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Cannabinoids Stimulate the TRP-Channel Dependent Release of Both Serotonin and Dopamine to Modulate Behavior in C. Elegans

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Cannabinoids Stimulate the TRP-Channel Dependent Release of Both Serotonin and Dopamine to Modulate Behavior in C. Elegans This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Behavioral/Cognitive Cannabinoids stimulate the TRP-channel dependent release of both serotonin and dopamine to modulate behavior in C. elegans Mitchell Oakes1, Wen Jing Law1 and Richard Komuniecki1 1Department of Biological Sciences, University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio, 43606-3390, USA https://doi.org/10.1523/JNEUROSCI.2371-18.2019 Received: 22 September 2018 Revised: 4 February 2019 Accepted: 8 March 2019 Published: 18 March 2019 Author contributions: M.O., W.J.L., and R.K. designed research; M.O. and W.J.L. performed research; M.O., W.J.L., and R.K. analyzed data; M.O., W.J.L., and R.K. edited the paper; R.K. wrote the first draft of the paper; R.K. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. We thank the C. elegans Genetics Center and the National Bioresources Center for null strains. This work was supported by NIH Grant AI072644 awarded to RK. Corresponding Author: Tel: 419 530 1545, Email: [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2371-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors ͳ Cannabinoids stimulate the TRP-channel dependent release of both serotonin and dopamine to ʹ modulate behavior in C. elegans ͵ Abbreviated title: TRP channels in cannabinoid signaling Ͷ ͷ Mitchell Oakes1, Wen Jing Law1 and Richard Komuniecki* ͸ ͹ Department of Biological Sciences, University of Toledo, 2801 W. Bancroft Street, Toledo, Ohio ͺ 43606-3390, USA ͻ 1Mitchell Oakes and Wen Jing Law contributed equally to this manuscript ͳͲ *Corresponding Author ͳͳ Tel: 419 530 1545 ͳʹ Email: [email protected] ͳ͵ ͳͶ Number of pages: 18 ͳͷ Number of figures: 7 ͳ͸ ͳ͹ Abstract: 200 ͳͺ Introduction: 686 ͳͻ Discussion: 1482 ʹͲ ʹͳ ʹʹ CONFLICT OF INTEREST ʹ͵ The authors declare no competing financial interest. ʹͶ ACKNOWLEDGEMENTS ʹͷ We thank the C. elegans Genetics Center and the National Bioresources Center for null ʹ͸ strains. This work was supported by NIH Grant AI072644 awarded to RK. ʹ͹ ʹͺ ʹͻ ͵Ͳ ͵ͳ ͵ʹ ͵͵ ͳ ͵Ͷ Abstract ͵ͷ Cannabis sativa alters sensory perception and exhibits potential medicinal ͵͸ benefits. In mammals, cannabinoids activate two canonical receptors, CB1/CB2, as well ͵͹ additional receptors/ion channels whose overall contributions to cannabinoid signaling ͵ͺ have yet to be fully assessed. In C. elegans, the endogenous cannabinoid receptor ͵ͻ agonist, 2-arachidonoylglycerol (2-AG) activates a CB1 orthologue, NPR-19, to ͶͲ modulate behavior (Oakes et al., 2017). In addition, 2-AG stimulates the NPR-19 Ͷͳ independent release of both serotonin (5-HT) and dopamine (DA) from subsets of Ͷʹ monoaminergic neurons to modulate locomotory behaviors through a complex Ͷ͵ monoaminergic signaling pathway involving multiple serotonin and dopamine receptors. ͶͶ 2-AG also inhibits locomotion in remodeled monoamine receptor mutant animals Ͷͷ designed to measure the acute release of either 5-HT or DA, confirming the direct Ͷ͸ effects of 2-AG on monoamine release. 2-AG-dependent locomotory inhibition requires Ͷ͹ the expression of TRPV1 and TRPN-like channels in the serotonergic or dopaminergic Ͷͺ neurons, respectively, and the acute pharmacological inhibition of the TRPV1-like Ͷͻ channel abolishes both 2-AG dependent 5-HT release and locomotory inhibition, ͷͲ suggesting the 2-AG may activate the channel directly. This study highlights the ͷͳ advantages of identifying and assessing both CB1/CB2-dependent and independent ͷʹ cannabinoid signaling pathways in a genetically-tractable, mammalian predictive model, ͷ͵ where cannabinoid signaling at the molecular/neuronal levels can be correlated directly ͷͶ with changes in behavior. ͷͷ ͷ͸ Significance statement ͷ͹ This study is focused on assessing CB1/CB2-independent cannabinoid signaling ͷͺ in a genetically-tractable, whole animal, model where cannabinoid signaling at the ͷͻ molecular/neuronal levels can be correlated with behavioral change. C. ͸Ͳ elegans contains a cannabinoid signaling system mediated by a canonical cannabinoid ͸ͳ receptor, NPR-19 with orthology to human CB1/CB2 (Oakes et al., 2017). The present ͸ʹ study has characterized and NPR-19-independent signaling pathway that involves the ͸͵ cannabinoid-dependent release of both serotonin and dopamine and the expression of ͸Ͷ distinct TRP-like channels on the monoaminergic neurons. Our work should be of ͸ͷ interest to those studying the complexities of CB1/CB2-independent cannabinoid ͸͸ signaling, the role of TRP channels in the modulation of monoaminergic signaling and ͸͹ the cannabinoid-dependent modulation of behavior. ͸ͺ ͸ͻ ͹Ͳ Abbreviations: THC, Δ9-tetrahydrocannabinol; 2-AG, 2-arachidonoylglycerol; 2-APB, 2- ͹ͳ aminoethoxydiphenyl borate, 5-HT, serotonin; 5-HT quint, ser-5;ser-4;mod-1;ser-7 ser-1 ͹ʹ 5-HT receptor quintuple null animal; AA-5-HT, N-arachidonoyl serotonin; AEA, N- ͹͵ arachidonoylethanolamine or anandamide; CAT-1, vesicular monoamine transporter ͹Ͷ (VMAT); CAT-2, tyrosine hydroxylase; CAT-4, GTP cyclohydrolase 1; CB, cannabinoid; ͹ͷ CB1, CB receptor type 1; CB2, CB receptor type 2; CBD, cannabidiol; DA, dopamine; DA ͹͸ quad, dop-1;dop-2;dop-3;dop-4 DA receptor quadruple null animal; DOP-4, Gαs-coupled ͹͹ DA receptor; eCBs, endocannabinoids; FAAH, fatty acid amide hydroxylase; GOA-1, G- ͹ͺ protein Gαo subunit; GPCR, G protein-coupled receptor; MAGL, monoacylglycerol ͹ͻ lipase; N2, wild-type animals; NGM, nematode growth media; NOMPC, ͺͲ mechanoreceptor potential channel; NPR, neuropeptide receptor; NPR-19, CB receptor; ͺͳ OSM-9, TRPV-1-like channel subunit; pCB, phytocannabinoid; SER-4, Gαo-coupled 5- ʹ ͺʹ HT1-like receptor; TPH-1, tryptophan hydroxylase; TRP, transient receptor potential ͺ͵ channel; TRP-4, the pore-forming subunit of a mechanosensitive NOMPC channel; ͺͶ TRPV1, TRP vanilloid channel type 1. ͺͷ ͺ͸ ͺ͹ Introduction ͺͺ Cannabis or marijuana alters sensory perception and has been purported to ͺͻ exert a wide range of recreational and medicinal effects (Grotenhermen and Muller-Vahl ͻͲ 2012; Pacher et al. 2006). Cannabis sativa contains more than 60 bioactive ͻͳ compounds, or phytocannabinoids (pCBs), including cannabidiol (CBD) and the ͻʹ hallucinogen, Δ9-tetrahydrocannabinol (THC). These pCBs and the endogenous ͻ͵ cannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine ͻͶ (AEA) differentially activate a canonical CB signaling pathway initiated by two receptors, ͻͷ CB1 and CB2. CB1 and CB2 are differentially expressed and, in part, mediate a ͻ͸ retrograde signal from postsynaptic neurons to inhibit neurotransmitter release. CB1 is ͻ͹ localized primarily to pre-synaptic nerve terminals in the brain and CNS. CB2 is also ͻͺ found in the CNS, but is most robustly expressed in the immune system (Glass et al. ͻͻ 1997; Herkenham et al. 1990; Ohno-Shosaku and Kano 2014; Tsou et al. 1998). CBs ͳͲͲ also modulate the release of dopamine (DA) and serotonin (5-HT) and some of the ͳͲͳ behavioral effects of CBs are mediated either, directly or indirectly, through changes in ͳͲʹ serotonergic, adrenergic and dopaminergic signaling (Cheer et al. 2005; Cheer et al. ͳͲ͵ 2004; Fitzgerald et al. 2012; Gantz and Bean 2017; Kurihara et al. 2001; McLaughlin et ͳͲͶ al. 2009; Romero et al. 2013; Sagredo et al. 2006; Winters et al. 2012). However, in ͳͲͷ many cases, it is unclear whether the CB-dependent modulation of monoaminergic ͳͲ͸ signaling involves CB1/CB2 directly or CB1/CB2-independent signaling pathways. For ͳͲ͹ example, CBs also differentially activate the recently de-orphanized GDi/o-coupled ͳͲͺ receptors, GPR18 and GPR55, and a range of transient receptor potential receptors, ͳͲͻ including the transient receptor potential vanilloid 1 receptor (TRPV1) (De Petrocellis et ͳͳͲ al. 2001; Di Marzo et al. 1998; Di Marzo and Maccarrone 2008; Maccarrone et al. 2008; ͳͳͳ Starowicz et al. 2007). However, less is known about how these non-canonical CB ͳͳʹ receptors/ion channels interact with CB1/CB2 signaling in the modulation of CB- ͳͳ͵ dependent behaviors. ͳͳͶ Given the complexity of the mammalian nervous it has been difficult to correlate ͳͳͷ studies of CB signaling at the molecular/neuronal levels with changes in individual ͳͳ͸ behaviors. In contrast, we have focused on the genetically-tractable, nematode model, ͳͳ͹ Caenorhabditis elegans, with the goal of examining the effects of CBs on the ͳͳͺ modulation of sensory integration and decision-making. Our recent work has ͳͳͻ demonstrated that CB signaling likely has ancient evolutionary origin and has identified ͳʹͲ a canonical CB signaling system in C. elegans (Oakes et al. 2017). For example, the ͳʹͳ CB-dependent modulation of nociception and feeding requires the human CB receptor ͳʹʹ orthologue, NPR-19 (Oakes et al. 2017). CBs activate NPR-19 directly with affinities ͳʹ͵ similar to human CB1 and CB-dependent phenotypes can be rescued in npr-19 null ͳʹͶ animals by the expression of the human CB1, confirming the proposed orthology of the ͳʹͷ two receptors (Oakes et al. 2017). CBs also extensively modulate monoaminergic ͳʹ͸ signaling through NPR-19 independent pathways (Oakes et al. 2017). ͳʹ͹ Therefore, the present study is focused on characterizing the effects of CBs on ͳʹͺ monoaminergic signaling and has used the 2-AG dependent modulation of locomotory ͵ ͳʹͻ behavior to probe NPR-19-independent CB signaling. Specifically, we have ͳ͵Ͳ demonstrated that 2-AG inhibits forward locomotion and increases turning through ͳ͵ͳ NPR-19 independent pathways that involve the activation of multiple TRP channels and ͳ͵ʹ the endogenous release of both 5-HT and DA from subsets of monoaminergic neurons. ͳ͵͵ For example, 2-AG dependent locomotory inhibition is dramatically reduced or absent in ͳ͵Ͷ tph-1 and cat-2 null animals that lack key enzymes required for 5-HT and DA ͳ͵ͷ biosynthesis, respectively and in ser-4 and dop-4 null animals that encode 5-HT and DA ͳ͵͸ receptors, respectively.
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