Corticolimbic changes in acetylcholine and cyclic guanosine monophosphate in the Flinders Sensitive Line rat: a genetic model of depression

Abstract

Objective: Depression is suggested to involve disturbances in cholinergic as well as glutamatergic pathways, particularly the N-methyl-d-aspartate receptor-mediated release of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The aim of this study was to determine whether the Flinders Sensitive Line (FSL) rat, a genetic model of depression, presents with corticolimbic changes in basal acetylcholine (ACh) levels and NO/cGMP signalling. Methods: Basal levels of nitrogen oxides (NOx) and both basal and l-arginine-stimulated nitric oxide synthase (NOS) formation of l-citrulline were analysed in hippocampus and frontal cortex in FSL and control Flinders resistant line (FRL) rats by fluorometric and electrochemical high-performance liquid chromatography, respectively. In addition, ACh and cGMP levels were analysed by liquid chromatography tandem mass spectrometry and radioimmunoassay, respectively. Results: Significantly elevated frontal cortical but reduced hippocampal ACh levels were observed in FSL versus FRL rats. Basal cGMP levels were significantly reduced in the frontal cortex, but not hippocampus, of FSL rats without changes in NOx and l-citrulline, suggesting that the reduction of cGMP follows through an NOS-independent mechanism. Conclusions: These data confirm a bidirectional change in ACh in the frontal cortex and hippocampus of the FSL rat, as well as provide evidence for a frontal cortical ACh-cGMP interaction in the depressive-like behaviour of the FSL rat.