Abstract
Background
Increasing the available repertoire of effective treatments for mood and anxiety disorders
represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid
(eCB) signaling has been suggested to represent a novel approach to the treatment
of anxiety disorders; however, the functional interactions between two canonical eCB
pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation
of anxiety are not well understood.
Methods
We utilized pharmacological augmentation and depletion combined with behavioral and
electrophysiological approaches to probe the role of 2-AG signaling in the modulation
of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling
in the modulation of anxiety-like behaviors in mice.
Results
Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented
stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast,
acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective
pharmacological augmentation of AEA signaling and via direct cannabinoid receptor
1 stimulation with Δ9-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala
glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of
2-AG augmentation.
Conclusions
Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological
and functional redundancy between these canonical eCB signaling pathways exists in
the modulation of anxiety-like behaviors. These data support development of eCB-based
treatment approaches for mood and anxiety disorders and suggest a potentially wider
therapeutic overlap between AEA and 2-AG augmentation approaches than was previously
appreciated.
Keywords
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References
- The epidemiology of anxiety disorders: A review.Dialogues Clin Neurosci. 2003; 5: 281-298
World Health Organization Media Center (2016): Investing in treatment for depression and anxiety leads to fourfold return. Available at: http://www.who.int/mediacentre/news/releases/2016/depression-anxiety-treatment/en/. Accessed November 1, 2016.
- Antidepressant-induced suicidality: Implications for clinical practice.South Med J. 2009; 102: 713-718
- Withdrawing benzodiazepines in patients with anxiety disorders.Curr Psychiatry Rep. 2016; 18: 8
- International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders.J Clin Psychopharmacol. 1999; 19: 23S-29S
- Benzodiazepine harm: How can it be reduced?.Br J Clin Pharmacol. 2014; 77: 295-301
- The molecular logic of endocannabinoid signalling.Nat Rev Neurosci. 2003; 4: 873-884
- Endocannabinoid-mediated control of synaptic transmission.Physiol Rev. 2009; 89: 309-380
- Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992; 258: 1946-1949
- 2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain.Biochem Biophys Res Commun. 1995; 215: 89-97
- Role of the basolateral amygdala in mediating the effects of the fatty acid amide hydrolase inhibitor URB597 on HPA axis response to stress.Eur Neuropsychopharmacol. 2014; 24: 1511-1523
- Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis.Endocrinology. 2004; 145: 5431-5438
- Neurobiological interactions between stress and the endocannabinoid system.Neuropsychopharmacology. 2016; 41: 80-102
- Modulation of anxiety through blockade of anandamide hydrolysis.Nat Med. 2003; 9: 76-81
- Inhibition of anandamide hydrolysis enhances noradrenergic and GABAergic transmission in the prefrontal cortex and basolateral amygdala of rats subjected to acute swim stress.J Neurosci Res. 2015; 93: 777-787
- Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation.Transl Psychiatry. 2014; 4: e408
- Cyclooxygenase-2 inhibition reduces stress-induced affective pathology.Elife. 2016; 5
- Amygdala FAAH and anandamide: Mediating protection and recovery from stress.Trends Pharmacol Sci. 2013; 34: 637-644
- Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.Nat Neurosci. 2013; 16: 1291-1298
- Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure.Mol Psychiatry. 2013; 18: 1125-1135
- Potential therapeutic value of a novel FAAH inhibitor for the treatment of anxiety.PLoS One. 2015; 10: e0137034
- Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.Neuropharmacology. 2008; 54: 141-150
- Inhibition of fatty acid amide hydrolase modulates anxiety-like behavior in PCP-treated rats.Pharmacol Biochem Behav. 2011; 98: 583-586
- Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks.Psychoneuroendocrinology. 2013; 38: 2952-2961
- Serum endocannabinoid content is altered in females with depressive disorders: A preliminary report.Pharmacopsychiatry. 2008; 41: 48-53
- Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.Cell Rep. 2014; 9: 1644-1653
- Anxiety, stress, and fear response in mice with reduced endocannabinoid levels.Biol Psychiatry. 2016; 79: 858-868
- Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses.Biol Psychiatry. 2011; 70: 479-486
- 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; 64: 226-234
- Endocannabinoid modulation of predator stress-induced long-term anxiety in rats.Neuropsychopharmacology. 2016; 41: 1329-1339
- Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis.Neuropsychopharmacology. 2009; 34: 2733-2745
- Adaptations in endocannabinoid signaling in response to repeated homotypic stress: A novel mechanism for stress habituation.Eur J Neurosci. 2008; 27: 2821-2829
- Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.J Neurosci. 2011; 31: 10506-10515
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press (US); 2011. Available at: https://www.ncbi.nlm.nih.gov/books/NBK54050/doi:10.17226/12910. Accessed April 13, 2017.
- Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.Nat Chem Biol. 2009; 5: 37-44
- Assessment of mouse anxiety-like behavior in the light-dark box and open-field arena: Role of equipment and procedure.Physiol Behav. 2014; 133: 30-38
- The mouse light-dark paradigm: A review.Prog Neuropsychopharmacol Biol Psychiatry. 2001; 25: 141-166
- Mood disorders and allostatic load.Biol Psychiatry. 2003; 54: 200-207
- Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission.Neuropsychopharmacology. 2012; 37: 2624-2634
- Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.J Neurosci. 2015; 35: 3879-3892
- Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition.Proc Natl Acad Sci U S A. 2016; 113: 26-33
- Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice.Horm Behav. 2013; 63: 752-758
- Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.Pharmacol Biochem Behav. 2011; 98: 21-27
- Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety.Neuropharmacology. 2016; 111: 59-69
- Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: A potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.Neuropsychopharmacology. 2011; 36: 2750-2761
- Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation.J Psychopharmacol. 2012; 26: 56-70
- Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling.Endocrinology. 2010; 151: 4811-4819
- An endocannabinoid mechanism for stress-induced analgesia.Nature. 2005; 435: 1108-1112
- Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling.Eur J Neurosci. 2005; 21: 1057-1069
- Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice.Neuropharmacology. 2008; 54: 108-116
- Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans.Neuropsychopharmacology. 2012; 37: 2416-2427
- Endocannabinoid signaling and synaptic function.Neuron. 2012; 76: 70-81
- Learning from other people’s fear: Amygdala-based social reference learning in social anxiety disorder.Psychol Med. 2016; 46: 2943-2953
- Sustained anxiety increases amygdala-dorsomedial prefrontal coupling: A mechanism for maintaining an anxious state in healthy adults.J Psychiatry Neurosci. 2014; 39: 321-329
- Acute stress suppresses synaptic inhibition and increases anxiety via endocannabinoid release in the basolateral amygdala.J Neurosci. 2016; 36: 8461-8470
- Endogenous cannabinoid signaling is essential for stress adaptation.Proc Natl Acad Sci U S A. 2010; 107: 9406-9411
- Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain.Biochim Biophys Acta. 2016; 1861: 491-500
- Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress.Psychoneuroendocrinology. 2009; 34: 1257-1262
Article Info
Publication History
Published online: March 16, 2017
Accepted:
March 6,
2017
Received in revised form:
February 13,
2017
Received:
November 17,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2017.
