Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice

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Highlights

  • We assessed the effects of MAGL inhibition on corticosterone and behavior in mice.

  • MAGL blockade increased basal but not stress-induced corticosterone levels.

  • MAGL inhibition had locomotoion enhancing and anxiolytic effects.

  • Anxiolysis was partly dependent on corticosterone effects.

Abstract

The hypothalamus–pituitary–adrenal-axis is strongly controlled by the endocannabinoid system. The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far. Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses. Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone. We found that in the elevated plus-maze, the effects of JZL184 on “classical” anxiety-related measures were abolished by corticosterone synthesis blockade. By contrast, effects on the “ethological” measures of anxiety (i.e. risk assessment) were not affected by metyrapone. In the open-field, the locomotion-enhancing effects of the compound were not changed either. These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone. This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade.

Introduction

There is an increasing amount of information suggesting that the activity of the hypothalamus–pituitary–adrenal axis (HPA-axis)—a crucial element in maintaining homeostasis under stress—is partly regulated by the endocannabinoid system. In laboratory models, cannabinoids seem to alter HPA-axis activity in a bidirectional manner. It was consistently shown, that basal levels of corticosterone are increased by treatments with phytocannabinoids (e.g. Δ9-tetrahydrocannabinol, cannabidiol or cannabinol), endocannabinoids (e.g. anandamide (AEA)) and synthetic cannabinoids (e.g. WIN55,212-2, HU210 or CP55,940) (Barna et al., 2009, Johnson et al., 1978, Martin-Calderon et al., 1998, Romero et al., 2002, Weidenfeld et al., 1994, Zuardi et al., 1984). Disparate data suggest that enhancement of endocannabinoid activity via the blockade of AEA degrading enzyme fatty acid amide hydrolase (FAAH) by the selective inhibitor URB597 also result in elevated basal corticosterone levels (Saber-Tehrani et al., 2010), however, these findings were not replicated (Hill et al., 2010, Kerr et al., 2012) and the effect of increased AEA levels on corticosterone was shown not to be mediated by signaling via the CB1 cannabinoid receptor (CB1R) (Wenger et al., 2003). In contrast with the effects of cannabinoids on basal HPA-function, increased endocannabinoid activity via treatment with CB1R agonists or inhibition of FAAH activity seem to dampen the activation of the HPA-axis in acute stress (Ganon-Elazar and Akirav, 2009, Hill et al., 2009, Hill et al., 2010, Patel et al., 2004). While there is a large amount of information available on the effects of CB1R agonists and FAAH blockade on corticosterone levels under basal or stressful conditions, similar effects resulting from the blockade of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-arachidonoylglycerol (2-AG), the other main endocannabinoid, are still to be studied. Recently, behavioral effects of MAGL inhibition were reported to depend on the stressfulness of the testing environment (Aliczki et al., 2012, Sciolino et al., 2011), which can suggest that MAGL blockade can alter HPA-axis function.

Endocannabinoids affect both brain areas involved in emotional behavior (e.g. the prefrontal cortex, amygdala and hippocampus; (Rubino et al., 2008a, Zarrindast et al., 2008) and the HPA-axis (at all levels, the hypothalamus, hypophysis, and adrenal cortex; (Cota et al., 2007, Di et al., 2003, Di et al., 2005, Pagotto et al., 2001). It is likely that the ultimate effects of endocannabinoid action result from an interaction between the neural and endocrine effects, as glucocorticoids are also powerful modulators of behavior (Mikics et al., 2004).

In the present study, we assessed the effects of JZL184-induced MAGL blockade on basal and stress-induced activity of the HPA-axis by the measurements of corticosterone levels. The findings showed that JZL184 treatment increases basal levels of plasma corticosterone, therefore we studied whether the behavioral effects of MAGL inhibition that we reported earlier (Aliczki et al., 2012) depended on corticosterone-synthesis. To study this issue, we inhibited corticosterone-synthesis with the steroid 11β-hydroxylase inhibitor metyrapone.

Section snippets

Subjects

Subjects were two month-old male CD1 (Charles River laboratories, Budapest, Hungary) mice weighting 30–35 g. They were kept under a light/dark cycle of 12 h with the lights on at 0700 h. Food and water were available ad libitum, temperature and humidity were kept at 23 ± 2 °C and 60 ± 10%, respectively. In contrast to rats that are highly social, individual housing is not stressful in the mouse, which is a solitary species (Arndt et al., 2009, Benton and Brain, 1981, Capanna et al., 1984). Moreover,

Results

In Experiment 1a, there was a significant interactions between factors (FTreatment  Stress (2,45) = 4.71; p = 0.013). The highest dose of JZL184 increased basal corticosterone levels 40 min after treatment, but—albeit some increase was noticed—did not alter stress-induced increases in corticosterone (Fig. 1). basal corticosterone levels in Experiments 1b and 1c were not affected by JZL184 (120 min: FTreatment (2,16) = 0.76; p = 0.48; FTreatment*Stress (2,16) = 1.30; p = 0.29; 240 min: FTreatment (2,20) = 0.43; p =

Discussion

MAGL blockade dose-dependently and dramatically increased basal corticosterone levels 40 min after treatment. Values returned to control levels within 2 h. The stress-induced corticosterone levels were unaltered by inhibition of MAGL. MAGL blockade also increased locomotor activity in a corticosterone-synthesis independent manner and exerted anxiolytic-related effects which were at least partly dependent on corticosterone. To our best knowledge, our study is the first to show that the inhibition

Conclusion

The inhibition of MAGL activity—the indirect upregulation of 2-AG signaling—causes a rapid increase in basal corticosterone levels which disappears in less than 2 h. The comparison of this finding with earlier reports suggests that the overall stimulation of CB1Rs, as well as the selective increase of AEA and 2-AG signaling produce partially overlapping but still different effects on corticosterone secretion. CB1R agonists dramatically increase basal and stress-induced corticosterone secretion;

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

The assistance of Dr. Istvan Barna in the statistical analysis of corticosterone data is greatly appreciated. This research was supported by Hungarian Scientific Research Fund (OTKA) grants nos. 72621 and 101645.

References (45)

  • S. Pellow et al.

    Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat

    J. Neurosci. Methods

    (1985)
  • E.M. Romero et al.

    Antinociceptive, behavioural and neuroendocrine effects of CP 55,940 in young rats

    Brain Res. Dev. Brain Res.

    (2002)
  • T. Rubino et al.

    CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour

    Neuropharmacology

    (2008)
  • N.R. Sciolino et al.

    Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

    Pharmacol. Res.

    (2011)
  • M. Toth et al.

    Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses

    Horm. Behav.

    (2011)
  • P.M. Wall et al.

    Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2003)
  • T. Wenger et al.

    Arachidonyl ethanolamide (anandamide) activates the parvocellular part of hypothalamic paraventricular nucleus

    Biochem. Biophys. Res. Commun.

    (1997)
  • M. Aliczki et al.

    The temporal dynamics of the effects of monoacylglycerol lipase blockade on locomotion, anxiety, and body temperature

    Behav. Pharmacol.

    (2012)
  • I. Barna et al.

    Cannabinoid-mediated regulation of the hypothalamo-pituitary-adrenal axis in rats: age dependent role of vasopressin

    Endocr. Regul.

    (2009)
  • D. Benton et al.

    Behavioral and adrenocortical reactivity in female mice following individual or group housing

    Dev. Psychobiol.

    (1981)
  • E. Capanna et al.

    Karyotype and intermale aggression in wild house mice: ecology and speciation

    Behav. Genet.

    (1984)
  • J.C. Cole et al.

    An ethological analysis of the effects of chlordiazepoxide and bretazenil (Ro 16-6028) in the murine elevated plus-maze

    Behav. Pharmacol.

    (1993)
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