Alteration in serotonin (5-HT) system is involved in the pathophysiology of stress-related anxiety disorder. Medications that modulate serotonergic transmission are widely used to treat anxiety disorder. Recently, evidence from animal studies indicates that endocannabinoid (eCB) system plays an important role in the regulation of stress responses and anxiety related behaviors. Genetic deletion or pharmacological blockade of type 1 cannabinoid receptors (CB1) results in a marked increase in anxiety-like behaviors and stress responses. These behavioral effects are mediated in part, via the modulation of the 5-HT system. However, the cellular and molecular mechanism by which stress modulates eCB signaling in 5-HT neurons has not been characterized. We have conducted preliminary studies to examine the impact of acute stress hormone corticosterone and severe stress on eCB signaling in dorsal raphe (DR) 5-HT neurons. We find that acute corticosterone enhances eCB synthesis/release, which in turn modulates glutamatergic transmission to DR 5-HT neurons. Our results also show that exposure to severe stress induces a down-regulation of eCB signaling in DR 5-HT neurons 24 hours later. This functional adaptation of eCB signaling in DR 5-HT neurons may play a role in stress-induced anxiety disorder. The long-term objective of this application is to delineate the cellular and molecular mechanisms by which stress modulates eCB signaling in DR 5-HT neurons. In this application, we plan to use a combination of electrophysiological, pharmacological and neurochemical approaches to 1) test the hypothesis that glucocorticoids acutely enhance eCB synthesis/release in DR 5-HT neurons, 2) elucidate the signal transduction mechanisms by which glucocorticoids enhance eCB signaling in DR 5-HT neurons, 3) to determine the mechanisms of severe stress-induced down-regulation of eCB signaling in DR 5-HT neurons. Given the role of 5-HT and eCB systems in the regulation of stress related behaviors, the results from the proposed studies will better our understanding of the etiology of anxiety disorder and may contribute to the development of more effective anxiolytics.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Desmond, Nancy L
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State University of New York at Buffalo
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Haj-Dahmane, Samir; Shen, Roh-Yu; Elmes, Matthew W et al. (2018) Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. Proc Natl Acad Sci U S A 115:3482-3487
Haj-Dahmane, Samir; Béïque, Jean Claude; Shen, Roh-Yu (2017) GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing-Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus. eNeuro 4:
Haj-Dahmane, Samir; Shen, Roh-Yu (2014) Chronic stress impairs ?1-adrenoceptor-induced endocannabinoid-dependent synaptic plasticity in the dorsal raphe nucleus. J Neurosci 34:14560-70
Hausknecht, Kathryn; Haj-Dahmane, Samir; Shen, Roh-Yu (2013) Prenatal stress exposure increases the excitation of dopamine neurons in the ventral tegmental area and alters their reponses to psychostimulants. Neuropsychopharmacology 38:293-301
Andrade, Rodrigo; Haj-Dahmane, Samir (2013) Serotonin neuron diversity in the dorsal raphe. ACS Chem Neurosci 4:22-5
Wang, Jue; Shen, Roh-Yu; Haj-Dahmane, Samir (2012) Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons. J Physiol 590:5795-808
Haj-Dahmane, Samir; Shen, Roh-Yu (2011) Modulation of the serotonin system by endocannabinoid signaling. Neuropharmacology 61:414-20
Haj-Dahmane, Samir; Shen, Roh-Yu (2010) Regulation of plasticity of glutamate synapses by endocannabinoids and the cyclic-AMP/protein kinase A pathway in midbrain dopamine neurons. J Physiol 588:2589-604
Haj-Dahmane, Samir; Shen, Roh-Yu (2009) Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors. J Pharmacol Exp Ther 331:186-96