Biomedical subjects

C M Bradshaw

Publications and source records attributed to C M Bradshaw.

At least 19 recordsLinked to original sources

PubMed1992

A comparison of the effects of fluvoxamine and amitriptyline on autonomic functions in healthy volunteers.

We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design. Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis. Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg). The results suggest that fluvoxamine has some anti-muscarinic activity in man, but is considerably less potent in this respect than amitriptyline.

Administration, Oral↗

PubMed1992

Impaired acquisition of temporal differentiation performance following lesions of the ascending 5-hydroxytryptaminergic pathways.

Nineteen rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 16 rats received sham injections. The rats underwent 50 daily training sessions under an interresponse-time-greater-than-15-seconds (IRT greater than 15 s) schedule of sucrose reinforcement. The lesioned group showed impaired acquisition of temporal differentiation, in that their response rates remained significantly higher and their obtained reinforcement frequencies significantly lower than those of the control (sham-lesioned) group. Comparison of the IRT frequency distributions obtained from the two groups during the last 5 days of training showed that the lesioned group produced a significantly higher proportion of very short IRTs (less than 3 s) than the control group; when these short IRTs were disregarded, the lesioned group displayed a significantly lower mean IRT and a significantly higher coefficient of variation than the control group. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results suggest that destruction of the ascending 5HTergic pathways may reduce animals' capacity to inhibit positively reinforced operant behaviour, and may impair temporal discrimination.

5,7-Dihydroxytryptamine↗

PubMed1992

Choice between delayed reinforcers in a discrete-trials schedule: the effect of deprivation level.

Choice between two reinforcers differing in magnitude and delay was investigated in rats using a discrete-trials schedule in which the two reinforcers were associated with two levers (A and B); in each session 5 free-choice trials (A and B both available) were interspersed among 44 forced-choice trials (A alone, 22 trials; B alone, 22 trials). In Experiment 1, preference for the more concentrated of two sucrose solutions declined as the delay to that reinforcer was progressively increased. In Experiment 2, progressively increasing the delay to both reinforcers by the same amount resulted in a shift in preference away from the less concentrated solution. In Experiment 3, it was found that the decline in preference for the more concentrated solution as a function of the delay to that reinforcer was steeper when the rats were maintained at 90% than when they were maintained at 80% of their free-feeding body weights. This effect of deprivation level on choice is inconsistent with some current models of "self-control".

Animals↗

PubMed1992

Effect of high ambient temperature on the kinetics of the pupillary light reflex in healthy volunteers.

Miotic responses to brief light stimuli were studied in healthy volunteers under two ambient temperature conditions, 22 degrees C and 40 degrees C. The latency and amplitude of the light reflex did not differ between the two conditions, but the recovery time of the reflex was significantly shorter under the 40 degrees C condition than under the 22 degrees C condition. The results are consistent with the hypothesis that exposure to high ambient temperature results in an increased sympathetic drive to the iris dilator muscle but does not influence the parasympathetic light reflex.

Adult↗

PubMed1992

Choice between delayed reinforcers in an adjusting-delay schedule: the effects of absolute reinforcer size and deprivation level.

Choice between two reinforcers differing in magnitude and delay was investigated in rats using an adjusting-delay discrete-trials schedule in which the two reinforcers were associated with two levers (A and B). The delay to Reinforcer A (the smaller reinforcer) was always 2 sec, whereas the delay to Reinforcer B was varied in accordance with the distribution of choices in successive blocks of trials. In Experiment 1, the mean delay to the large reinforcer during the last 5 of 60 training sessions was greater when the rats were maintained at 80% than when they were maintained at 90% of their free-feeding body weights. In Experiment 2, the delay to the larger reinforcer was greater when the two reinforcers consisted of one and two 45-mg food pellets than when they consisted of three and six pellets. The results are consistent with a model of "self-control" which posits hyperbolic relations between reinforcer value and reinforcer magnitude, and between reinforcer value and delay of reinforcement.

Animals↗

PubMed1991

Evidence for an involvement of 5-hydroxytryptaminergic neurones in the maintenance of operant behaviour by positive reinforcement.

The possible involvement of the ascending 5-hydroxytryptaminergic (5HTergic) pathways in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Nine rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham injections. The rats were trained to steady-state in a series of variable-interval schedules of sucrose reinforcement affording a range of reinforcement frequencies. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value of KH (the parameter expressing the reinforcement frequency needed to obtain the half-maximum response rate) was significantly lower in the lesioned group than in the control group; the values of Rmax (the parameter expressing the maximum response rate) did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, nucleus accumbens and hypothalamus were markedly reduced in all four regions in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected. The results indicate that damage to the central 5HTergic pathways resulted in an increase in the "value" of the sucrose reinforcer, without affecting the animals' response capacity. The results are consistent with the suggestion that the 5HTergic pathways may exert some limiting control on the "values" of certain reinforcers.

5,7-Dihydroxytryptamine↗

PubMed1991

Effects of clonidine and yohimbine on the pupillary light reflex and carbachol-evoked sweating in healthy volunteers.

The effects of single doses of clonidine hydrochloride (200 micrograms), yohimbine hydrochloride (22 mg), a combination of the two treatments, and placebo, on some autonomic functions were studied in healthy volunteers using a double-blind crossover design. Clonidine prolonged the recovery time of the light reflex, lowered systolic blood pressure and reduced subjectively rated alertness; these effects were reversed by yohimbine. Responsiveness of sweat glands to carbachol was not affected by the treatments.

Adult↗

PubMed1991

Relative and absolute reinforcement frequency as determinants of choice in concurrent variable interval schedules.

Rats were trained under concurrent schedules consisting of two equal variable interval component schedules providing sucrose solutions of different concentrations (0.6 M, 0.2 M; 50 microliters in each case) as the reinforcers. The mean interreinforcement interval specified by the schedules was varied from 10 to 640 sec. Absolute response rate in each component was an increasing hyperbolic function of reinforcement frequency. Relative response rate and relative time allocation revealed a consistent preference for the more concentrated solution; neither measure of preference was systematically related to reinforcement frequency. The results are consistent with Baum and Rachlin's (1969) extension of the matching law, and with a derivation of the matching law from the hyperbolic relation between absolute response rate and reinforcement frequency in variable interval schedules (Herrnstein, 1970).

Animals↗

PubMed1990

A comparison of the anticholinergic effects of two formulations of disopyramide in healthy volunteers.

Eight healthy male volunteers took a single oral dose of one of the following: Rythmodan (conventionally formulated disopyramide) 150 mg; Rythmodan 250 mg; Rythmodan Retard (controlled-release disopyramide) 250 mg; placebo. The subjects were allocated double-blind to sessions and treatments according to a Latin square design. In each session pupil diameter, heart rate, salivation, and QT interval were measured immediately before and at 1, 2, 3, 4, 6, 8, and 24 h after the drug. QT interval was corrected for heart rate (QT60). Plasma concentrations of total and unbound disopyramide were also determined at each time point. Both formulations of disopyramide reduced salivary output and increased QT60 interval, but there was not significant difference between the effects of the three active treatments. Neither formulation had any effect on pupil diameter or heart rate. The peak plasma concentration of unbound disopyramide was reached 2 h after Rythmodan and 4 h after Rythmodan Retard. The peak plasma concentration of disopyramide was significantly lower after Rythmodan Retard 250 mg than after Rythmodan 250 mg. The plasma concentration of unbound disopyramide was positively correlated with the reduction in salivation and prolongation of the QT60 interval. The reduction in salivation is likely to reflect blockade of muscarinic receptors by disopyramide, whereas the increase in QT60 interval is likely to be related to a direct effect of the drug on the heart. The results of this single-dose study do not indicate that disopyramide in the controlled-release formulation would be better tolerated by patients than conventionally formulated disopyramide.

Administration, Oral↗

PubMed1990

Interaction between antidepressants and d-amphetamine on variable-interval performance.

Four experiments were carried out investigating the interactions between some antidepressant drugs (imipramine, desipramine, fluvoxamine, trazodone (4 and 8 mg/kg) and d-amphetamine (0.1-3.2 mg/kg) on operant behaviour maintained under a variable-interval 80-s schedule of sucrose reinforcement; each experiment employed 12 rats. d-Amphetamine exerted a dose-related suppressant effect on response rate. Imipramine and desipramine given alone had no effect on response rate, whereas fluvoxamine (both doses) and the higher dose of trazodone produced significant increases in response rate. Pretreatment with imipramine, desipiramine or fluvoxamine significantly potentiated the suppressant effect of d-amphetamine on responding; pretreatment with trazodone had no significant effect. The potentiating effect of imipramine and desipramine may be related to their well known uptake blocking actions. The fact that fluvoxamine, a selective inhibitor of 5-hydroxytryptamine (5HT) uptake, also potentiated the effect of d-amphetamine suggests that the suppressant effect of d-amphetamine on operant behaviour may involve 5HT as well as catecholamine release. The lack of effect of trazodone may reflect its failure to influence uptake mechanisms. On the basis of a formal model couched in terms of Herrnstein's (1970) equation, it is suggested that imipramine, desipramine and fluvoxamine may have enhanced d-amphetamine's ability to reduce response capacity; it is suggested that the data do not provide evidence for an interaction between the antidepressants and the putative "motivation-enhancing" effect of d-amphetamine.

Animals↗

PubMed1990

Attenuation of the pupillary light reflex in anxious patients.

1. The miotic responses evoked by brief light stimuli were compared between a group of 10 patients suffering from generalized anxiety disorder and 10 age- and sex-matched healthy control subjects. 2. Resting pupil diameter in the dark did not differ significantly between the two groups. 3. In both groups, the amplitude of the light reflex was linearly related to the logarithm of the intensity of the light stimulus; responses in the anxious patient group had consistently lower amplitudes than those in the control group. 4. In both groups, the time taken for 75% recovery of the baseline pupil diameter following a light stimulus was linearly related to the logarithm of the light intensity; the 75% recovery times did not differ significantly between the two groups. 5. It is suggested that these results are consistent with a greater supranuclear inhibition of the parasympathetic oculomotor reflex arc in the anxious patients.

Adult↗

PubMed1989

Seasonal variation in responsiveness of human eccrine sweat glands to phenylephrine.

The responses of eccrine sweat glands to intradermally injected phenylephrine were studied in six healthy male volunteers in two experiments carried out in February and June. Phenylephrine (10(-7)-10(-2) M, 50 microliters) had no consistent effect on sweat gland activity during February, but evoked dose-related increases in sweat gland activity during June. Responsiveness to phenylephrine could be antagonized by prazosin (10(-5) and 10(-4) M) added to the injection solution.

Adult↗

PubMed1988

DSP4 and Herrnstein's equation: further evidence for a role of noradrenaline in the maintenance of operant behaviour by positive reinforcement.

The effect of the selective noradrenaline neurotoxin DSP4 on steady-state operant behaviour was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation, which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Eleven rats received injections of DSP4 (two doses of 50 mg/kg, intraperitoneally), and 12 rats received injections of the vehicle alone. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement, affording scheduled reinforcement frequencies of 4-360 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The value of KH (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) was higher in the DSP4-treated rats than in the control rats; the value of Rmax (the parameter expressing the maximum response rate) did not differ significantly between the two groups. At the end of the behavioural experiment the rats were sacrificed for determination of the concentrations of catecholamines in the brain by high-performance liquid chromatography. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum of the DSP4-treated rats were less than 20% of those of the control rats. The results provide further evidence that central noradrenergic neurones are involved in the maintenance of operant behaviour by positive reinforcement.

Animals↗

PubMed1988

Consensual pupillary responses to mydriatic and miotic drugs.

1. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated fellow eye, in healthy volunteers. 2. In Experiment 1, the effects of four subjects, using photography in an illuminated room to assess pupil diameter. The drug evoked a dose-dependent mydriasis in the index eye which was accompanied by a simultaneous dose-dependent miosis in the fellow eye. 3. In Experiment 2, the same method was used to assess pupil diameter as in Experiment 1. The effects of mydriatic (methoxamine and tyramine) and of miotic (pilocarpine) drugs instilled into the fellow eye, were studied on the sizes of pupillary responses to the same drugs instilled into the index eye. The presence of a mydriatic drug in the fellow eye resulted in a decrease in the size of the mydriatic responses in the index eye. 4. In Experiment 3, the effects of three concentrations of phenylephrine hydrochloride (0.15-0.60 M) and of three concentrations of pilocarpine hydrochloride (0.002-0.008 M), were studied in darkness using an infra-red binocular television pupillometer, in seven subjects. Phenylephrine evoked dose-dependent mydriasis and pilocarpine evoked dose-dependent miosis. The pupillary responses of the index eye were not accompanied by any changes in the diameter of the pupil of the fellow eye. 5. It is concluded that drug-induced mydriasis in the index eye is accompanied by a consensual miosis in the fellow eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1987

DSP4 alters the effect of d-amphetamine on variable-interval performance: analysis in terms of Herrnstein's equation.

The effect of d-amphetamine (0.1-3.2 mg/kg) on performance in variable-interval 1-min and variable-interval 12-min schedules of positive reinforcement was examined in ten rats treated with the selective noradrenaline neurotoxin DSP4 and 12 control rats. In the control group d-amphetamine had a dose-dependent suppressant effect on response rates maintained under variable-interval 1-min; under variable-interval 12-min, response rates were increased by low doses and suppressed by higher doses of the drug. In the case of both schedules, lower doses of d-amphetamine were more suppressant and higher doses less suppressant in the DSP4-treated group than in the control group. The levels of noradrenaline in the parietal cortex, hippocampus and cerebellum (determined by high-performance liquid chromatography) were reduced to approximately 15% of control levels in the DSP4-treated rats. The results indicate that treatment with DSP4 attenuated both the facilitatory and the suppressant effects of d-amphetamine on variable-interval performance. A formal model couched in terms of Herrnstein's (1970) equation is put forward to account for these results. It is suggested that the noradrenergic pathways emanating from the locus caeruleus are involved in both the facilitatory and suppressant effects of d-amphetamine on operant behaviour.

Animals↗

PubMed1987

Effect of 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle on steady-state operant behaviour.

The possible role of the dorsal noradrenergic bundle (DNAB) in the maintenance of operant behaviour by positive reinforcement was examined using a quantitative behavioural paradigm based on Herrnstein's (1970) equation which defines a hyperbolic relationship between steady-state response rate and reinforcement frequency in variable-interval schedules. Twelve rats received bilateral injections of 6-hydroxydopamine (4 micrograms/2 microliters) into the DNAB; ten rats received sham injections. The rats were trained to steady state in a series of six variable-interval schedules of sucrose reinforcement affording reinforcement frequencies of 8-350 reinforcers per hour. Herrnstein's equation was fitted to the data obtained from each rat and to the averaged data obtained from the two groups. The values of both Rmax (the parameter of the equation expressing the theoretical maximum response rate) and KH (the parameter expressing the reinforcement frequency needed to maintain the half-maximal response rate) were significantly higher in the DNAB-lesioned group than in the sham-lesioned group. At the end of the behavioural experiment the rats were sacrificed for determination of catecholamine levels in the brain by high-performance liquid chromatography. The levels of noradrenaline in the neocortex and hippocampus of the DNAB-lesioned rats were approximately 10% of those of the sham-lesioned rats. The results indicate that destruction of the DNAB reduced the "value" of the reinforcer without impairing the animals' capacity to respond.

Animals↗

PubMed1987

Attenuation by pimozide of the suppressant effect of d-amphetamine on operant behaviour.

The interaction between pimozide (a selective D2-dopamine receptor antagonist) and d-amphetamine on the operant performance of rats maintained under variable-interval schedules of positive reinforcement was examined. In Experiment 1, eight rats responded under variable-interval 30-s and variable-interval 300-s. Pimozide (0.0625, 0.125, 0.25, 0.5 mg/kg) suppressed performance maintained under both schedules in a dose-dependent manner, the degrees of suppression being equivalent in the two schedules. In Experiment 2, 12 rats responded under the same schedules. d-Amphetamine (0.1-3.2 mg/kg) suppressed performance under both schedules, the degree of suppression being somewhat greater in the case of variable-interval 30-s. Pre-treatment with pimozide (0.0625, 0.125 mg/kg) significantly attenuated the suppressant effect of d-amphetamine under both schedules. It is suggested that D2-dopamine receptors may be involved in mediating the suppressant effect of d-amphetamine on operant behaviour.

Animals↗

PubMed1987

Involvement of M1-muscarinic receptors in the excitation of neocortical neurones by acetylcholine.

The technique of microelectrophoresis was used to investigate the cholinoceptor pharmacology of spontaneously active single neurones in the parietal cortex of the rat. Acetylcholine, carbachol and the selective M1-muscarinic receptor agonist, McN-A-343, were each potent excitants (rank order of apparent potency: carbachol greater than acetylcholine greater than McN-A-343). When measured in vitro, the apparent mobilities of carbachol and acetylcholine were similar although significantly less than that of McN-A-343, suggesting that the lower potencies of acetylcholine and McN-A-343 probably reflect a genuine biological phenomenon. In addition to excitation, carbachol also evoked biphasic (excitation/depression) and depressant responses. In contrast to the other cholinoceptor agonists, nicotine produced weak and inconsistent excitations. Excitatory responses to acetylcholine and carbachol were significantly attenuated by the selective M1-muscarinic receptor antagonist, pirenzepine, at a time when the excitatory response to McN-A-343 was also significantly reduced. Responses to phenylephrine were not diminished. On several cells an excitatory response to carbachol was converted to a depression by pirenzepine. These results suggest that the excitatory responses of cortical neurones to cholinoceptor agonists are mediated predominantly by M1-muscarinic receptors. The identity of the receptor mediating the depressant response to carbachol remains uncertain, although nicotinic cholinoceptors do not appear to be involved.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗