Fonseca MS

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Current Pharmaceutical Design, 2013, 19, 000-000 1
Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction: New Roles for Acylethanolamides and Lysophosphatidic Acid
Laura Orio1,+, Francisco Javier Pavn2,+, Eduardo Blanco2,+, Antonia Serrano2, Pedro Araos2, Mara Pedraz2, Patricia Rivera2, Montserrat Calado2, Juan Surez2 and Fernando Rodrguez de Fonseca1,2,*
1 Departamento de Psicobiologa, Facultad de Psicologa, Universidad Complutense de Madrid, Campus de Somosaguas E-28223 Madrid, Spain. 2Instituto IBIMA. Unidad de Gestin Clnica de Salud Mental. Hospital Carlos Haya de Mlaga. Avenida Carlos Haya 82. E-29010 Mlaga, Spain
Abstract: This review analyzes the roles of lipid transmitters, especially those derived from the cleavage of membrane phospholipids, in cocaine-associated behaviors. These lipid signals are important modulators of information processing in the brain, affecting transmitter release, neural plasticity, synaptogenesis, neurogenesis, and cellular energetics. This broad range of actions makes them suitable targets for pharmaceutical development of cocaine addiction therapies because they participate in the main cellular processes underlying the neuroadaptations associated with chronic use of this psychostimulant. The main lipid transmitters reviewed here include a) acylethanolamides and acylglycerols acting on cannabinoid receptors, such as anandamide and 2-arachidonoylglycerol; b) acylethanolamides that do not act on cannabinoid receptors, such as oleoylethanolamide; c) eicosanoids derived from arachidonic acid, including prostaglandins; and d) lysophosphatidic acid, focusing on the role of its LPA-1 receptor. Direct experimental evidence for the significance of these lipids in cocaine-related behaviors is presented and discussed. Additionally, the roles for both their biosynthesis and degradation pathways, as well as the participation of their receptors, are examined. Overall, lipid transmitter signaling can offer new targets for the development of therapies for cocaine addiction.
Keywords: Oleoylethanolamide, PPAR , knockout, cocaine, motor sensitization, reinforcement. LIPID TRANSMITTERS AS TARGETS FOR PHARMACEUTICAL DEVELOPMENT IN ADDICTION Lipid transmitters are small molecules that are primarily generated enzymatically by the cleavage of phospholipids, which are structural components of the cell membrane. Each year, new members of this class of transmitters are discovered, as well as a number of receptors and metabolic pathways for their synthesis and degradation. The present review intends to explore the roles of the main lipid transmitters that have been implicated in cocaine addiction by the scientific literature. These transmitters include acylethanolamides and acylglycerols acting on endocannabinoid receptors [1,2], the acylethanolamides that act in non-cannabinoid targets [1,2], eicosanoid derivatives (mainly prostaglandins) [3] and lysophospholipids and their receptors [4]. These lipid transmitters share several features. They have been very well preserved through evolution and are present in almost all tissues, including the central nervous system (CNS). Some of these transmitters share metabolic pathways and can be interconverted though simple enzymatic processes (i.e., lysophospholipids can yield endocannabinoids, and endocannabinoids may be converted into prostaglandin analogs) (Fig. 1). Because of their enzymatic generation and hydrophobic nature, they are not stored in vesicles, such as with classical transmitters (i.e., monoamines or peptides). Upon specific stimuli, they are released on demand, serving as pleiotropic signals that regulate multiple cell functions. Their release is controlled by simple enzymatic pathways that can be controlled by depolarization or the activation of specific membrane receptors [1-4]. They can target either membrane or nuclear receptors, activating both classical second messenger systems and transcription processes. Finally, lipid transmitters are rapidly inactivated by specific enzymes. Thus, any pharmaceutical designed to modulate these lipid transmitter systems can act at
*Address correspondence to this author at the Hospital Carlos Haya de Mlaga. Avda. Carlos Haya 82, E-29010 Mlaga, Spain; Tel: +34 669426548; E-mail: fernando.rodriguez@fundacionimabis.org +These authors contributed equally to this work.
the biosynthetic pathway, the receptor interaction or the degradation enzymes. In the CNS, these lipid transmitters have been involved in all of the major aspects of information processing, including transmitter release, retrograde signaling, short- and long-term neural plasticity and synaptogenesis [1-4]. They also participate in neurogenesis, glial cell dynamics, neuroinflammation and the control of cellular energetics. Considering all the processes that are modulated by these transmitters, it is reasonable to think that they might also be engaged in the neuroadaptive processes underlying cocaine addiction (see Fig. 1). In the following sections, the neuropharmacology of these lipid transmitters and their implications for cocaineassociated behaviors will be discussed. 1. ACYLETHANOLAMIDES: BEYOND THE ENDOCANNABINOID SYSTEM Acylethanolamides are endogenous bioactive lipid mediators that are involved in a wide range of physiological activities. Generally, acylethanolamides are formed in response to different stimuli in the nervous system and other peripheral tissues in mammals, but they are also released in cerebral areas at certain points in the circadian cycle [1,2]. These fatty acid ethanolamides include the endocannabinoid arachidonoylethanolamide (also known as anandamide, AEA), the anti-nociceptive and anti-inflammatory mediator palmitylethanolamide (PEA) and the satiety factor oleoylethanolamide (OEA). Though widely divergent in function, acylethanolamides share common biosynthetic and degradative mechanisms that have been characterized in various tissues, particularly neurons. These acyl derivatives are formed by sequential catalysis following a classical transacylation-phosphodiesterase pathway from glycerophospholipids via N-acylphosphatidylethanolamines (NAPEs). The membrane phospholipid precursor NAPE is primarily synthesized by cAMP- and Ca-dependent N-acyltransferase. Then, acylethanolamides are released, together with a phosphatidic acid molecule, by the action of a specific NAPE-hydrolyzing phospholipase D (NAPE-PLD) activated by depolarization or G protein-coupled
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Fig. (1). Lipid transmitters reviewed in the present manuscript. Fatty acids (AA, OA or PA) obtained through diet or derived of endogenous synthesis are incorporated into membrane phospholipids. Specific depolarizing signals, such as those associated with cocaine (or other drugs of abuse), are capable of inducing the cleavage of specific phospholipids, leading to the appearance of lipid transmitters (such as LPA), ECS (such as AEA or 2-AG), eicosanoids derived from AA or monounsaturated acylethanolamides (such as OEA and PEA). Some of these lipid signals are linked through simple metabolic pathways. Lipid transmitters activate specific receptors that are capable of modifying the pharmacological responses to cocaine, leading to changes in transmitter release, neural plasticity, synaptogenesis, neurogenesis and cellular energetics. These changes might contribute to the acquisition of the addicted phenotype, opening alternatives for pharmaceutical development. [AA: arachidonic acid; OA: oleic acid; PA: palmitic acid; LPA: lysophosphatidic acid; ECS: endocannabinoids; AEA: anandamide; 2-AG: 2-arachidonoylglycerol; OEA: oleoylethanolamide; PEA: palmitylethanolamide].
receptor stimulation [2]. However, recent studies have shown that acylethanolamide-generating pathways are more complex than previously thought and include the participation of several enzymes poorly characterized in this classical pathway. Furthermore, other lipid-transmitter synthesis enzymes have been identified by alternative methods, including the analysis of mice lacking NAPE-PLD. In fact, two such enzymes have recently been reported, a secretory phospholipase-2 capable of hydrolyzing NAPE into acyllysophosphatidylethanolamides and the enzyme /-hydrolase 4 (Abh4), which participates as a NAPE-selective lipase in mouse brain [1,2]. Acylethanolamide signaling function appears to be inactivated by a two-step process that includes transport into cells and hydrolysis. Both steps exert tight control over these lipid mediators to rapidly remove them from tissue, although only the hydrolytic enzyme has been totally characterized. Acylethanolamide uptake was thought to be mediated by an energy-independent protein transporter, which has been well-described for AEA [2]. However, other recent reports appear to confirm that transport and degradation are independent processes, at least with AEA. Degradation is mainly performed by a fatty acid amide hydrolase (FAAH), which is a membrane-bound enzyme that belongs to the serine-hydrolase family, although another isozyme has been found to be localized on endoplasmic reticulum [2,5]. This hydrolase is widely distributed throughout the body, with high concentrations in the brain and liver, and it has been previously characterized. Mice lacking FAAH have been utilized in the characterization of the endocannabinoid system and other acylethanolamides. A second recently identified enzyme is the acylethanolamide-hydrolyzing acid amidase (also
known as acylsphingosine amidohydrolase-like), which degrades bioactive fatty acid amides to their corresponding acid. It is expressed in several tissues, with the highest levels in the liver and kidney, followed by the pancreas [6]. Alternatively, other enzymes, such as cyclooxygenase 2, lipoxygenases and cytochrome P450 isoforms, are able to inactivate these acylethanolamides by oxygenation, generating other active molecules [2,7]. In neurons, acylethanolamides are not stored in intracellular compartments, such as the case for classical neurotransmitters, but are synthesized on demand by cleavage from membrane precursors. OEA (Fig. 2 ) and other acylethanolamides are able to target their specific receptors in three locations: in the cell where they were formed via diffusion within the plasmalemma; at proximal targets, such as presynaptic receptors, thus working as retrograde signals; or at distant targets, presumably via serum protein carriers, such as lipocalins or albumin. The acylethanolamides produce a variety of physiological effects by binding to their several receptors. AEA has been extensively studied and identified as a partial agonist at cannabinoid receptors type 1 and 2 (CB1 and CB2, respectively) [7]. Unlike AEA, OEA is inactive on cannabinoid receptors, instead activating the peroxisome proliferator-activated receptor alpha (PPAR), a nuclear transcription factor [8]. Although PEA was initially described as a potential CB2 receptor agonist, it is also inactive at both cannabinoid receptor types and was shown to bind to PPAR but with a lower potency than OEA. In addition to cannabinoid and nuclear receptors, acylethanolamides have been found to modulate other targets, such as vanilloid receptors and orphan G protein-
Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction
Current Pharmaceutical Design, 2013, Vol. 19, No. 00
Fig. (2). Mechanisms for the activation of the nuclear receptor PPAR by OEA in the CNS. (1) This acylethanolamide is a lipid modulator that directly binds to PPAR as a ligand to induce changes in target gene expression. It may also produce non-genomic effects through the interaction with membrane receptors (orphan receptors GPR55 and GPR119 and the vanilloid channel TPRV1). (2) OEA activates PPAR within cell nuclei, leading to the transcription and translation of target proteins. PPAR regulates gene expression by binding to specific DNA sequences (PPRE) in the promoter regions of target genes. Prior to DNA binding, PPAR forms a heterodimer with the RXR, another member of the nuclear receptor family. (3) At the cellular level, PPAR participates in various metabolic processes, including stimulating the uptake of fatty acids through membranes and synthesis of lipoproteins, stimulating the oxidation of fatty acids in mitochondria, peroxisomes and microsomes and contributing to lipoprotein assembly and transport. (4) At the physiological level, activation of PPAR by OEA may have specific functions in the control of appetite/body weight, neuroprotection, synaptic plasticity, learning and memory, pain perception and reward-based behaviors. [PPAR: peroxisome proliferator-activator receptor alpha; OEA: oleoylethanolamide; CNS: central nervous system; TPRV1: transient potential receptor vanilloid type-1; PPRE: PPAR response element; RXR: retinoic X receptor].
coupled receptors. The transient receptor potential vanilloid type-1 (TRPV-1) channel is activated by AEA [9]. OEA has been extensively reported to act as a TRPV-1 agonist [10], although some recent studies have suggested a possible opposite activity on this channel [10-11]. Two other G protein-coupled receptors, GPR55 and GPR119, have recently been found to be additional targets for acylethanolamides [12-14]. Given these recent developments, there are surely other additional targets for these lipid mediators that will be elucidated in the next few years. Because acylethanolamide production is linked to neural activity and plays a relevant role on information processes in the brain, we will discuss its implications for cocaine addiction. We consider two different groups of signals, those acting on cannabinoid receptors (endocannabinoids) and those acting on non-cannabinoid targets (e.g., OEA). We include a brief description of the acylglycerols in the endocannabinoid section because they also include CB1 and CB2 agonists. Compared with acylethanolamides, acylglycerols can be characterized more as chemical entities, with different origins
and metabolic pathways, and acylethanolamides must also be considered when discussing the role of cannabinoid receptors in addiction. a. Endocannabinoids The term endocannabinoids refers to endogenous polyunsaturated fatty acid derivatives that bind and functionally activate cannabinoid receptors. To date, several endocannabinoids have been identified, including AEA, 2-arachidonoylglycerol (2-AG) [15,16] and more recently, noladin ether (2-arachidonoylglycerol ether) [17], N-arachidonoyl-dopamine (NADA) [18] and virodhamine (oarachidonoyl-ethanolamine) [19]. The pharmacological activity and metabolic pathways of the recently discovered endocannabinoids remains uncharacterized, and consequently, AEA and 2-AG are considered the primary endocannabinoid molecules. AEA and 2AG are arachidonic acid (AA) derivatives that are structurally similar to eicosanoids but synthesized by a different metabolic pathway. They are derived from phospholipid precursors that are present in
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neurons, immune cells and endocrine cells [2]. The production of both AEA and 2-AG is regulated by depolarization and/or activation of classical neurotransmitter receptors [9,20,21], although other AEA biosynthetic pathways have been described [2,22,23]. Activation of D2 receptors increases the levels of AEA [24,25], whereas activation of group I metabotropic glutamate receptors (mGluR1) appears to increase 2-AG production [26]. 2-AG is generated through multiple routes of lipid metabolism, predominantly by the hydrolysis of 1,2-diacylglycerol (DAG) mediated by sn-1-selective DAG lipases [2,27]. Endocannabinoids exert their main actions through binding to cannabinoid receptors. CB1 and CB2 are the two major types of cannabinoid receptors characterized to date [28,29], although there is recent evidence for other potential cannabinoid receptors, such as GPR55 and GPR119 [12-14,30]. CB1 is highly expressed in the cerebral cortex, hippocampus, basal ganglia and cerebellum and to a lesser extent, in the hypothalamus and spinal cord [31,32]. CB1 is primarily present in neurons but is also found in glial cells [33,34]. The neural localization of CB1 receptors is mainly presynaptic, in which their activation by endocannabinoids inhibits the release of neurotransmitters such as glutamate or GABA by retrograde transmission [35-37]. CB2 is primarily located in immune cells and peripheral organs, such as the spleen or pancreas [29,38], and there is also evidence for its expression on neurons and glia [39-40]. The brain areas expressing CB2 include the striatum, hypothalamus, cortex, substantia nigra, amygdala and hippocampus [40]. AEA and 2-AG exert agonist activity at both CB1 and CB2. Additionally, AEA potently activates the non-cannabinoid receptor TRPV-1 [9]. Once endocannabinoids exert their actions through CB1 and CB2, they are inactivated by a two-step mechanism: cellular reuptake into neurons/glial cells and subsequent intracellular specific hydrolysis, as described above [2,41,42]. 2-AG clearance is performed by multiple enzymes, although the most plausible mechanism involves monoacylglycerol lipase (MAGL), which cleaves 2AG into AA and glycerol [43,44]. Interestingly, MAGL regulates an AA metabolic pathway in the brain that includes both endocannabinoids and eicosanoids. FAAH can also hydrolyze 2-AG and other bioactive fatty acid amides [2]. AEA and 2-AG can also be inactivated by cyclooxygenase-2 (COX-2) oxidation into ethanolamide analogs of prostaglandins (PG-EAs) and prostaglandin glycerols (PG-Gs), respectively [45-49], or undergo metabolism by lipoxygenase (LOX) [50-52] (see Fig. 3 and below in the eicosanoid section). Endocannabinoids and Cocaine Addiction Substantial evidence has implicated the endocannabinoid system in the modulation of different aspects of ethanol, nicotine, opioid and psychostimulant addiction (reviewed in [53]), consistent with the widespread distribution of CB1 within the reward circuitry and other addiction-related brain areas [32,54]. Different pharmacological manipulations have allowed the investigation of the influence of endocannabinoids, which affect cocaine addiction mainly through CB1. However, the specific role of the endocannabinoid system in cocaine addiction remains inconclusive. In general, the influence of the endocannabinoid system on specific aspects of cocaine addiction has been documented, although its influence in cocaine-related behaviors appears to be less robust than its effects on other classes of abused drugs, such as ethanol or opiates. Acute rewarding properties are essential for the establishment of cocaine addiction. The rewarding effects of cocaine are primarily mediated by the direct and strong release of dopamine from neurons through inhibition of the dopamine transporter, resulting in high extracellular dopamine levels in the mesolimbic areas. The crosstalk between the endocannabinoid and dopamine systems has been well documented [25,55]. Activation of CB1 mediates dopamine release in animals and humans [56,57], and stimulation of dopamine D2 receptors leads to increases in endocannabinoid production
[25]. It has been shown that CB1 antagonism decreases the rise in dopamine levels in the nucleus accumbens mediated by several drugs of abuse, including cocaine [58]. Additionally, CB1 knockout mice display reduced basal dopamine levels, and both deletion and pharmacological blockade of CB1 reduce cocaine-induced accumbal dopamine release [59]. Other authors have observed that blockade or lack of CB1 does not alter cocaine-induced increases in dopamine levels in the nucleus accumbens [60, 61]. However, despite the absence of changes in accumbal dopamine levels, the same authors found that a lifelong lack of CB1 impairs cocaine selfadministration acquisition and consolidation [61]. Some articles have demonstrated that the behavioral consequences of CB1 inactivation in cocaine reward are consistent with a lack of dopamine level modulation. For example, CB1 deletion does not the affect conditioned place preference or locomotor activity induced by cocaine [62]. However, CB1 antagonists reduce the expression of cocaine behavioral sensitization [35,63] and may also determine the hedonic value and sensitivity to natural [64] and cocaine-reinforced [65] reward systems. There is contradictory information regarding the influence of CB1 blockade in cocaine self-administration. Whereas several studies have suggested no role for CB1 in cocaine self-administration per se [60-62,66-68], other reports have demonstrated a CB1 involvement in cocaine self-administration [61,65,69]. In general, positive results of CB1 antagonism on cocaine self-administration have been found by using the novel CB1 antagonist AM251 versus the classic SR141716A or by testing the compounds in progressive ratio schedules of self-administration, thus indicating an endocannabinoid influence in the motivational strength of cocaine. Additionally, the efficacy of SR141716A in reducing cocaine self-administration under progressive ratio schedules is enhanced in cocainedependent rats that are exposed to long periods of cocaine administration, resulting in escalated levels of drug self-administration [69]. There is evidence for an attenuation of cocaine-induced facilitation of brain stimulation reward mediated by CB1 receptor activation [70], whereas CB1 antagonism slightly reduces or has no effect on brain stimulation reward [71]. There is more robust evidence to suggest that the endocannabinoid system plays a role in cocaine relapse. The CB1 antagonists SR141716A and AM251 dose-dependently attenuate the cocaineprimed and cue-induced reinstatement of cocaine seeking [69, 72,73]. CB1 activation influences also stress-induced cocaine reinstatement by interaction with noradrenergic mechanisms [74] or the corticotropin-releasing factor (CRF) system [63], and the CB1 antagonist AM251 was found to reverse behavioral anxiety during cocaine withdrawal [75]. Studies in humans have shown that cannabis use has a permissive role in cocaine relapse [76] and causes a progression to cocaine use and dependence [77]. The progressive characterization of the endocannabinoid machinery, including the biosynthesis and inactivation enzymes, has incorporated the use of novel pharmacological manipulations to complete the landscape of endocannabinoid effects in cocaine addiction. In this regard, the FAAH inhibitor URB597 failed to modulate the cocaine-induced alterations in mesolimbic dopamine levels [78] and fixed-ratio cocaine self-administration [79,80], whereas blockade of AEA transporter by AM404 attenuated the cocaineinduced facilitation of brain stimulation reward [71]. In addition, the FAAH inhibitors URB597 and PMSF diminish priming and cue-induced cocaine relapse [79]. The neurochemical impact of cocaine on brain endocannabinoid levels and cannabinoid receptors has been studied to some extent. Non-contingent acute cocaine administration induces an increase in 2-AG levels but not AEA in the limbic forebrain, whereas chronic cocaine administration slightly reduces 2-AG levels in the same area with no alteration in AEA levels [80]. Cocaine inhibits FAAH and enhances the activity of NAPE-PLD in vitro, thus increasing AEA tone in the striatum [24]. By using intracerebral microdialysis
Fig. (3). AA is released from membrane phospholipids through the action of cytosolic PLA2. Endocannabinoids (AEA and 2-AG) and eicosanoids (PGs, TXA and leukotrienes) are structurally similar AA derivatives. The endocannabinoid AEA is derived from the phospholipid precursor NAPE though the action of a specific PLD, and 2-AG synthesis requires the formation of DAG and its subsequent hydrolysis by a DAG lipase. AEA and 2-AG are in turn degraded into AA by FAAH and MAGL activity, respectively, producing AEA-derived ethanolamides and 2-AG-derived glycerols. Both AEA and 2-AG can be inactivated by COX-2 oxygenation into PG-EAs and PG-Gs, respectively. Evidence has indicated that both AEA and 2-AG can also be metabolized by LOX enzymes, mainly into hydroxyl-AEA and HPETE-glycerol esters, respectively. The eicosanoid cascade is mediated by the COX, LOX and EPOX pathways. COX-1 and COX-2 enzymes catalyze the conversion of AA into PGG2/PGH2, which is the precursor of the prostanoids PGI2, PGD2, PGE2, PGF2 and TXA; the final products are generated by the actions of specific synthases. The LOX enzyme produces HPETE/HEPES intermediates that are further reduced to leukotrienes and other bioactive molecules. The cytochrome P-450 EPOX mostly originates EETs. The lipid transmitters represented in the figure exert specific actions by binding different receptors; AEA and 2-AG bind to cannabinoid CB1 and CB2, and AEA also activates TPRV1. The prostaglandins PGI2, PGD2, PGE2 and PGF2 bind to different subtypes of IP, DP, EP and FP receptors, respectively, and TXA2 binds TP receptors. PGE2 also binds to PPAR, and the nonenzymatic PGD2 product, the 15-deoxi-PGJ2, binds to PPAR. The existence of specific prostamide receptors for PG-EAs and PG-Gs is unknown, although some PG-EAs bind to cannabinoid CB2 or prostaglandin EP receptors. [AA: arachidonic acid; PG: prostaglandins; TX: tromboxanes; PLA2: phospholipase A2; PLD: phospholipase D; NAPE: N-arachidonoyl-phosphatidylethanolamide; DAG: diacylglycerol; FAAH: fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; COX: cyclooxygenase; LOX: lypooxygensase; EPOX: epooxygenase; PG-EAs: prostaglandin-ethanolamines; PG-Gs: prostaglandin-glycerols; HETE: hydroxyeicosatetraenoic acid; HETE-Gs: hydroxyeicosatetraenoic acid glycerol esters; HPETE: hydroperoxyeicosatetraenoic acid; EET: epoxyeicosatrienoic acid; TPRV1: transient potential receptor vanilloid type-1; PPAR: peroxisome proliferator-activator receptor].
in vivo, Caille and colleagues collected microdialyzed samples from the nucleus accumbens of rats during a drug self-administration session. They found specific alterations in endocannabinoid levels after self-administration of alcohol and heroin but not cocaine. Consistent with those results, they observed reductions in ethanol and nicotine self-administration after CB1 antagonism. Cocaine self-administration in a limited intake fixed ratio schedule was unaltered after SR141716A injection [66]. Regarding the density of CB1 receptors, chronic cocaine self-administration under an extendedaccess fixed-ratio (FR) 1 schedule [69] or under a FR5 schedule [81] induces a long-lasting upregulation of CB1 receptors in several areas, whereas chronic cocaine administration under limited-access conditions does not modify CB1 protein levels [69,81,83]. Chronic non-contingent cocaine also increases CB1 density in several brain
areas [81], although other authors found decreases in CB1 receptor mRNA, with no changes in protein expression in the hypothalamus and cerebral cortex [82]. Cocaine-escalated rats (rats chronically exposed to long periods of cocaine self-administration) show upregulation of both phosphorylated and total CB1 protein in the nucleus accumbens and amygdala, and these are highly responsive to CB1 antagonist injections in the nucleus accumbens, reducing the rates of cocaine self-administration compared with rats that selfadminister cocaine under limited conditions [69]. These results suggest that prolonged cocaine use may alter CB1 expression in the brain, influencing the addictive cycle. Conversely, polymorphisms in the CNR1 gene encoding CB1 have been associated with cocaine addiction in an African-Caribbean population [83,84].
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b. Oleoylethanolamide and PPAR OEA is an acylethanolamide that acts as agonist of nuclear receptors called PPAR to exert their biological functions, including the regulation of appetite and metabolism [8,86,86]. OEA also targets the vanilloid channel TRPV-1 [11] and has been proposed to activate the orphan receptor GPR119 [13]. Peripherally, activation of PPAR by either OEA or its analog PEA exerts effects on the control of appetite, lipolysis, inflammation and pain [8,85,87-89]. Additionally, it has been shown that OEA has neuroprotective properties both in vitro and in vivo in models of neurotoxicity [90] and cerebral ischemia [91]. In the CNS, OEA has been found to modulate appetite through the regulation of several hypothalamic neuropeptides involved in energy homeostasis, including oxytocin [92], and to enhance memory consolidation through its actions on noradrenergic inputs into the amygdala [93,94]. Oleoylethanolamide and Cocaine Addiction Although OEA is structurally related to endocannabinoids, it neither activates nor binds to cannabinoid receptors but is instead the endogenous ligand of PPAR. This might be a convergent target with cannabinoids because those compounds also activate PPAR receptors. Genes regulated by PPAR isoforms are involved in basic physiological processes, including lipid homeostasis, adipogenesis, inflammatory responses, wound repair, proliferation, differentiation, cell death and carcinogenesis [95,96]. Despite these multiple physiological roles, there is growing evidence suggesting that OEA might participate in the control of reward-based behaviors. Thus, FAAH inhibition, which enhances the bioavailability of OEA and endocannabinoids, also blocks nicotine-induced activation of neurons in the nucleus accumbens shell and ventral tegmental area. Furthermore, these actions appear to be mediated by both CB1 and PPAR receptors, as they were found to be mimicked by PPAR receptor agonist administration, which also modulated nicotine reward and reinstatement [78]. There are a few studies linking OEA and PPAR receptors in cocaine addiction, and these receptors have been studied using two specific behavioral paradigms: sensitization to cocaine-induced locomotion and conditioned place preference (CPP). These two tests have been extensively used to model the core components of drug addiction [64]. Behavioral sensitization consists of a progressively escalating locomotor response to a fixed drug dose, and CPP is used to measure reinforcement and drug-seeking behavior, by repeated pairings of a given context with the drug, resulting in a preference for this environment. The role for OEA in these behavioral responses has recently been characterized [97]. In one study, PPAR was found to be necessary for the control of morphine but not cocaine-induced behavior [96]. In another study, the role of OEA and its receptor, PPAR, was investigated in both cocaineinduced sensitization and cocaine-associated reward responses [97]. In this study, OEA was found to be effective at reducing cocaineinduced psychomotor effects through a PPAR-independent mechanism. PPAR was not critical for the mediation of cocaineinduced responses, as the PPAR-knockout mouse showed no effects on the short- and long-term psychomotor and rewarding effects of cocaine. In conclusion, these results clearly show that the effectiveness of OEA on cocaine responses is PPAR-independent and that PPAR does not mediate cocaine-related phenotypes. In C57/Bl6 mice, the acute administration of OEA at 5 or 20 mg/kg but not 1 mg/kg resulted in locomotor reduction, and these same doses were also able to reduce acute cocaine-induced locomotor activation. After repeated administrations, OEA was able to prevent the development of locomotor sensitization to cocaine (Fig. 4A), as cocaine-injected mice pretreated with OEA displayed lower locomotor activity than cocaine-treated mice on the fourth day. TRPV-1, which is activated by OEA and abundantly expressed in motor circuits, including the dopaminergic neurons of the substantia nigra [55], may be a mediator of the hypolocomotion induced by
OEA. However, this distribution has been recently challenged by other studies that have suggested a minor role for these receptors in motor control [98]. It is also important to note that OEA might counteract cocaine-dependent responses not exclusively inducing locomotor suppression, as it has also been shown to be effective at reducing CPP and conditioned locomotion (Fig. 4B). Thus, regardless of the locomotion-attenuating effect that could counteract the hyperactivity induced by cocaine (reducing its behavioral efficacy), OEA may also potentially affect the cocaine-mediated implicit learning processes necessary for the acquisition of a CPP or conditioned locomotion responses. Considering this possibility, these data could indicate that the non-PPAR OEA targets are a signaling system implicated in neural plasticity. Indeed, there are multiple additional targets through which OEA might induce such changes, including the extracellular-regulated kinases that are activated by OEA in several tissues [99] and are major regulators of synaptic plasticity. The orphan receptors GPR55 [100] and GPR119 [13] can be discarded based on receptor distribution or the pharmacology of OEA at those receptors. In summary, regardless of whether the OEA-induced effect on cocaine CPP and conditioned locomotion is due to impaired motor activity, implicit learning processes or both, these data raise questions about the interpretation of the specific behavioral effects of OEA. Experiments performed with PPAR knockout mice have helped clarify this question and support the hypothesis of a nonhypolocomotion-induced and non-PPAR-dependent effect of OEA on cocaine responses. Acute administration of OEA (1, 5 and 20 mg/kg, i.p.) did not induce any alteration in the basal activity of these mutants. The finding that OEA was not effective in PPAR knockout mice is consistent with the hypothesis that OEA acts through PPAR [97]. In acutely cocaine-treated mice, OEA was still able to reduce locomotor activity in PPAR knockout mice but with less efficiency than in wild-type mice. These findings indicate that OEA only partially modulates cocaine responses acting through PPAR and that PPAR is not a critical mediator of the psychomotor responses to cocaine. The present results are consistent with several findings reporting a lack of mediation of OEA signaling through PPAR in cocaine addiction. Although many of the effects of OEA, such as feeding inhibition [8,86], metabolic actions [85,99], anti-inflammatory effects [101,102] or learning processes [13], have been attributed to OEAs ability to stimulate PPAR, there is a growing body of evidence showing that the effects of OEA are not mediated by this nuclear receptor. These include effects on visceral pain perception [102] and Ca2+ fluxes in pancreatic -cells [103]. Indeed, the effects of PPAR agonists that are not structurally related to OEA, such as WY 14643, seem to be specifically mediated by nicotinic acetylcholine receptors located on dopaminergic neurons in the ventral tegmental area [104]. In line with these findings, PPAR appears to be specifically relevant for addiction to nicotine and not cocaine, as demonstrated by behavioral, electrophysiological and biochemical findings [78,105]. From these studies, it can be deduced that any role for PPAR in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine is not critical. However, further research is needed to identify the targets of OEA in its inhibitory effect on cocaine-mediated responses. 2. PROSTAGLANDINS Prostaglandins (PGs) are oxygenated derivatives of AA or eicosapentenoic acid (EPA) that function as lipid mediators. PGs are, together with the thromboxanes (TX) and leukotrienes, biologically potent eicosanoids present in different tissues. Two series of PGs are formed from AA and three series from EPA, although the EPA precursor is much less abundant than AA, at least in animals fed western European diets [106]. Regarding the PG biosynthesis, a stimulus-dependent phospholipase A2 (PLA2) cleaves AA from the membrane phospholipids, and subsequently, the final synthesis of PGs depends on consecutive actions of multiple synthetic enzymes.
Fig. (4). OEA attenuates the acquisition and expression of cocaine-induced reward-related behaviors in mice. A. Co-administration of OEA (1, 5 or 20 mg/kg) and cocaine (20 mg/kg) attenuated the induction of the cocaine-induced locomotor sensitization observed after four consecutive daily doses of the psychostimulant. B. Similarly, the co-administration of OEA plus cocaine in a similar dose regimen blunted the induction of CPP induced by the psychostimulant. OEA administration resulted in neither locomotion sensitization nor CPP. [OEA: oleoylethanolamide; CPP: conditioned place preference]. Studies were performed in at least eight mice per experimental group. The data are presented as the means S.E.M. See [97] for further details.
COX is the rate-limiting enzyme in the overall synthesis of PGs, and specific PG synthases complete the production of each PG. The enzymes known as COX are PH endoperoxide H synthases that oxygenate AA to form the unstable intermediate PGG2, which is rapidly and irreversibly converted to PGH2. The precursor PGH2 is then catalytically converted in a cell-specific manner to different prostanoids, PGI2 (prostacyclin), PGD2, PGE2, PGF2 or TXA2, by action of a PGI-, PDG-, PGE-, PGF- or TX- synthase, respectively. Similar to endocannabinoids, these PGs are synthesized on demand and are not stored because they are metabolically unstable [106,107]. Once formed, PGs rapidly diffuse to and activate their specific receptors, which belong to the G-protein-coupled rhodopsin receptor family. These receptors are designated DP, EP, FP, IP and TP for PGD2, PGE2, PGF2 , PGI2 and TXA2, respectively, and several subtypes of each receptor have been found. Some PGs may
also bind the nuclear receptor PPAR (see Fig. 3 ). Once released, PGs typically function in an autocrine or paracrine fashion near their sites of synthesis, coordinating responses to circulating hormones (revised in [108]). Central PGs modulate other transmitter systems, such as catecholaminergic, serotonergic and cholinergic neurons [109-111], and play important roles in neural function, including synaptic plasticity, long term potentiation, sleep induction, inflammation and neuroprotection (reviewed in [112]). PGs are regulated by PG transporters and largely inactivated and degraded by an initial oxidation catalyzed by the enzyme 15-prostaglandin dehydrogenase [113]. The AA eicosanoid cascade is mediated by COX, LOX and cytochrome P-450 epooxygenase (EPOX) pathways. Prostanoids, such as PGs and TXs, are produced by the COX pathway, whereas leukotrienes and hepoxilins are generated by the LOX pathway (see Fig. 3). COX is an enzyme constitutively expressed in the brain, of
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which at least two isoforms have been identified. COX-1 is constitutively expressed in the brain and generally involved in normal physiological functions. COX-2 is an inducible form responsible for the pathological production of PGs in response to different stimuli, although there is also a constitutive expression of COX-2 in neurons, glia and endothelial cells [114-116]. A splice variant of the COX-1 transcript has been described and named COX-3 [117]. COX-2 appears to be the predominant form in neurons, and it mediates PG signaling in the brain [116]. Endocannabinoid hydrolysis exerts crucial control over PG production by controlling the quantity of AA available [45]. Additionally, AEA and 2-AG may undergo COX-2 metabolism, generating a new class of lipid mediators known as prostamides (see Fig. 3). These novel PG-like substances are prostaglandin ethanolamides, including PGE2-EA, PGI2-EA, PGD2-EA, PGF2-EA and TXA2-EA, which derive from AEA metabolism [47,49,118], and prostaglandin glycerol esters (PG-Gs), including PGD2-G, PFI2-G, PGE2-G, PGF2-G, TXA2-G, which are derivatives of 2-AG cyclooxygenase metabolism [46,47,118]. PGE2-EA has some affinity for CB2 and is 40-fold less potent than PGE2 at EP receptors. The distribution of prostamide receptors is unknown. The pharmacological activity of these endocannabinoid-derived prostanoids has not yet been well characterized. These unique lipid mediators may act potently in the brain because they are more metabolically stable than classic PGs [119]. Prostaglandins and Cocaine Addiction There is not much information about a possible role for PGs in the mediation of cocaine addiction. The influence of cocaine on the endothelial or plasma levels of PGI2, PDE2 or TXA2, which are related with the vascular effects induced by cocaine intoxication, has been well documented [120-122]. Nevertheless, it is unknown whether the peripheral effects of cocaine on PG levels may influence central structures related to the addictive process. Some PGs, however, have been involved in opioid dependence. For example, PGE2 facilitates and PGF2 attenuates acute morphine dependence [123], the prostaglandin EP3 receptor is involved in attenuation of morphine withdrawal [124], and COX inhibitors attenuate opioidinduced tolerance and dependence [125]. Given the importance of other lipid transmitters in certain aspects of cocaine addiction and the fact that PGs in the CNS modulate synaptic plasticity [126] and the release of other neurotransmitters, such as catecholamines [110] and glutamate [127], it is conceivable to expect some role for PGs in cocaine addiction. Thus, it is interesting to note that PGs have been shown to modulate certain dopamine-mediated behaviors [128]. More specifically, it has been shown that PGE2 is formed in response to dopamine receptor stimulation, and this PG amplifies both dopamine D1 and D2 receptor signaling in the striatum via the EP1 receptor [129]. Reid and colleagues proposed in 1996 that PLA2 activity in mesolimbic dopamine neurons is involved in the development of cocaine sensitization [130]. As previously noted, PLA2 activation induces the AA cascade of eicosanoids. Subsequently, the same authors found that COX-1 and COX-2 activity mediates the development of cocaine sensitization [131]. Postmortem studies have shown that chronic cocaine users have decreased PLA2 activity in the striatum, a brain region with high dopamine receptor density, suggesting a role for PLA2 in dopamine-related behavioral effects of cocaine [132]. Additionally, activators of the AA pathway regulate the functional activity of the human dopamine transporter [133], and cocaine blocks this AA-stimulated dopamine transporter current [134]. Interestingly, low levels of polyunsaturated fatty acids, including AA, are good predictors of relapse vulnerability in cocaine addicts [135], although polyunsaturated fatty acids failed to protect against cocaine-conditioned place-preference behavior in animals [136]. In 2005, a clinical study tested the COX-2 inhibitor celecoxib in cocaine addicts and showed a weaker improvement in cocaine use and craving in the celecoxib group, bringing into ques-
tion the effectiveness of this treatment for cocaine dependence [137]. As discussed above, AA is primarily metabolized to eicosanoids by COX and LOX pathways. The LOX enzymes metabolize AA into biologically active hydroxyeicosatetraenoic (HETE) and hydroxyeicosapentaenoic (HEPE) acids, which are further reduced to leukotrienes and other biologically active compounds (see Fig. 3). Some findings point to a role for the LOX pathway in aspects of cocaine addiction; the 5-LOX pathway appears to be involved in the development of cocaine sensitization and alteration of the phosphorylation status of mGluR1 glutamate receptors [138], and 12LOX gene disruption augments the cocaine-mediated increases in locomotion following acute drug administration [139]. 3. LYSOPHOSPHATIDIC ACID (LPA) AND LPA-1 RECEPTORS Lysophosphatidic acid (monoacyl-sn-glycerol-3-phosphate) is a bioactive molecule that belongs to the family of lysophospholipids. In mammals, LPA species play a functional role as mediators for different developmental events and adult physiological processes. Lysophospholipid receptors were identified more than 10 years ago by Chuns group [140,141], and more than five of these receptors have been well characterized [141-146]. The LPA receptors are proteins that belong to the G protein-coupled receptor superfamily [144,147]. LPA activates multiple signal transduction pathways, and some of these pathways are mediated by Rho-family GTPases (RhoA, Rac1 and Cdc42) [148], with possible implications in diverse processes, such as brain development, vascular remodeling and tissue healing. Activation of these small GTPases helps to explain LPAs effects on the control of the assembly of the actin cytoskeleton in response to extracellular changes. Some of these changes might impact synaptic remodeling and thus affect neuronal plasticity and memory processes. In addition, LPA may play an essential role in neurogenesis in the brain. LPA-1-null mice (maLPA-1-null variant) showed a reduced ventricular zone, altered neuronal markers and increased cell death, which resulted in a loss of cortical cell density during the formation of the cerebral cortex [149]. In related regions, such as the hippocampal formation, the dentate gyrus showed defects in all processes from proliferation and differentiation to survival and cerebral neurogenesis in adult mice under normal and enrichedenvironment housing conditions [150]. Hippocampal adult-born neurons, specifically from the subgranular zone of the dentate gyrus, appear to be necessary for synaptic plasticity, learning and memory. Recent behavioral results indicated that after evaluating functions of LPA-1 in sensorimotor activity, emotional and cognitive areas in adult mice, maLPA-1-null mice exhibited deficiencies in spatial memory retention, abnormal use of searching orientation strategies [151] and defective working and reference memory, independent of the exploratory and emotional impairments attributed to hippocampal malfunction [152]. Other findings have demonstrated an impairment of prepulse inhibition response in LPA-1-null mice. LPA-1-null mice display a reduced ability to filter out irrelevant auditory stimulation, which may lead to the development of cognitive deficits and schizophrenia-like psychoses [153,154]. The relationship between the LPA-1 receptor and its influence in neuropathological states could be related to the functions of the LPA-1 receptor in generating and controlling anxiety-like behaviors and altering learning and memory. Role for Lysophosphatidic Acid and LPA-1 Receptors in Cocaine Addiction Because of its role in the control of both neural plasticity events and neurogenesis and its interrelation with the endocannabinoid system, LPA and its receptors might be involved in drug-addictionassociated neuroadaptations. Drug abuse induces long-term changes in neuroplasticity in the brain reward system, including modifica-
tions in the synaptogenesis and functional relations between glutamatergic, GABAergic and dopaminergic neurons. [155]. As with the endocannabinoid lipids, the role of LPA1 receptors and their interactions with glutamatergic and dopaminergic synaptic neurotransmission in synaptic plasticity and addictive behavior is poorly understood. Currently, little is known about the possible modulation of LPA over long-term alterations in gene expression patterns, neural plasticity and behavioral control induced by repeated exposure to cocaine. A recent work [156] has given light to the role of LPA-1 receptors in cocaine addiction processes. Chronic cocaine administration resulting in behavioral sensitization was examined in LPA-1-receptor-null mice. In these animals, cocaine induced a clear sensitization to its locomotion effects but was unable to promote associative learning, leading to the appearance of conditioned locomotion (Fig. 5). These results indicate that the
LPA-1 receptor might be involved in the regulation of associative (hippocampus-dependent) learning but not implicit (striatumdependent) learning, such as cocaine-induced sensitization. Lack of conditioned locomotion responses by maLPA1-null mice could indicate a failure to correctly learn the association between properties of an environment (open field) and cocainerewarding properties. The memory deficit in the expression of cocaine-induced conditioned locomotion in the absence of LPA1 receptors might be associated with alterations in either the mesocorticolimbic dopaminergic network that supports associative learning of the glutamatergic projections to the basal ganglia or the dorsal hippocampus. Because LPA1-null mice developed a robust acquisition of the cocaine-conditioning and behavioral sensitization responses after a cocaine priming injection (10 mg/kg), with no differences from wild-type control mice, the dopaminergic network
Fig. (5). The administration of cocaine did not induce cocaine-induced conditioned locomotion in mice lacking LPA-1 (maLPA-1 receptor knockout mice). A Total activity in cocaine-conditioned mice habituated to the open field, showing the lack of cocaine-induced conditioned locomotion. B. Total activity in cocaine-conditioned mice, including the first 30 minutes of habituation. The time course indicated that after the first 30 minutes of field-habituation, maLPA-1 knockout mice did not exhibit the persistent conditioned hyperlocomotion observed in normal wild-type mice. [LPA-1: lysophosphatidic acid receptor 1]. Studies were performed in at least eight mice per experimental group. The data are presented as the means S.E.M. See [156] for further details.
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appeared to be intact. This was confirmed by the lack of changes in mRNA levels of the enzyme for dopamine synthesis, TH, the expression of the D1 receptor or the dopamine transporter in the striatum, nucleus accumbens, substantia nigra and hippocampus. The dissociation between cue-induced reward-seeking behavior and behaviors directly producing contingent rewards reflects the involvement of different functional neural circuits [156] that might be differentially modulated by LPA/LPA1 receptor. Of these circuits, the dorsal hippocampus plays an essential role in the recall of contextual memories of cocaine-induced reward [159,160]. Specifically, the hippocampal dentate gyrus appears to be essential for generating and expressing contextual memories of fear and cocaine drug-induced reward in a CPP test [161]. Behavioral results reported in LPA-1-receptor-null mice are consistent with previous studies that have demonstrated an essential role for the hippocampus in both self-administration reinstatement by contextual cues and the CPP test [160,162]. The impaired conditioned locomotion in maLPA-1-null mice was related to an alteration in the expression of the mGluR3 in the hippocampus [156]. Recent studies have demonstrated that functional upregulation of mGluR2/3 and downregulation of mGluR5 could be factors in the transition to dependence in cocaine selfadministration in laboratory animals [163,164,165]. Although most of our knowledge of glutamate receptor changes induced by cocaine has been described in the nucleus accumbens, their role in the contextual/hippocampal expression of cocaine reinforcement remains largely unknown. Thus, finding an LPA1 modulation of glutamate receptors in the dorsal hippocampus has opened a new approach to the study of memories associated with cocaine craving. Cocaineinduced conditioned locomotion deficits showed in maLPA1-null mice cannot be explained by alterations in the expression of genes related to dopaminergic transmission in the striatal system. However, the changes in mGluR3 in maLPA-1-null mice and ionotropic (AMPA and NMDA) glutamate receptors after chronic cocaine pretreatment in dorsal hippocampus could explain these disturbances. These results have suggested LPA-1 receptors as a relevant target for affecting cocaine-induced associative learning. 4. FUTURE DEVELOPMENTS The above-described actions of these four classes of lipid transmitters as mediators of cocaine-associated responses indicate that drugs acting on lipid transmitter enzymatic production, lipid transmitter degradation or the lipid transmitter-lipid receptor interaction might offer new therapies for cocaine addiction. To date, pharmaceutical research on lipid transmitters has primarily focused on lipid receptor ligands (agonists or antagonists) and inhibitors of the degradation of these lipids. Much less emphasis has been placed on developing inhibitors for the production of lipid transmitters, although it is reasonable to think that they will be available soon. All of these classes of drugs have potential utility at the different levels of the addiction cycle: a) the control of positive reinforcement, for which acylethanolamides and endocannabinoids might offer alternatives; b) the consolidation-reconsolidation of associative and implicit memories (i.e., habit formation), in which all of these lipids have been involved; c) the development of negative reinforcement and stress responses associated with chronic drug use, in which inhibitors of acylethanolamide/endocannabinoids are clearly positioned; d) neurogenesis, in which both LPA and endocannabinoids were found to affect adult hippocampal neurogenesis; and e) long-term use-derived neurotoxic actions, in which the proinflammatory roles of LPA and the anti-inflammatory profile of OEA can be used to reduce psychostimulant-driven neurotoxicity. The challenge now is to describe precise pharmacological models to establish a defined indication that can lead these lipids to clinical trials for addiction treatment.
CONFLICT OF INTEREST The present work received financial support solely from public sources, with no commercial or company-mediated grants. This work was supported by grants RD06/0001/0000 and RD012/ 0028/0001 of the Red de Trastornos Adictivos RETICS network from the Spanish Health Institute Carlos III; grant SAS 111224 from the Andalusian Health Service; grant number TV3 386/C/2011 from Fundaci La Telemarat; and grant EU-ERDF CTS-433 from the Andalusian Ministry of Economy, Innovation and Science; these grants were to Fernando Rodriguez de Fonseca and the members of the team that are co-authors of the present study. J. Surez is recipient of a Miguel Servet contract (number CP12/03109) from the National System of Health. Eduardo Blanco is a recipient of a "Marie Curie" COFUND fellowship (U-Mobility, number 246550) from the Universidad de Mlaga and the 7th Framework Programme (FP7). ACKNOWLEDGEMENTS Declared none. AUTHORS CONTRIBUTIONS F.R.D.F. and L.O. designed and structured the review and wrote the final version of the manuscript. L.O., J.S. and P.R reviewed the role of ECS and prostaglandins in cocaine addiction. E.B., P.A. and J.S. reviewed the role of LPA on behavior and addiction. F.J.P., A.S., M.P. and M.C. reviewed the role of non-cannabinoid oleoylethanolamide on cocaine addiction. ABBREVIATIONS 2-AG = AA = AEA = CB1 = = CB2 CNS = COX = CPP = CRF = DAG = ECS = EET = EPA = EPOX = FAAH = FR = HETE = HEPE = HPETE = LOX = LPA = MAGL = mGluR = NAPE = NAPE-PLD = OA = OEA = PA = PEA = PG =
2-arachidonoylglycerol Arachidonic acid Arachidonoylethanolamide or anandamide Cannabinoid receptor type 1 Cannabinoid receptor type 2 Central nervous system Cyclooxygenase Conditioned place preference Corticotropin-releasing factor 1,2-diacylglycerol Endocannabinoids Epoxyeicosatrienoic acid Eicosapentaenoic acid Epooxygenase Fatty acid amide hydrolase Fixed-ratio Hydroxyeicosatetraenoic acid Hydroxyeicosapentaenoic acid Hydroperoxyeicosatetraenoic acid Lipooxygenase Lysophosphatidic acid Monoacylglycerol lipase Metabotropic glutamate receptors Acylphosphatidylethanolamide NAPE-hydrolyzing phospholipase D Oleic acid Oleoylethanolamide Palmitic acid Palmitylethanolamide Prostaglandin
11
PG-EA PG-G PLA2 PPAR RXR TRPV-1 TX
= = = = = = =
Prostaglandin-ethanolamide Prostaglandin-glycerol Phospholipase A2 Peroxisome proliferator-activated receptor alpha Retinoid X receptor Transient receptor potential vanilloid type-1 Thromboxane
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Accepted: April 4, 2013
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Received: February 26, 2013

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2 Current Pharmaceutical Design, 2013, Vol. 19, No. 00

Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

4 Current Pharmaceutical Design, 2013, Vol. 19, No. 00

Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

6 Current Pharmaceutical Design, 2013, Vol. 19, No. 00

Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

8 Current Pharmaceutical Design, 2013, Vol. 19, No. 00

Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

10 Current Pharmaceutical Design, 2013, Vol. 19, No. 00

Lipid Transmitter Signaling as a New Target for Treatment of Cocaine Addiction

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

PG-EA PG-G PLA2 PPAR RXR TRPV-1 TX

[2] [3] [4]

[9] [10] [11]

[14] [15] [16]

[47] [48] [49]

Current Pharmaceutical Design, 2013, Vol. 19, No. 00

[111] [112] [113]

[88] [89] [90]

[114] [115] [116]

[117] [118] [119]

[121] [122] [123]

[100] [101] [102] [103] [104]

[142] [143] [144]

[147] [148] [149] [150] [151] [152] [153]

Received: February 26, 2013

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