Overlapping and Distinct Brain Regions Associated with the Anxiolytic Effects of Chlordiazepoxide and Chronic Fluoxetine

Abstract

Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test. In the first experiment, rats were treated acutely with the anxiolytic, chlordiazepoxide (2.5 or 5 mg/kg, i.p.). In separate experiments, animals were implanted with osmotic minipumps delivering vehicle or fluoxetine (5 or 20 mg/kg per day s.c.) for 3 or 28 days. NIH was assessed by giving animals access to a familiar palatable food in a novel environment. Associated brain areas were identified using c-fos immunohistochemistry. NIH was mitigated by acute chlordiazepoxide and chronic fluoxetine. Both drugs reversed novelty-induced changes in c-fos expression in the lateral division of the posterolateral part of the bed nucleus of the stria terminalis (STLP), cingulate cortex (Cg), and dorsal field CA2 of the hippocampus (dCA2). Chronic fluoxetine additionally increased c-fos expression in the anterior nucleus accumbens (aAcb) and the piriform cortex (Pir). The effects of the drugs on c-fos expression in many regions correlated with anxiolytic efficacy. These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs.

Early-life stress has persistent effects on amygdala function and development in mice and humans

“…Neuronal activity has been shown to correlate with the expression of the early immediate gene, c-fos (40,41). Further, c-Fos expression in the BLA is selectively down-regulated by both acute benzodiazepine and chronic antidepressant treatment in rats performing similar behavioral paradigms (42), suggesting that c-Fos is a reliable marker for activity in circuits involved in anxiety-related phenomena. We used immunohistochemical techniques to measure c-Fos expression in the amygdala 90 min after the 10-min epoch spent approaching and avoiding the milk in the threatening context (i.e., the novel cage) of the novelty-induced hypophagia paradigm (43).…”

Comparison of ΔFosB Immunoreactivity Induced by Vagal Nerve Stimulation with That Caused by Pharmacologically Diverse Antidepressants

“…Longterm treatment of rats with either paroxetine (Muigg et al, 2007) or citalopram (Kuipers et al, 2006) did not increase c-Fos in any brain region examined, including the CeA. In contrast, Bechtholt et al (2008) showed that long-term fluoxetine increased c-Fos in multiple brain areas including the BNST, cingulate cortex, anterior NAc, and hippocampus and long-term mirtazapine treatment increased c-Fos in the CeA and dentate gyrus (Gerrits et al, 2006). There are very few studies that examined the effects of antidepressant drug treatments on ⌬FosB.…”

“…In general, increases have not been reported in the DRN although Fraga et al (2005) found an increase after short-term administration of fluoxetine. Most studies show increases in c-fos or c-Fos in the CeA and BNST after short-term administration of different classes of antidepressants (Beck, 1995;Fraga et al, 2005;Slattery et al, 2005;Bechtholt et al, 2008). Longterm treatment of rats with either paroxetine (Muigg et al, 2007) or citalopram (Kuipers et al, 2006) did not increase c-Fos in any brain region examined, including the CeA.…”

Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress

“…The NSF test is a test of anxiety and has previously been shown to be sensitive to chronic anti-depressant treatment (Bechtholt et al, 2008;Dulawa et al, 2004;Santarelli et al, 2003). Longer latency to eat in a novel environment is associated with increased anxiety.…”