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

Abstract

Previously, we reported that R(+)HA-966, a weak partial agonist for the glycine/NMDA receptor, and guanfacine, a noradrenergic alpha2 agonist, have anxiolytic-like 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 x 0.5 sec, 0.8 mA paired with a 5-sec tone]. In saline-treated 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 stress-induced Fos-li were different than those observed with benzodiazepine agonists. Both putative anxiolytics, R(+)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(+)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(+)HA-966 and guanfacine, have actions on the stress-sensitive mesoprefrontal system which appear distinct from those of traditional anxiolytics.

Male Rats Exposed to Cocaine in utero Demonstrate Elevated Expression of Fos in the Prefrontal Cortex in Response to Environment

“…This tone did not result in any startle response in the rat, as previously reported (Morrow et al 1995). Rats exposed to this tone/footshock protocol do not generally jump or display overt escape behaviors, but tend to remain immobile for an increasing interval after the tone/footshock, starting at about 5-10 s after the first tone/footshock and increasing to about 40-50 s after the final tone/footshock (Morrow et al 1995(Morrow et al , 1999b(Morrow et al , 2000a. The chamber was cleaned between animals with 70% ethanol and was contained within a dimly lit sound attenuating chamber with a white noise generator to minimize external noises.…”

“…This allowed for clear identification of the number of Fos-ir nuclei as well as identification of anatomical location. Nonshocked, prenatal saline rats show low levels of Fos-ir expression, as expected from studies with untreated controls (Morrow et al 1999a(Morrow et al , 2000a. In the handled, non-shocked rats, prenatal cocaine exposure was associated with dramatically elevated expression of Fos-ir in the orbital cortex (LO and VO), the medial prefrontal cortex (IL, PL, and aCg), see Figure 2 for representative photomicrographs of the PL region and Figure 3 for quantification.…”

Effects of two kinds of noradrenergic ADHD medicines on sign-tracking and goal-tracking in male rats.

“…Indeed, Serrano-Barroso et al (2019) found that lesioning medial prefrontal cortex increased the prevalence of goal-trackers in a treated sample. Interestingly enough, guanfacine has been suggested to enhance activity of the ventral medial prefrontal cortex (Arnsten, 2010; Morrow et al, 2000; Steere & Arnsten, 1997), which may explain the difference in effect shown in this study. Differing effects may also have to do with the distribution of α 2A receptors in cerebral cortex (Nicholas et al, 1996).…”

Chronic Stress-induced Behaviors Correlate with Exacerbated Acute Stress-induced Cingulate Cortex and Ventral Hippocampus Activation

“…Although the precise mechanisms underlying these changes are unclear, one candidate is glutamatergic excitotoxicity 10,121 , supported by evidence that acute stress enhances extrasynaptic glutamate activity in the PFC and vHPC 5,[122][123][124][125] , consistent with our c-Fos findings. This is supported by evidence that antidepressants and anxiolytics prevented the induction of stress-induced c-Fos activation in the ACC, HPC, CeA, PVN, and VTA 72,[126][127][128] , supporting that dysregulation of the adaptive stress response precedes the structural and functional deficits that are targeted by pharmacological treatments.…”