Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity

Abstract

Alcohol is likely to affect neurons nonselectively, and the understanding of its action in the CNS requires elucidation of underlying neuronal circuits and associated cellular processes. We have identified a Drosophila signaling system, comprising neurons expressing neuropeptide F (NPF, a homolog of mammalian neuropeptide Y) and its receptor, NPFR1, that acutely mediates sensitivity to ethanol sedation. Flies deficient in NPF͞NPFR1 signaling showed decreased alcohol sensitivity, whereas those overexpressing NPF exhibited the opposite phenotype. Furthermore, controlled functional disruption of NPF or NPFR1 neurons in adults rapidly confers resistance to ethanol sedation. Finally, the NPF͞NPFR1 system selectively mediates sedation by ethanol vapor but not diethyl ether, indicating that the observed NPF͞NPFR1 activity reflects a specialized response to alcohol sedation rather than a general response to intoxication by sedative agents. Together, our results provide the molecular and neural basis for the strikingly similar alcohol-responsive behaviors between flies and mammals.acute ethanol response ͉ neuropeptide Y ͉ neuropeptide F receptor A lcohol, a widely abused drug, impacts the functioning of the CNS in diverse animals. The behavioral responses to acute alcohol exposure are remarkably similar among humans, rodents, and even fruit flies. Alcohol induces an excitatory state at lower concentrations but exerts a sedative effect at higher doses (1, 2). The current knowledge about how this drug impacts the functioning of the CNS is rather limited. Ethanol is highly soluble in both water and lipids, and is likely to act on neurons in a nonselective manner. However, the sensitivity of neurons in different neural circuits to this drug may vary greatly (3). Thus, elucidation of neuronal circuits and underlying molecular mechanisms essential for alcohol sensitivity is a prerequisite for understanding how alcohol interferes with the functioning of the CNS.Neuropeptides are a group of chemically diverse signal molecules implicated in modulating a broad spectrum of physiological processes and behaviors (4). Mammalian neuropeptide Y (NPY) is a 36 aa neuromodulator present abundantly in many regions of the CNS, and acts thorough a number of Y receptor subtypes (5). Mice lacking NPY or Y1 displayed increased ethanol consumption and resistance to alcohol sedation, whereas animals overexpressing NPY showed opposite behavioral phenotypes (6, 7). These results provide genetic evidence of a critical role of the NPY signaling system in acute ethanol response. However, the elucidation of the physiological role of the NPY system and the action sites has been difficult largely because of the complexity of mammalian models.NPY family molecules have been found in diverse organisms (8-10). Neuropeptide F (NPF) is the sole member of the NPY family in the Drosophila genome, and its action is mediated by G protein-coupled seven-transmembrane receptors related to mammalian NPY receptors (11). Both NPY and NPF are present prominently, although...

Peptidomics of Neuropeptidergic Tissues of the Tsetse FlyGlossina morsitans morsitans

“…Like its mammalian counterpart neuropeptide Y, NPF is primarily known for its role in feeding behavior [86], but is also involved in several other behavioral processes including mating behavior-associated activity [87][88][89], sleep [90], aggression [91], and ethanol sensitivity [92]. Dipteran NPF expression is observed in larval and adult brain tissue and endocrine cells in the midgut [93,94].…”

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

“…Many biological phenomena contribute to ethanolinduced responses. These include the involvement of neuropeptide-Y related pathways, [1][2][3][4] glutamate receptors, 5,6 GABA receptors, 7,8 the cAMP signalling pathway, 9,10 the BK potassium channel, SLO-1 [11][12][13] , and membrane perturbation. 14 Many genes and proteins are conserved between Caenorhabditis elegans and humans, including many of those that have been identified as playing a possible role in the effects of ethanol.…”

The Novel Genetank, a Tumor Suppressor Homolog, Regulates Ethanol Sensitivity inDrosophila

“…The PI is a major locus of peptidergic neurons (Park et al, 2008). Neuropeptides modulate neuronal activity or other cellular properties and have been linked to many types of behavior, including ethanol responses (Corl et al, 2005;Wen et al, 2005;Nässel and Winther, 2010). We observed that downregulating tank in four different classes of peptidergic cells within the PI, including insulin-producing cells that were implicated previously in ethanol sensitivity (Corl et al, 2005), did not affect ethanol sedation.…”

“…As in humans and rodents, lower doses of ethanol stimulate locomotor activity in flies (Wolf et al, 2002), whereas higher doses induce motor incoordination and sedation (Moore et al, 1998;Rothenfluh et al, 2006). Many evolutionarily conserved genes regulate acute ethanol responses in both flies and mammals, such as protein kinase A (Moore et al, 1998;Thiele et al, 2000), epidermal growth factor receptor (EGFR) (Corl et al, 2009), and neuropeptide F/Y (NPF/NPY ) (Thiele et al, 1998;Wen et al, 2005). Drosophila also offers powerful tools for studying neural circuits (Kaun et al, 2012); however, the neurons mediating ethanol sedation in flies are largely unknown.…”

“…Drosophila also offers powerful tools for studying neural circuits (Kaun et al, 2012); however, the neurons mediating ethanol sedation in flies are largely unknown. NPF-expressing cells promote sedation sensitivity (Wen et al, 2005), as do cells expressing the neural sex determination factor fruitless ( fru; Devineni and Heberlein, 2012), whereas insulin signaling in cells within the pars intercerebralis (PI) promotes sedation resistance (Corl et al, 2005). Additional studies have identified the neurons in which specific genes function to regulate ethanol sedation, but most of these studies did not determine whether the activity of these neurons acutely regulates ethanol sedation (Urizar et al, 2007;Corl et al, 2009;Eddison et al, 2011).…”