Previous work on the unconditioned effects of amphetamine in rats has examined qualitative changes in behaviours which become stereotyped and
quantitative changes in locomotion. Stereotyped behaviours have been adopted as a
model of raised caudate-putameri function whilst locomotion has been adopted as a
model of raised mesolimbic dopamine function. These models have been used to study
drugs which are effective in the treatment of schizophrenia. Only locomotion is
reliably antagonised by all classes of antipsychotic drugs, although it has been
hypothesised that, under some doses of amphetamine, locomotion may also become
stereotyped. The Lyon-Robbins hypothesis of the behavioural effects of amphetamine
predicts competition between the output of the mesolimbic and caudate-putamen, and
would predict that stereotyped locomotion represents a 'blending' of mesolimbic and
caudate-putamen behavioural output.
An experiment was conducted to test the Lyon-Robbins hypothesis using
contrast-based image analysis to determine the spatio-temporal characteristics of
open-field locomotion. A further four experiments examined the effects of a classic
antipsychotic (haloperidol), the atypical antipsychotics (clozapine and sulpiride)
and a putative antipsychotic (a 5-HT3 antagonist, ondansetron) on open-field
locomotor routes taken by rats following treatment with 3.5mg/kg amphetamine.
Measures of stereotyped locomotion derived from image analysis were
supported by a novel form of behavioural analysis based on multi-dimensional
scaling which provided an integrated analysis of behavioural change following drug
treatment. Haloperidol blocked locomotion and stereotyped behaviours including
stereotyped locomotion, whereas clozapine, sulpiride and ondansetron blocked
locomotion but not stereotyped locomotion and in some cases increased stereotyped
behaviours. This suggests that stereotyped locomotion represents synergistic
functioning of both mesolimbic and caudate-putamen systems, when the output from
the caudate-putamen is insufficient to over-ride that of the mesolimbic system.
Antagonism of a 5-HT3 enhancement of mesolimbic locomotor activity by ondansetron
allowed latent 5-HT and dopamine mediated behaviours to be expressed. This
effectively mimicked a leftwards shift of the amphetamine dose response curve,
hypothesised as amplification of the caudate-putamen output. These findings lend
support to the Lyon-Robbins hypothesis of the behavioural effects of amphetamine.
Date of Award | 1994 |
---|
Original language | English |
---|
Awarding Institution | |
---|
Studies into Amphetamine-Induced Unconditioned Behaviour in the Rat.
McHale, S. L. (Author). 1994
Student thesis: PhD