Divergent effects of putative anxiolytics on stress-induced Fos expression in the mesoprefrontal system of the rat

✍ Scribed by Bret A. Morrow; John D. Elsworth; Edward J.K. Lee; Robert H. Roth

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 314 KB
• Volume: 36
• Category: Article
• ISSN: 0887-4476
• DOI: 10.1002/(sici)1098-2396(200005)36:2<143::aid-syn7>3.0.co;2-h

✦ Synopsis

Previously, we reported that R(ϩ)HA-966, a weak partial agonist for the glycine/NMDA receptor, and guanfacine, a noradrenergic ␣2 agonist, have anxiolyticlike actions on the biochemical activation of the mesoprefrontal dopamine neurons and fear-induced behaviors. Here, we examined these two putative anxiolytic agents, both with primary actions independent of GABAergic systems, for their ability to alter stress-induced Fos-like immunoreactivity in the mesoprefrontal cortex and in tyrosine hydroxylase-stained, presumed dopaminergic, neurons in the ventral tegmental area. The benzodiazepine agonist, lorazepam, and partial agonist, bretazenil, were also tested in this footshock paradigm [10 ϫ 0.5 sec, 0.8 mA paired with a 5-sec tone]. In salinetreated rats, footshock resulted in an increase in Fos-li in the prelimbic and infralimbic cortices and tyrosine hydroxylase-labeled cells in the ventral tegmental area. Treatment with lorazepam or bretazenil prevented the stress-induced activation in Fos-li nuclei in all regions of the medial prefrontal cortex and in dopaminergic neurons in the ventral tegmental area. In contrast, the actions of the novel anxiolytic-like agents on stressinduced Fos-li were different than those observed with benzodiazepine agonists. Both putative anxiolytics, R(ϩ)HA-966 and guanfacine, did not reduce, but significantly enhanced the stress-induced Fos-li in the prelimbic region of the medial prefrontal cortex. Additionally, treatment with R(ϩ)HA-966 completely blocked, while guanfacine attenuated, the stress-induced increase in the number of Fos-li, TH-li cells in the ventral tegmental area. These results indicate that the putative anxiolytics, R(ϩ)HA-966 and guanfacine, have actions on the stress-sensitive mesoprefrontal system which appear distinct from those of traditional anxiolytics.