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Biomedical subjects

P Redgrave

Publications and source records attributed to P Redgrave.

At least 91 records · Page 5Linked to original sources
PubMed1982

Suppression of apomorphine-induced oral stereotypy in rats by microinjection of muscimol into midbrain.

Rats with large lesions of the superior colliculus do not display the oral stereotypy normally induced by high systemic doses of dopamine-agonists. It has been suggested that collicular lesions have such an effect because they destroy the GABAergic nigrotectal pathway. This suggestion was investigated by observing the effects of bilateral microinjections of the GABA-agonist muscimol into midbrain sites in rats given 8 mg/kg subcutaneous apomorphine. A low dose of muscimol (25 ng in 0.5 ul saline/side) injected into regions of the superior colliculus with nigrotectal innervation almost abolished apomorphine-induced licking and gnawing. Control microinjections of saline into the superior colliculus, or of muscimol into overlying cerebral cortex, were ineffective. This result is consistent with the GABAergic nigrotectal projection being important for the expression of dopamine-related oral stereotypy. It was also found, however, that 25 ng of muscimol suppressed oral stereotypy when microinjected into the mesencephalic reticular formation underlying the superior colliculus. The anatomical basis of this latter effect is uncertain.

Animals↗
PubMed1982

Increased food intake following the manipulation of intracerebral dopamine levels with gamma-hydroxybutyrate.

The administration of gamma-hydroxybutyric acid (GHB) initially causes a temporary "sleep-like" state during which there is an increase in forebrain dopamine levels. The present series of experiments examined whether in the period following the GHB-induced behavioural depression, when accumulated dopamine is dispersed, there is any behavioural evidence of increased dopaminergic activity. The first experiment, in which GHB was injected directly into the cerebral ventricles, demonstrated that in the immediate post-recovery period rats exhibited various forms of stereotyped oral behaviour and stereotyped sniffing. Unexpectedly, it was also observed that if food were present animals preferred to eat. The nature of this feeding response was examined in two further experiments. Firstly, it was shown that in the period following the behavioural depression animals would perform, in a dose-dependent fashion, an operant response which was rewarded by food. Secondly, the GHB-induced increase in feeding was abolished by the pre-treatment of animals with either the dopamine synthesis inhibitor alpha-methyl-p-tyrosine, or the dopamine receptor blocker haloperidol. These data indicate that (i) in the period when it is known that the GHB-induced accumulation of dopamine is dispersing, there is behavioural evidence of increased dopaminergic activity; (ii) the feeding response is not a simple oral reflex; and (iii) in addition to being essential for food intake dopaminergic transmission may play a direct role in the production of feeding.

Amphetamine↗
PubMed1982

Oral behaviour induced by intranigral muscimol is unaffected by haloperidol but abolished by large lesions of superior colliculus.

It has been suggested that the GAbAergic striatonigral projection may form part of the efferent pathway responsible for the expression of dopamine-related oral behaviour. Consistent with this suggestion are reports that bilateral injection of the GABA agonist muscimol can produce stereotyped gnawing and biting. We report here two experiments on this effect: (1) A dose of the dopamine receptor blocker haloperidol (0.4 mg/kg), which effectively antagonised oral stereotypy induced by systemically administered apomorphine or intranigral carbachol, had no effect on either the latency or the intensity of the gnawing produced by intranigral muscimol (1 nM); (2) large lesions involving the superior colliculus which effectively suppressed the oral stereotypy induced by 8 mg/kg apomorphine completely abolished the gnawing induced by intranigral injection of muscimol. Collicular lesions suppressed both the gnawing which occurred spontaneously and that elicited by a perioral probe. These findings are consistent with the view that the substantia nigra is a relay station between the caudate nucleus and the superior colliculus in an efferent pathway mediating dopamine-related oral behaviour. In addition, they raise the possibility that such behaviour is produced by the sensitisation of a collicular-mediated perioral reflex.

Animals↗
PubMed1982

A quantitative analysis of stereotyped gnawing induced by apomorphine.

An apparatus was designed and constructed to enable a quantitative analysis of the stereotyped gnawing produced by the dopamine agonist apomorphine. Using this apparatus it was discovered that increasing the subcutaneous dose of apomorphine increased (1) the number of animals that gnawed, and (2) the duration of gnawing in those animals that gnawed at all doses. Other aspects of apomorphine-induced gnawing, in particular the latency to respond and the frequency and duration of individual gnaws, were relatively unaffected. Likely properties of the system responsible for the organization of sterotyped gnawing are discussed.

Animals↗
PubMed1982

Locomotor activity of rats in open field after microinjection of procaine into superior colliculus or underlying reticular formation.

Whereas large lesions of the superior colliculus in rats increase locomotor activity in the open field, bilateral collicular microinjections of muscimol (an agonist of the inhibitory neurotransmitter GABA) have been reported to reduce open-field activity. This difference might be due to muscimol's acting on a subpopulation of collicular neurones, or to some feature of the microinjection technique. The issue was investigated by observing open-field behavior after reversible lesions produced by bilateral microinjections of the local anaesthetic procaine (10-300 micrograms in 0.5 microliter) into midbrain sites. Injections of procaine into the superior colliculus produced effects similar to those reported after muscimol injections: both locomotor activity and other exploratory responses were suppressed, with the rats spending much of their time motionless in an alert posture. In contrast, animals with injections of procaine into the mesencephalic reticular formation (MRF) ventral to the superior colliculus resembled rats given large collicular lesions: they showed very striking increases in locomotor activity, while their rearing and exploratory head movements were reduced. It is suggested that in some experiments large collicular lesions may have increased locomotor activity in the open field because they invaded underlying MRF. However, it is also possible that in rodents the acute effects of collicular inactivation, as assessed by microinjection of muscimol or procaine, are different from the chronic effects that are observed in experiments with electrolytic or radiofrequency lesions.

Animals↗
PubMed1982

Photometric assessment of glyoxylic acid-induced fluorescence of dopamine in the caudate nucleus.

New procedure for quantitative photometric assessment of glyoxylic acid-induced fluorescence of dopamine in the caudate nucleus are presented. A recently published cryostat method was used to process a series of 24 micrometer sections taken from the caudate nucleus of each animal. Fluorescent light contained within a circular field (0.8 mm diameter) was measured photometrically. Several defined positions within the caudate nucleus on each tissue section were selected for measurement. Thus, a grid of measurements taken throughout the caudate nucleus provided a three-dimensional description of fluorescence intensity within this structure on both sides of the brain. Several experiments were performed to evaluate both the reliability and validity of these procedures as an index of the relative regional content of dopamine within the caudate: (1) the relative distribution of fluorescence intensity within the mouse striatum was in good agreement with previously reported distributions based on biochemical determination of regional dopamine levels within the rodent brain; (2) pharmacological manipulation of dopamine levels with gamma-butyrolactone and alpha-methyl-p-tyrosine combined with amphetamine produced predictable changes in the fluorescence intensity measurements of mouse caudate relative to untreated controls; (3) in rats pre-treated with alpha-methyl-p-tyrosine, unilateral electrical stimulation of the substantia nigra caused overall differences in fluorescence intensity between the caudate nucleus on each side of the brain, which were a function of both the duration of stimulation and the stimulating pulse frequency; (4) local injections of 6-hydroxydopamine unilaterally into the ventral tegmentum of animals pretreated with desmethylimipramine caused significant reductions in the intensity of fluorescence recorded from the ipsilateral striatum. It is concluded that the photometric procedures presented in this report constitute a significant improvement in the description of regional variations in the intensity of dopamine-related fluorescence in the caudate nucleus.

Animals↗
PubMed1982

Functional validation of projection topography in the nigrostriatal dopamine system.

Anatomical investigations have revealed that the nigrostriatal pathway is topographically organised. In two experiments, nigrostriatal topography was investigated with catecholamine specific procedures, using paradigms which reflect the functional activity of dopaminergic neurones. Data were analysed with the intention of discovering possible relationships between the mesencephalic location of stimulating electrodes or injection cannulae, the extent and location of dopamine histofluorescence depletion within the striatum, and the effects of amphetamine and apomorphine on rotational behaviour. In animals pretreated with 250 mg/kg alpha-methyl-p-tyrosine it was found that unilateral stimulation with medially-placed nigral electrodes produced maximal depletion of dopamine histofluorescence in anterior dorso-medial regions of the striatum, while laterally-located electrodes principally depleted posterior, ventro-lateral areas. In the second experiment, 2 micrograms of 6-hydroxydopamine in a volume of 0.5 microliter was injected unilaterally at varying loci within the ventral midbrain of animals pre-treated with desmethylimipramine (25 mg/kg). It was discovered that the lateral injection coordinate was significantly associated with both the extent and location of the depletion of dopamine-related fluorescence from the ipsilateral striatum. Rotational behaviour, induced by dopamine-agonists was related firstly, to the overall extent of dopamine depletion from the striatum, and secondly, the contraversive turning induced by apomorphine in particular was related to the dorsoventral coordinate of the mesencephalic 6-hydroxydopamine injection. The results provide functional validation for the pattern of topographical projection within the nigrostriatal dopaminergic system proposed on the basis of intracellular tracing techniques.

Amphetamine↗
PubMed1981

Rewarding effects of hypothalamic self-stimulation altered by unilateral lesions of superior colliculus in rats.

The effects of unilateral lesions of the superior colliculus were determined on self-stimulation of the medial forebrain bundle. It was found that the lesions had different effects depending upon the precise location of the stimulating electrode: self-stimulation on far-laterally located electrodes was abolished while on more medially placed electrodes this behaviour was enhanced. These data are inconsistent with explanations of intracranial self-stimulation which treat it as a unitary phenomenon.

Animals↗
PubMed1981

Gnawing and changes in reactivity produced by microinjections of picrotoxin into the superior colliculus of rats.

Lesions of the superior colliculus in rats attenute the oral stereotypy produced by systemic administration of dopamine agonists. Current evidence suggest that such drugs affect the superior colliculus by reducing transmission in the inhibitory GABAergic nigrotectal pathway. To investigate whether the superior colliculus plays a direct role in producing stereotyped oral movements, the present experiment therefore examined the effects of collicular microinjections of the GABA antagonist picrotoxin on the behaviour of rats observed in an open-field. Gnawing was observed after injections of picrotoxin (25 ng) into sites in the intermediate and deep layers of the superior colliculus, consistent with the superior colliculus playing a direct part in producing the stereotyped gnawing seen after systemic administration of dopamine agonists. However, gnawing was only observed after a period in which the animal showed strong avoidance reactions to stimuli that normally evoked orienting or little reaction. This change in reactivity was observed after injections of picrotoxin into all parts of the colliculus, but the most sensitive (responding to doses as low as 12.5 ng) were mainly in the superficial and intermediate layers. It appears that there may be more than one GABAergic system within the superior colliculus.

Animals↗
PubMed1981

Collicular picrotoxin alleviates akinesia but not sensory neglect in rats with bilateral 6-hydroxydopamine lesions of ventral midbrain.

Anatomical and biochemical investigations have suggested that GABA transmission in the superior colliculus consequent upon activity of the nigrotectal pathway is increased following 6-hydroxydopamine (6-OHDA) lesions of the ascending dopamine systems. Moreover, it has been proposed that this increase in inhibitory activity within the colliculus may be responsible for the sensory neglect commonly observed after dopamine denervation. The present experiment sought to test this proposal by examining the effects of injections of the GABA antagonist picrotoxin into the superior colliculus of 6-OHDA lesioned rats, in the hope that the neglect caused by the 6-OHDA would be reversed. However, in 33 of 36 cases studied intracollicular microinjections of picrotoxin produced no detectable improvement in orientation to sensory stimuli, although a wide range of other behavioural effects was observed. These included stereotyped exploratory movements (e.g. head waving, walking, sniffing and rearing) similar to those produced in the 6-OHDA treated rats by systemic injection of apomorphine (0.1 mg/kg). These data indicate that 6-OHDA lesions of substantia nigra and ventral midbrain areas do not produce sensory neglect simply by increasing GABA transmission within the nigrotectal pathway. Instead, such an increase in nigrotectal activity may impair production of particular kinds of movement, possibly related to exploratory behaviour.

Animals↗
PubMed1980

Dissociation of d-amphetamine-induced locomotor activity and stereotype behaviour by lesions of the superior colliculus.

To investigate the role of the nigrotectal pathway in the expression of the behavioral effects of increased dopamine transmission, the behavior of rats with lesions of the superior colliculus was studied in open-field and hole-board after systemic administration of d-amphetamine. The rats with collicular lesions had higher locomotor activity scores than controls after saline injections, and after all doses of amphetamine studied (0.5-24 mg/kg): the difference was particularly marked at the highest doses used (16 and 24 mg/kg). Stereotyped behavior, on the other hand, was less pronounced in the rats with collicular lesions, who unlike controls rarely showed stereotyped sniffing, head waving, or forepaw padding while moving about in either apparatus, and never licked or gnawed in the hole-board. This evidence suggests that the nigrotectal pathway may play a role in the expression of some of the stereotyped behaviors observed after the administration of dopamine agonists, but that it is not necessary for the increased locomotor activity produced by such drugs.

Animals↗