decrements in both total responses and number of reinforced responses; however, extended responses exhibited within-session increases at the lowest dose. The results were discussed from both behavioral and pharmacological perspectives. The former emphasized motor effects and response initiation deficits, while the latter jointly considered neuronal responses to neuroleptic challenge and the dopamine release that results from behavioral activity itself.