Elsevier

Neuroscience

Volume 132, Issue 4, 2005, Pages 1159-1171
Neuroscience

Blunted response to cocaine in the Flinders hypercholinergic animal model of depression

https://doi.org/10.1016/j.neuroscience.2005.01.043Get rights and content

Abstract

The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. Considering the strong comorbidity between depression and cocaine dependence we investigated the well-documented behavioral and molecular effects of cocaine in the FSL and their control Flinders resistant line (FRL) rats. First, we found no difference between the two lines to establish cocaine self-administration; both lines reached stable responding within 10 days of training at a fixed ratio-1 schedule of reinforcement (1.5 mg/kg/injection). However, the FSL rats exhibited reduced cocaine intake at a dose of 0.09 mg/kg/injection in a within-session dose-response curve (0.02, 0.09, 0.38, 1.5 mg/kg/injection). Second, we examined the effects of repeated cocaine administration on locomotor activity, dopamine overflow and striatal prodynorphin mRNA expression. We found the FSL rats to be low responders to novelty and to exhibit less locomotor activation after repeated cocaine administration (30 mg/kg, i.p., daily injections for 10 days) than their controls. Microdialysis sampling from the nucleus accumbens shell revealed no significant difference in the dopamine overflow between the rat lines, neither during baseline nor after cocaine stimulation. Postmortem analyses of striatal prodynorphin mRNA expression (using in situ hybridization histochemistry) revealed a differentiated response to the cocaine exposure. In contrast to control FRL rats, the FSL rats showed no typical cocaine-evoked elevation of prodynorphin mRNA levels in rostral subregions of the striatum whereas both strains expressed increased prodynorphin mRNA levels in the caudal striatum after cocaine administration. In conclusion, the FSL animal model of depression demonstrates marked blunting of the locomotor and dynorphin neuroadaptative responses to cocaine in accordance with its enhanced cholinergic sensitivity.

Section snippets

Animals

For experiment 1, adult male FSL (n=11) and FRL (n=9) rats, approximately 9 weeks old and weighing 230–370 g, were used from a colony maintained at the department of Pharmacology, Karolinska Institute. For experiment 2, 24 male FSL and FRL rats, approximately 7 weeks old, were transferred from the breeding colony maintained at the department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA to the department of Pharmacology, Karolinska Institute (Stockholm, Sweden). The

Experiment 1

The first 10 days of cocaine self-administration are shown in Fig. 2A. ANOVA analysis revealed a main effect of day (F9,117=29.56, P<0.0001) and a line×day interaction (F9,117=3.27, P<0.001), but no main effect of line. The number of responses increased as training continued over days. There was no significant difference between the Flinders lines at any day studied. Furthermore the total cocaine intake over 10 days was similar between the FSL and FRL rats (114±14 and 128±12 injections,

Discussion

The present study provides experimental support that a depression genotype affects the response to psychostimulants. The FSL hypercholinergic rats showed marked blunting of cocaine-evoked responses in locomotor activity and prodynorphin mRNA regulation but only a subtle effect on self-administration behavior. The differences were, however, not correlated to extracellular dopamine overflow monitored in the Acc-Sh.

The underlying hypercholinergic depression genotype of the FSL rat did not

Acknowledgments

We thank Marjan Pontén and Åse Elfving for technical assistance and Prof. Alexander Mathé for providing animals from the Karolinska Flinders colony. This work was supported by grants from the Swedish Medical Research Council (11252), and the Karolinska Institute.

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