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. 2023 Jan 13:14:1067420.
doi: 10.3389/fnsyn.2022.1067420. eCollection 2022.

Exercise reduces the anxiogenic effects of meta-chlorophenylpiperazine: The role of 5-HT2C receptors in the bed nucleus of the stria terminalis

James H Fox  1 , Melissa N Boucher  1 , Khalil S Abedrabbo  1 , Brendan D Hare  1 , Bethany A Grimmig  1 , William A Falls  1 , Sayamwong E Hammack  1
Affiliations

Exercise reduces the anxiogenic effects of meta-chlorophenylpiperazine: The role of 5-HT2C receptors in the bed nucleus of the stria terminalis

James H Fox et al. Front Synaptic Neurosci. .

Abstract

Introduction: Two weeks of voluntary exercise in group-housed mice produces a reduction in anxiety-like behaviors across a number of different measures, including a reduction in the anxiety levels typically produced by the anxiogenic serotonergic drug m-chlorophenylpiperazine (mCPP), an agonist at 5-HT2C/2b receptors. We have previously demonstrated that 2-weeks of voluntary exercise blunted the anxiogenic effects of systemic mCPP, and we have also shown that mCPP infused into the bed nucleus of the stria terminalis (BNST) is anxiogenic. Here we follow up on these reports.

Methods: In Experiment 1 we infused several doses of mCPP into the BNST with or without the 5-HT2C antagonist SB242084. In Experiment 2, we administered mCPP into amygdala subregions and the dorsal hippocampus to investigate site specificity. In Experiment 4 we lesioned the BNST and subsequently infused mCPP systemically, and in Experiment 4 we used RNAscope® to assess BNST 5-HT2C transcripts following wheel running.

Results: BNST mCPP infusion increased acoustic startle responding, which was by 5-HT2C antagonism, while neither mCPP infused into the amygdala nor hippocampus was anxiogenic. Lesions of the BNST prevented the anxiogenic effect of systemically administered mCPP. Lastly, exercise reduced 5-HT2C transcripts in the BNST.

Discussion: These results suggest that the BNST is a critical site of action for the effects of exercise on mCPP. Together these data suggest that exercise may reduce 5-HT2C receptor function in the BNST, which may, in part, explain some of the anxiolytic effects associated with wheel running.

Keywords: anxiety; extended amygdala; serotonin; stress; wheel running.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) mCPP increases the acoustic startle response in non-exercising (locked wheel) mice and exercise (unlocked wheel) blocks this effect. ANOVA revealed a significant interaction between running wheel condition and dose of mCPP as well as significant main effects for running wheel group and dose. Non-exercising mice showed significant increases in the acoustic startle response with the 10 μg dose of mCPP infused into the BNST (denoted by an asterisk). In contrast, the exercising mice did not show any significant effect on the acoustic startle response with any dose. (B) The 5-HT2C antagonist SB242084 blocks the potentiation of the startle response in non-exercising mice. ANOVA was not significant and there was no effect of mCPP when co-infused with SB242084 into the BNST. (C) Outlined in gray are BNST regions in which cannula tips deemed acceptable for analysis were located. Images were adapted from Süß et al. (2022).
Figure 2
Figure 2
(A) mCPP does not potentiate the acoustic startle response when directly infused into the amygdala. Unpaired t-test did not show a significant effect of 10 μg of mCPP on the acoustic startle response in non-exercising mice animals. (B) Outlined in gray are amygdala regions in which cannula tips deemed acceptable for analysis were located. (C) mCPP does not potentiate the acoustic startle response when infused into the dorsal hippocampus. Unpaired t-test did not show a significant effect of 10 μg of mCPP on the acoustic startle response in non-exercising mice. (D) Outlined in gray are hippocampal regions in which cannula tips deemed acceptable for analysis were located. Images were adapted from Süß et al. (2022).
Figure 3
Figure 3
(A) BNST lesions made with NMDA blocked mCPP induced potentiation of the acoustic startle response. Sham animals showed a significant increase in their startle response when administered 1 mg/kg of mCPP i.p. (denoted by an asterisk). (B) Outlined in gray include all of the regions in which NMDA lesions extended in the analysis. Images were adapted from Süß et al. (2022).
Figure 4
Figure 4
(A) Using RNAscope®, 2 weeks of exercise (unlocked wheel) reduced 5-HT2C transcripts in the BNST. Two-way ANOVA revealed a main effect of exercise (denoted by an asterisk), but no effect of sex or interaction. (B) An example of 5-HT2C puncta observed using RNAscope®. Scale bar = 20 μm.
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