Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioural response to d-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys

The effects of excitotoxic lesions of the prefrontal cortex on behavioural, neurochemical and molecular indices of dopamine function in the caudate nucleus were studied in the marmoset. The lesion, which encompassed both the lateral and orbital regions of prefrontal cortex, made the animals more sensitive to the performance disrupting effects of the dopamine releasing drug, d-amphetamine, in a variation of the object retrieval task. Specifically, following drug administration, the lesioned marmosets were less able to gain access to food reward in the minimum number of responses. Analysis of the nature of the errors suggested that the deficit was not due to inhibition of a prepotent response as the lesioned monkeys were just as likely to make a detour reach to the unopened side of the box as a direct “line-of-sight” reach into the unopened front of the box. Rather, the data indicated a general disorganization of behaviour. The enhanced behavioural responsiveness to manipulations increasing presynaptic dopamine function was accompanied by neurochemical changes indicating a reduced responsiveness, as revealed by in vivo microdialysis. Thus, in lesioned animals, whilst there were no effects on baseline levels of extracellular dopamine in dorsolateral caudate, evoked release, both to systemic d-amphetamine and to a local depolarizing pulse of potassium ions, was attenuated. These opposite effects of the prefrontal cortex lesion on behavioural and neurochemical indices of striatal dopamine function occurred in the absence of any changes in striatal dopamine receptors of the D1 and D2 subtype, as determined both by radioligand binding assays and measurements of messenger RNA using in situ hydridization techniques. These data provide further insight into the interactions between prefrontal cortex and striatal dopamine function in the non-human primate. In particular, when taken in the light of our previous studies they indicate that following prefrontal manipulations, concurrence between behavioural and neurochemical indices of striatal dopamine function depends, critically, on the behavioural task. These findings are discussed with respect to the growing body of evidence implicating abnormalities in frontostriatal neurotransmission in complex disorders such as schizophrenia

Chemical signalling in the basal ganglia Manipulation of dopamine neurotransmission

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Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases