| Abstract No.: | C-C3092 |
| Country: | Canada |
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| Title: | ROLE OF CHOLINERGIC NEURONS IN THE NUCLEUS ACCUMBENS AND THEIR POSSIBLE INVOLVEMENT IN SCHIZOPHRENIC SYMPTOMATOLOGY. |
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| Authors/Affiliations: | 2 François Laplante*; 1 Douglas Lappi;
1 Advanced Targeting Systems Inc., San Diego, CA, USA; 2 Centre de Recherche Fernand-Séguin, Université de Montréal, QC, Canada
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| Content: | Objective: Schizophrenia is a mental disorder characterized by dysfunctions in several neurotransmitter systems including the central cholinergic system. While alterations in cholinergic neurotransmission have been demonstrated in schizophrenic brains, their biological significance remains to be established and the exact role of acetylcholine in the neuropsychopathology of schizophrenia remains somewhat controversial. Post-mortem studies of schizophrenic patients have shown a reduction in the density of cholinergic interneurons in the striatum, most prominently in the ventral striatum or nucleus accumbens (N. Acc). Intra-accumbens acetylcholine interacts functionally with the mesolimbic DA system and is believed to dampen the effects of excessive DA release. Therefore, we hypothesize that a reduction in the density of cholinergic neurons in the N. Acc will be behaviorally relevant, if not causal, to the enhanced (ventral) striatal dopaminergic neurotransmission described in schizophrenia and may contribute substantially to the emergence of schizophrenic symptomatology. The purpose of this study is to reproduce in rats the reduction in N.Acc. cholinergic cell density seen in schizophrenia, and study the neurophysiological and behavioural consequences relevant to the neuropsychopathology of schizophrenia of these lesions.
Materials and methods: A novel saporin immunotoxin coupled with an antibody targeting choline acetyltransferase (ChAT) has been developed by Advanced Targeting Systems (San Diego) and has been microinjected bilaterally into the N. Acc of adult rats.
Results: We have confirmed histologically using immunohistochemistry, that this toxin caused a quantifiable loss of cholinergic neurons in this region within two weeks post-lesion. Lesioned rats were shown to be hypersensitive to the locomotor activating effects of amphetamine, which is suggestive of an enhanced DA reactivity in the N.Acc. Furthermore, in separate groups of animals, we have observed in lesioned rats, a reduction in the prepulse inhibition of the acoustic startle response, which is known to be regulated by N.Acc.
Conclusion: Taken together, it is proposed that reduction of cholinergic neurons in the N. Acc will prove highly effective in reproducing behavioral abnormalities analogous to those found in schizophrenia. This relatively direct and unique approach may prove highly useful in future animal studies of relevance to the pathophysiology of schizophrenia. (supported by CIHR)
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