Biomedical subjects

P Willner

Publications and source records attributed to P Willner.

At least 91 records · Page 5Linked to original sources

PubMed1989

Effects of dopamine receptor antagonists on sucrose consumption and preference.

Effects of the dopamine D2 receptor antagonist sulpiride and the D1 antagonist SCH-23390 were examined, in rats, in two-bottle preference tests (sucrose versus water) and in single-bottle tests, at different sucrose concentrations. Both drugs decreased sucrose intake in single bottle tests, at low sucrose concentrations, but had no effect at high concentrations; reducing drive level had exactly the opposite pattern of effects. In two-bottle tests, both drugs reduced preference for the weakest sucrose concentration (0.7%) but increased preference for the strongest concentration (34%). The effects of antagonizing either subtype of DA receptor appear to be similar to those of reducing the concentration of sucrose.

Animals↗

PubMed1989

Noradrenergic receptor interactions in feeding elicited by stimulation of the para-ventricular hypothalamus.

Food intake and feeding behaviour were examined after the administration of noradrenaline (NA) or clonidine to the para-ventricular nucleus of the hypothalamus, or after systemic administration of clonidine. In 20-hr deprived animals all treatments dose-dependently reduced pellet consumption; however, at a low dose (2-5 micrograms) central clonidine increased eating time and bout length. In 4-hr deprived animals all treatments increased sucrose consumption. Clonidine (peripheral and central) increased feeding time but did not alter feeding rate; NA did not alter feeding time, but did increase feeding rate; NA also increased activity and decreased resting. The effects of NA on feeding rate, activity and resting were blocked by propranolol; however, the propranolol-NA combination increased feeding time. Thus, NA and clonidine increased feeding by different mechanisms, but after propranolol pretreatment the effects of NA were similar to those of clonidine. It is concluded that clonidine enhances feeding by inhibiting satiety and that the feeding stimulant effect of NA is mediated by a complex interaction of alpha- and beta-receptors.

Animals↗

PubMed1988

Fenfluramine disrupts the behavioural satiety sequence in rats.

Previous studies have shown that when hungry rats are fed to satiety, the offset of eating is followed by a short period of activity superseded by resting behaviour. Observations of rats consuming wet mash or sucrose confirmed this "behavioural satiety sequence" and showed that the duration of resting was related to the intake of calories rather than of bulk. Fenfluramine reduced the consumption of sucrose and wet mash, but at anorectic and subanorectic doses, fenfluramine also suppressed resting behaviour; the effects of dl- and d-fenfluramine were qualitatively similar. It is argued that the suppression of resting behaviour by fenfluramine is incompatible with an enhancement of satiety.

Animals↗

PubMed1988

Tests of functional equivalence between pimozide pretreatment, extinction and free feeding.

Both pimozide pretreatment and free feeding caused within-session and between-session decrements in variable interval operant performance; response decrements generated under pimozide were maintained on transfer to free feeding, and vice versa. On subsequently testing under extinction conditions (after food deprivation and drug free) large initial increases in responding were seen in all groups, and subsequent response decrements in extinction were steeper than in either pimozide or free feeding conditions. The effects of pimozide pretreatment do not resemble those of extinction, but may in some circumstances be functionally equivalent to a decrease in drive level.

Animals↗

PubMed1988

Changes in dopamine autoreceptor sensitivity in an animal model of depression.

Rats exposed for 6 weeks to a variety of mild unpredictable stressors showed reduced consumption of a preferred sucrose solution. The deficit was apparent after 1 week of stress and was maintained for at least 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 2 weeks of treatment with the tricyclic antidepressant DMI but returned to normal after 3 weeks of DMI treatment. Subsensitivity to the anorexic effect of a low dose of apomorphine was seen in vehicle-treated stressed animals, and in unstressed animals following withdrawal from DMI. In both cases, the changes resulted from a failure of apomorphine to reduce eating time (rather than from changes in eating rate); this effect is assumed to represent a subsensitive response to stimulation of dopamine cell body autoreceptors. As the same effect is seen in anhedonic stressed animals and in animals withdrawn from DMI, it is concluded that dopamine autoreceptor desensitization probably does not contribute to clinical improvement following chronic antidepressant treatment.

Animals↗

PubMed1988

Behavioural specificity of 8-OH-DPAT-induced feeding.

8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) has been reported to increase food intake. This effect was confirmed in rats consuming plain or sweetened wet mash. However, the consumption of a 35% sucrose solution or of a range of other flavoured liquids was enhanced marginally if at all by a single low dose of 8-OH-DPAT, and the drug actually decreased the consumption of a high protein liquid diet. 8-OH-DPAT did, however, increase gnawing on a wooden block. These results suggest that 8-OH-DPAT-induced "hyperphagia" may to some extent be secondary to the elicitation of chewing behaviour. 8-OH-DPAT also caused certain other behavioural changes, including a suppression of grooming.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

Apomorphine anorexia: the role of dopamine receptors in the ventral forebrain.

The inhibition of feeding following the administration of apomorphine, systemically or directly into the nucleus accumbens/ventral striatum, was studied using a microstructural analysis paradigm. On systemic administration, apomorphine reduced food consumption, eating rate and eating time; the effects were blocked by sulpiride but not by SCH-23390. Two doses of apomorphine were administered centrally. Both doses reduced total food intake and eating rate; only the higher dose also reduced eating time; all of these effects were blocked by sulpiride pretreatment. Only the lower dose reduced locomotor activity and rearing in the open field. The results suggest that apomorphine reduces eating rate by an action on dopamine (DA) axon terminal autoreceptors. We have previously demonstrated that apomorphine reduces eating time by an action on DA cell body autoreceptors. Therefore, the two populations of DA autoreceptors appear to be differentially involved in behaviour.

Animals↗

PubMed1988

Behavioural microanalysis of the role of dopamine in amphetamine anorexia.

A microstructural analysis paradigm was used to study amphetamine anorexia. Doses above 0.40 mg/kg significantly reduced food intake by reducing eating time; in contrast, eating rate was increased at these doses. Examination of the frequency distribution of interresponse times (IRTs) revealed a significant shift to shorter IRTs at doses as low as 0.125 mg/kg. Pimozide blocked amphetamine anorexia at 0.5 and 1.0 mg/kg, suggesting that at both doses amphetamine anorexia has a dopaminergic substrate. However, the atypical neuroleptic thioridazine did not antagonize amphetamine. Furthermore, effects of amphetamine were additive with those of apomorphine, administered at a dose known to suppress feeding by inhibiting mesolimbic DA neurons. These results provide evidence against an involvement of the mesolimbic DA system in amphetamine anorexia.

Animals↗

PubMed1987

Effects of pimozide on sucrose consumption and preference.

The effects of pimozide on sucrose intake were examined, in a two-bottle preference test (sucrose versus water), and in single-bottle tests at five different sucrose concentrations. In the two-bottle test, pimozide dose dependently decreased sucrose intake but increased water intake. In the single-bottle test pimozide decreased sucrose intake at low concentrations but had no effect at high concentrations. The results support a role for dopamine in mediating the rewarding effect of sucrose.

Animals↗

PubMed1987

Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.

Rats exposed chronically (5-9 weeks) to a variety of mild unpredictable stressors showed a reduced consumption of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 2-4 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression.

Animals↗

PubMed1987

A novel procedure for dissociating the anatomical bases of the behavioral effects of amphetamine.

A novel operative procedure is described in which the same cannula may be used to administer drugs either to the caudate nucleus (CN) or to the nucleus accumbens (NAcc) of the rat. Microinjections of amphetamine (10 or 20 micrograms) into the CN produced a reliable and robust stereotyped response; when administered to the NAcc of the same animal the higher dose increased locomotor activity. The stereotypy following peripheral administration of amphetamine (5 mg/kg) was antagonised by infusions of haloperidol (30 micrograms) into the CN but not into the NAcc. Conversely, the locomotor activity following a lower dose of amphetamine (1 mg/kg) was antagonised by infusions of haloperidol (5 micrograms) into the NAcc but not into the CN. The results confirm earlier reports that different anatomical structures mediate the behavioral effects of low and high doses of amphetamine.

Amphetamine↗

PubMed1986

Apomorphine anorexia: a further pharmacological characterization.

Low doses of apomorphine reduce food intake, primarily by decreasing the rate of eating and also by reducing eating time. We have previously reported that the effect on eating time is mediated by dopamine cell body autoreceptors in the ventral tegmental area. The present experiments were designed to elucidate the pharmacological basis of the effect of apomorphine on eating rate. In the first experiment dopamine was also found to reduce food intake, but mainly by an effect on eating time. The peripheral DA antagonist domperidone abolished the effects of DA, but enhanced the effects of apomorphine. In the second experiment phentolamine, yohimbine, propranolol, scopolamine, naloxone and methergoline all failed to reverse the effect of apomorphine on eating rate. However, in the third experiment, effects of apomorphine on total food intake, eating time and eating rate were all blocked by the neuroleptics, pimozide and sulpiride. It is concluded that the reduction of eating rate by apomorphine is also mediated by an interaction with central DA receptors, but that this receptor population is anatomically distinct from that responsible for the effect of apomorphine on eating time.

Animals↗

PubMed1986

Dopamine autoreceptors in the ventral tegmental area show subsensitivity following withdrawal from chronic antidepressant drug treatment.

The suppression by apomorphine of food intake and eating time was used to assay the sensitivity of dopamine cell body autoreceptors during the course of treatment with DMI, amitriptyline and mianserin. Brief (2-4 days) DMI treatment enhanced the effects of apomorphine, administered systemically or centrally to DA cell body regions. During chronic DMI treatment (3-7 weeks) some evidence of autoreceptor subsensitivity was observed with systemic apomorphine, but not with central apomorphine. Responses to apomorphine applied systemically were reduced during withdrawal from chronic DMI, and responses to apomorphine applied to the ventral tegmental area were reduced during withdrawal from all three antidepressants. As evidence of DA autoreceptor subsensitivity was only observed reliably during withdrawal, this effect is unlikely to be of clinical importance.

Animals↗

PubMed1986

Conditioned taste aversion and conditioned drinking: two independent and opposing effects of 5-hydroxytryptophan?

Four experiments were carried out to examine the effects of 5-HTP in a conditioned taste aversion (CTA) paradigm. Using two-choice tests to measure the CTA, administration of 5-HTP following consumption of a novel flavour caused aversions to saline and saccharin solutions. In single-choice tests 5-HTP reduced consumption of saccharin, sugar cubes and beef-flavoured stock cubes, but only reduced saline consumption if animals had been pretreated with the 5-HTP decarboxylase inhibitor benserazide or the 5-HT receptor antagonist xylamidine, both of which act peripherally. Benserazide did not attenuate the CTA in any experiment. The results are interpreted in terms of two competing behavioural effects of 5-HTP: a centrally-mediated CTA and a peripherally-mediated conditioned drinking response.

5-Hydroxytryptophan↗

PubMed1986

Apomorphine anorexia: the role of dopamine cell body autoreceptors.

Anorectic effects of apomorphine were studied in a microstructural analysis paradigm. Systemic apomorphine reduced food intake by reducing both the rate of eating and the time spent eating. Peripheral administration of sulpiride reversed the apomorphine effect on both eating rate and eating time but central administration of this neuroleptic into the ventral tegmental area (VTA) selectively reversed the apomorphine effect on eating time, sparing eating rate. Administration of apomorphine directly into the VTA reduced eating time but not eating rate; the effect on eating time was blocked by peripheral sulpiride. The results imply that the two components of apomorphine anorexia result from actions at different sites. Effects of apomorphine on eating time appear to result from an action on DA cell body autoreceptors. The apomorphine effect on eating rate appears to be mediated elsewhere.

Animals↗

PubMed1986

Specific disruption of spatial behaviour in rats by central muscarinic receptor blockade.

Three groups of rats were required to locate a single water bottle from an octagonal array of eight otherwise empty bottles. For one group (place navigation) the goal bottle remained in the same place from trial to trial; for a second group (cue navigation) the position of the goal bottle was cued by a black card over the nozzle; for the third group the goal bottle was uncued and moved randomly from trial to trial. Place and cue groups improved more than controls on all measures of performance. Scopolamine (0.2 mg/kg) substantially impaired performance in the place group, but had no effect on either of the other groups; the peripherally acting anticholinergic drug meth-scopolamine (0.2 mg/kg) had no effect in any group. In a second experiment, using food rewards, scopolamine caused a dose-dependent impairment of place navigation at doses from 0.025 to 0.4 mg/kg; 0.4 mg/kg also impaired cue navigation, but at this dose behaviour was visibly abnormal. In both experiments, scopolamine primarily affected speed of performance rather than accuracy. Olfactory cues were shown not to contribute to performance in either group. The results implicate central cholinergic transmission in the processing of visuo-spatial information.

Animals↗

PubMed1986

Effects of chlordiazepoxide and sodium valproate in two tests of spatial behaviour.

The effects of chlordiazepoxide (CDP) and sodium valproate (VPA) were studied in rats trained to asymptotic performance on two tests of spatial behaviour, the 8-arm radial maze and the 8-choice arena. The task in the 8-arm maze was to locate a single food pellet at the end of each arm. Both CDP and VPA caused an increase in errors, an increase in performance time, and the utilization of a non-spatial response strategy. The task in the 8-choice arena was to locate a single water bottle from an octagonal array of eight otherwise empty bottles. For one group the goal bottle remained in the same place from trial to trial; for a second group the position of the goal bottle was cued by a black card over the nozzle; for the third group the goal bottle was uncued and moved randomly from trial to trial. VPA had no effect on performance, but CDP impaired performance in all three groups. These patterns of effects suggest that VPA may specifically disrupt working memory, but that the impairment of spatial performance by CDP probably results from a non-specific perceptual or attentional deficit.

Animals↗

PubMed1986

Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case.

Three sets of criteria are proposed for assessing animal models of human mental disorders: predictive validity (performance in the test predicts performance in the condition being modelled), face validity (phenomenological similarity) and construct validity (theoretical rationale). The problems inherent in each of these validation procedures are discussed, and their application to the learned helplessness model of depression is examined. It is concluded that whilst the model has good predictive validity, important questions about face validity remain unanswered, and construct validity has not yet been established. The distinctions between animal models and some related experimental procedures are also discussed.

Animals↗