N-acyldopamines control striatal input terminals via novel ligand-gated cation channels Samira G. Ferreira a , Tonia Lomaglio a , Antonio Avelino b, c , Francisco Cruz b, d , Catarina R. Oliveira a , Rodrigo A. Cunha a , Attila Ko ¨ falvi a, * a Center for Neuroscience and Cell Biology of Coimbra, Department of Zoology, Faculty of Medicine, University of Coimbra, 1 Rua Larga, 3004-504 Coimbra, Portugal b Institute of Histology and Embryology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal c Institute for Molecular and Cell Biology, University of Porto, 4200-319 Porto, Portugal d Department of Urology, Hospital Sa ˜o Joa ˜o, 4200-319 Porto, Portugal article info Article history: Received 2 October 2008 Received in revised form 20 November 2008 Accepted 1 December 2008 Keywords: N-acyldopamines Ca 2þ entry Glutamate release Dopamine release TRPV 1 vanilloid receptor Cannabinoid Striatum abstract Endogenous analogues of capsaicin, N-acyldopamines, were previously identified from striatal extracts, but the putative presynaptic role of their receptor, the TRPV 1 R (formerly: vanilloid or capsaicin receptor) in the caudate–putamen is unclear. We found that the endogenous TRPV 1 R agonists, N- arachidonoyldopamine (NADA) and oleoyldopamine (OLDA) with EC 50 values in the nanomolar range, as well as the synthetic TRPV 1 R activator 2-aminoethoxydiphenylborane (2APB), and palmytoyldopamine (PALDA, another endogenous N-acyldopamine inactive at the TRPV 1 R), but not capsaicin or other endogenous and synthetic cannabinoids, triggered a rapid Ca 2þ entry with the concomitant stimulation of glutamate and dopamine release. These effects persisted in the TRPV 1 R null-mutant mice, and were insensitive to antagonists of common ionotropic receptors, to several TRPV 1 R antagonists and to the absence of K þ . Furthermore, these N-acyldopamine receptors in glutamatergic and dopaminergic terminals are different based on their different sensitivity to anandamide, capsazepine and Gd 3þ at nanomolar concentrations. Altogether, novel ion channels instead of the TRPV 1 R mediate the presynaptic action of N-acyldopamines in the striatum of adult rodents. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The transient receptor potential vanilloid type-1 receptor (TRPV 1 R) is a non-selective Ca 2þ and Na þ channel activated by heat, protons, inflammatory agents, endovanilloids and the pungent substance, capsaicin of chilli pepper, and is involved in peripheral and central pain transmission and procession (Caterina et al., 1997; Avelino and Cruz, 2006; Nagy et al., 2008). The so-called endova- nilloids are diverse lipidomics (mostly arachidonate-derivatives) (Starowicz et al., 2007), and among them, perhaps anandamide (arachidonoylethanolamine, AEA, Fig. 1C) is the most studied as it also activates the inhibitory metabotropic type-1 cannabinoid receptor (CB 1 R) (Devane et al., 1992; Lovinger, 2008). N-arach- idonoyldopamine (NADA) is another endogenous ligand capable of activating both the CB 1 R and the TRPV 1 R, and belongs to the recently described family of N-acyldopamines (Starowicz et al., 2007). Several similar fatty acid dopamide conjugates have been identified in striatal extracts, among which NADA and N-oleoyldopamine (OLDA) (Fig. 1C) are as efficacious and potent as capsaicin at the TRPV 1 R(Huang et al., 2002; Chu et al., 2003). However, the obser- vation that palmytoyldopamine (PALDA; Fig. 1C) lacks agonist activity at the TRPV 1 R(Chu et al., 2003) prompts the hypothesis that N-acyldopamines may have additional targets. In the brain, TRPV 1 Rs display higher density in the cortex, the hippocampus, the preoptic area, the medial basal hypothalamus, the locus coeruleus and the basal ganglia (Mezey et al., 2000; Sanchez et al., 2001; Szabo ´ et al., 2002; Roberts et al., 2004; To ´ th et al., 2005; Cristino et al., 2006). Marinelli et al. (2003, 2005, 2007) found that TRPV 1 R activation can directly stimulate dopamine release or glutamatergic transmission in the substantia nigra pars compacta, the ventral tegmental area and the nucleus accumbens of the rat. In the striatum, presynaptic TRPV 1 Rs desensitize rapidly, but the activation of protein kinase C (PKC) unmasks TRPV 1 R- mediated presynaptic facilitatory actions (Musella et al., 2009). Thus, in the absence of PKC activation, predominantly post- synaptic TRPV 1 R activation can be detected which down-regulates the post-synaptic release of 2-arachidonoylglycerol (2-AG) (Maccarrone et al., 2008). Importantly, 2-AG (Fig. 1C) is another * Corresponding author. Tel.: þ351 239 820190; fax: þ351 239 822776. E-mail address: akofalvi@yahoo.com (A. Ko ¨ falvi). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2008.12.001 Neuropharmacology 56 (2009) 676–683