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Ontogeny of Muscarinic Cholinergic Supersensitivity in the Flinders Sensitive Line Rat

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Abstract

The present study examined the ontogeny of muscarinic sensitivity in the Flinders Sensitive Line (FSL) rat, a model for human depression that was selectively bred for increased cholinergic function. In most cases, the FSL rats were more sensitive to the muscarinic agonists, oxotremorine and oxotremorine-M, early postnatally [13 days postpartum (P13)], suggesting that muscarinic supersensitivity is an inherent characteristic of FSL rats. The emergence of increased sensitivity to muscarinic agonists in FSL rats did not correlate with either the emergence of subsensitivity to the muscarinic antagonist, scopolamine, at P60 or with increased muscarinic (M1 or M2) receptor density. Relative to FRL rats, FSL rats did not exhibit increases in muscarinic receptor binding until P32 in the striatum and hippocampus and P120 in the hypothalamus. These results are consistent with the suggestions that (a) muscarinic supersensitivity, which appears early in development, may be associated with depressive disorders, and (b) the differences in muscarinic sensitivity early postnatally cannot be accounted for by an increase in the number of muscarinic receptors, per se.

Section snippets

Animals

FSL and FRL male and females rats were from the 40th to 49th generations bred and maintained in the School of Biological Sciences, The Flinders University of South Australia. Each new generation of rats was screened for behavioral sensitivity to muscarinic agonists and the subsequent generation of FSL rats obtained by mating the 10 most “sensitive” males and females, while the 10 most “resistant” males and females were mated to produce the next generation of FRL rats. Breeding pairs were

Baseline Measures

There were age, F(19, 2244) = 2571.64, p < 0.001, gender, F(1, 2244) = 1402.17, p < 0.001, and line, F(1, 2244) = 20.71, p < 0.001, effects on the changes in body weight. Interaction effects were apparent between (a) age and line, F(19, 2244) = 1.62, p < 0.05, where both male and female FSL rats weighed more than their FRL counterparts through to P51 and less thereafter; and (b) gender and age, F(19, 2244) = 99.64, p < 0.001. The expected gender difference did not emerge until P31 and increased

Discussion

The main aim of this study was to examine the ontogeny of muscarinic sensitivity in the FSL rat, a model of human depression that was selectively bred for increased cholinergic function. It is now well recognized that humans with depressive disorders are more sensitive to the behavioral and physiological effects of muscarinic drugs than are nondepressed controls 6, 25, 55, 62. Controversy remains as to whether this altered cholinergic function is a cause or a consequence of the depressive

Acknowledgements

This work was supported by a Dora Lush National Health and Medical Research Council Biomedical Postgraduate Scholarship (927435) to L.C.D. and funds provided by the Flinders University Research Budget. The authors would like to greatfully acknowledge Cheryl Greaves and Leah Nesbitt for their excellent care and maintenance of the animals and George Daws for research assistance. Our thanks to Drs Grant Schiller and Joe Orbach for valuable discussions and their assistance with this study.

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