Short communicationBehavior in the open field predicts the number of KCl-induced cortical spreading depressions in rats
Highlights
▸ Anxiety disorders are frequently comorbid with migraine. ▸ Cortical spreading depression (CSD) is a culprit for migraine aura. ▸ Anxious rats have low activity in the open field test. ▸ Low open field activity predicted higher CSD susceptibility in rats. ▸ Migraine prophylaxis drugs affected correlation between behavior and CSD numbers.
Introduction
Migraine is a neurological disorder, characterized by recurrent attacks of severe headache, nausea, photo- and/or phonophobia. In 20% of subjects the migraine headache is preceded by a transient neurological disturbance known as the aura. Cortical spreading depression (CSD) has been suggested to be a trigger for aura, and, possibly, headache. CSD is a wave of neuronal and glial depolarization, slowly propagating in the cortex (3–5 mm/min), and followed by a long-lasting suppression of neuronal activity and excitability.
Anxiety disorders are highly comorbid with migraine [1] and could share neurobiological abnormalities in the same neuronal networks [2]. Anxiety and other psychiatric comorbid disorders are known to aggravate migraine disability and have also been associated with a more chronic course of migraine [3]. The basis for the relationship between anxiety and migraine is not known, and may implicate a range of mechanisms. Whatever the precise relationship may be, it is known that anxiety increases brain excitability in humans [4] and it could thus in theory augment susceptibility to CSD.
In a previous study we noted that chronic administration of anti-migraine drugs differentially influenced susceptibility to KCl-induced CSD in rats [5]. As part of this study we assessed anxiety-like behavior in the open field test (OFT) in order to search for a possible relationship between level of anxiety and CSD frequency and to verify if previously observed migraine prophylaxis drug effects on CSD susceptibility were accompanied by a change in anxiety levels.
Section snippets
Animals and drugs
Male adult Sprague-Dawley rats, 287.5 ± 16.1 g average initial body weight, were chosen among the sample of animals used in our previous study on drug effects [5] for the behavioral study: 5 randomly chosen animals in the group treated for 4 weeks with daily i.p. injections of saline (1 ml/kg), 10 animals in the groups treated with i.p. injections of valproate (200 mg/kg, Merck, Belgium) and 10 animals in the group receiving i.p injections of flavin mononucleotide as a donor of riboflavin
Between-group differences in behavior and CSD susceptibility
During the first session of the OFT, animal behavior differed only in the riboflavin group (p < 0.05) demonstrating a 1.8 fold increase in time of vertical activity and 3.2 fold elevation of the time spent in the OF center compared to the control group. No differences in behavior were found between animal groups in the second session of behavior studies.
The number of anterior CSDs (CSDs propagating from the stimulation site toward posterior and then anterior recording sites, see Fig. S1,
Between-group differences in behavior
In our study, only chronic riboflavin treatment resulted in novelty-linked increases in locomotion parameters. Riboflavin treatment could be linked to increased novelty-seeking behavior by promoting serotonin turnover via flavin containing monoamine oxidase. Decreased serotonin content in the frontal cortex was reported in a high rearing subpopulation of rats [8]. Conversely, in serotonin transporter knockout mice, an increase in extracellular concentrations of serotonin was accompanied by
Conclusions
Our work provides evidence for a link between open field behavior and susceptibility to cortical spreading depression. The results may be contributed to research on the pathophysiology of migraine and the shared neurological basis of CSD and anxiety deserves further investigation.
Acknowledgments
This study was supported by the research convention 3.4.650.09 from the National Fund for Scientific Research – Belgium to JS and by research grants from the Faculty of Medicine – University of Liège. We thank Dr. Vincent Seutin, University of Liege, GIGA neuroscience for kindly affording us the behavioral assessment facilities.
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