Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.657232
Title: Behavioural responses to manipulation of central monoamine systems in the rat
Author: Makanjuola, Roger Olatokunbo Aderibigbe
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1978
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Abstract:
In psychiatric illnesses, particularly in the affective disorders, and to a lesser extent in the schizophrenics, there are marked deviations from normal behaviour which have components which may be described, in psychological terms as aberrant, stereotyped, activity and as abnormalities in locomotor and exploratory drives. A hypothesis that a disturbance in one or more of the dopaminergic, noradrenergic or serotonergic neuronal systems in the brain may play a role in psychiatric illness has engendered much research into the functional roles of these systems in animals and man. The published work has been reviewed, particularly that in relation to the behavioural abnormalities which may be induced in lower animals such as the rat and which appear to mimic to some degree the abnormalities in behaviours seen in psychiatric illness in man. The experimental work presented in this thesis is a further contribution to this investigation using an animal model. Previous reports in the literature had, when considered together, indicated that in animals dopaminergic systems played a major role in the mediation of all three types of behaviour monitored - exploratory, locomotor and stereotyped behaviour - with lesser roles being assigned to noradrenergic and serotonergic systems. Individually, the previous studies tended to depend on visual observation of one, or, at most two, of these aspects of behaviour, with exploratory behaviour receiving much less attention than stereotyped or locomotor behaviour. This thesis reports the use of a specially designed automated wholeboard apparatus for the automated recording of exploratory, locomotor and stereotyped behaviour in rats. The automated recordings were backed up by visual observation of behaviour through closed-circuit television monitoring. The behavioural responses to a variety of drugs with varying degrees of selectivity on individual monoamine systems were studied. Amphetamine, which releases all three monoamines from neuronal terminals, at low doses (2 and 4 mg/kg of the DL-sulphate i.p.) led to a stimulation of exploratory and locomotor behaviour as well as sniffing and rearing while a larger dose (8 mg/kg) induced intense stereotyped activity. Baloperidol, a selective dopamine receptor antagonist, virtually abolished both spontaneous and amphetamine-stimulated exloratory, locomotor and stereotyped behaviour in a dose-related manner. Repeated weekly administration of amphetamine led to a potentiation of the response to the drug. Paradoxically, chronic haloperidol pretreatment also led to a potentiation of the response to amphetamine. Phenoxybenzamine (20 mg/kg of the hydrochloride i.p.), and adrenoceptor blocker reduced amphetamine-induced exploratory and locomotor behaviour but not stereotypy. Methysergide, a 5-HT receptor blocker, led to a moderate potentiation of the stimulation of all three behaviours by amphetamine; this was not statistically significant. The "tricyclic" antidepressant drugs desmethylimipramine and chlorimipramine caused a reduction in spontaneous activity which was more marked with the former drug. GPI 654, a selective inhibitor of neuronal 5-HT uptake, induced a moderate stimulation of locomotor and hole-dipping behaviour not statistically significant. Those three drugs, as well as SKF-525A, an inhibitor of the hepaticmicrosomal enzyme systems, all potentiated the behavioural response to amphetamine; this potentiation was in the same rank order as their ability to elevate plasma and brain amphetamine levels. LRCL 5182, a selective inhibitor of neuronal dopamine uptake, and benztropine, an inhibitor of neuronal dopamine uptake which also has potent anticholinergic activity, both induced a marked stimulation of exploratory, locomotor and stereotyped behaviour. Selective bilateral destruction of dopaminergic neuronal terminals in the accumbens nuclei with 6-hydroxydopamine reduced spontaneous and amphetamine-induced locomotor and exploratory behaviour and sniffing activity; amphetamine-induced stereotyped behaviour appeared to be potentiated. Similarly induced bilateral destruction of dopaminergic nerve endings in the caudate-putamen reduced spontaneous activity; amphetamine-induced stereotyped behaviour was abolished. Some animals with severe degrees of neostriatal dopamine depletion were completely unresponsive to amphetamine, apart from intense sniffing activity. Bilateral electrolytic lesions of the accumbens nuclei did not lead to any change in spontaneous or amphetamine-induced activity. Bilateral stereotactically-controlled injections of dopamine (5-50 μg of the hydrochloride salt) into the nucleus accumbens of nialamide-pretreated rats induced a marked stimulation of exploratory and locomotor activity, accompanied by intense sniffing and rearing. Conversely, bilateral injection of dopamine (12.5-50 µg of the hydrochloride salt) into the caudate-putamen induced intense stereotyped activity which was dose-related. The responses were blocked by ip haloperadol. Bilateral injection of noradrenaline (50 μg of the hydrochloride salt) into the accumbens nuclei did not produce any significant behavioural change. The same injection into the caudate-outamen led to a moderate stimulation of stereotyped activity. Bilateral injection of 5-FIT (50 μg of the bimaleinate salt) into the accumbens nuclei induced a moderate locomotor activity with some hole-dipping activity and sniffing; these behaviours were incoordinated and indecisive. The same injection into the caudate-putamen led to a stimulation of locomotor activity and hole-dipping which was predominantly "stereotyped" in character; on visual observation no other striking abnormalities were noted. The experimental results have been critically discussed. It was concluded that dopaminergic inputs into the accumbens nuclei exerted a major mediatory influence on exploratory and locomotor behaviours while dopaminergic inputs into the caudate-putamen were responsible for the mediation of stereotyped activities. The implications of these findings with respect to the behavioural changes in psychotic illness were discussed. On the basis of comparisons between the changes in psychotic illness and the changes in behaviour induced by stereotactic manipulations of the accumbens nuclei and caudate putamen, it was proposed that dopaminergic influences in the accumbens nuclei probably play a major role in the affective disorders, with probable additional involvement of the caudate-putamen in severe illness. Two animal models of mania were proposed based on the stimulation of exploratory locomotor and stereotyped behaviour in animals by amphetamine and the stimulation of locomotor and exploratory activity by application of dopamine into the accumbens nuclei. There were less clear-cut resemblances between the effects of manipulation of the three monoamine systems of behaviour in animals and the behavioural changes seen in the seems irenias. It was suggested that serotonergic influences may be involved in the behavioural changes seen in schizophrenia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.657232  DOI: Not available
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