Studies in several species of rodents show that arginine vasopressin (AVP) acting through a V 1A receptor facilitates offensive aggression, i.e., the initiation of attacks and bites, whereas serotonin (5-HT) acting through a 5-HT 1B receptor inhibits aggressive responding. One area of the CNS that seems critical for the organization of aggressive behavior is the basolateral hypothalamus, particularly the anterior hypothalamic region. The present studies examine the neuroanatomical and neurochemical interaction between AVP and 5-HT at the level of the anterior hypothalamus (AH) in the control of offensive aggression in Syrian golden hamsters. First, specific V 1A and 5-HT 1B binding sites in the AH are shown by in vitro receptor autoradiography. The binding for each neurotransmitter colocalizes with a dense field of immunoreactive AVP and 5-HT fibers and putative terminals. Putative 5-HT synapses on AVP neurons in the area of the AH are identified by double-staining immunocytochemistry and laser scanning confocal microscopy. These morphological data predispose a functional interaction between AVP and 5-HT at the level of the AH. When tested for offensive aggression in a resident /intruder paradigm, resident hamsters treated with fluoxetine, a selective 5-HT reuptake inhibitor, have significantly longer latencies to bite and bite fewer times than vehicle-treated controls. Conversely, AVP microinjections into the AH significantly shorten the latency to bite and increase biting attacks. The action of microinjected AVP to increase offensive aggression is blocked by the pretreatment of hamsters with fluoxetine. These data suggest that 5-HT inhibits fighting, in part, by antagonizing the aggressionpromoting action of the AVP system. Two neurotransmitter systems implicated in the control of aggressive behavior are arginine vasopressin (AVP) and serotonin (5-HT). AVP is a neurochemical signal affecting numerous brain functions (DeWied, 1971;Cooper et al., 1979;Pittman et al., 1982;Fehm-Wolfsdorf et al., 1988;Dantzer and Bluthe, 1992), including aggression (Ferris and Potegal, 1988, Koolhaas et al., 1990Potegal and Ferris, 1990;Winslow et al., 1993; Delville et al., 1996a,b). For example, microinjection of AVP V 1A -receptor antagonist into the anterior hypothalamus (AH) of a hamster causes a dose-dependent inhibition of offensive aggression, i.e., initiated attacks and bites toward a conspecific placed into their home cage (Ferris and Potegal, 1988). Similarly, AVP receptor blockade in the AH significantly reduces aggression between hamsters paired together in a neutral arena .Although AVP facilitates offensive aggression, 5-HT is reported to have the opposite effect and diminishes aggressive behavior (for review, see Olivier and Mos, 1990). For example, rats show an increase in offensive aggression after treatment with neurotoxins that deplete 5-HT levels in the hypothalamus (Vergnes et al., 1988). Conversely, rats treated with eltoprazine, a 5-HT 1 receptor agonist, show a dose-dependent decrease in offensive aggressi...

Anandamide (arachidonylethanolamide) is a novel lipid neurotransmitter first isolated from porcine brain which has been shown to be a functional agonist for the cannabinoid CB1 and CB2 receptors. Anandamide has never been isolated from human brain or peripheral tissues and its role in human physiology has not been examined. Anandamide was measured by LC/MS/MS and was found in human and rat hippocampus (and human parahippocampal cortex), striatum, and cerebellum, brain areas known to express high levels of CB1 cannabinoid receptors. Significant levels of anandamide were also found in the thalamus which expresses low levels of CB1 receptors. Anandamide was also found in human and rat spleen which expresses high levels of the CB2 cannabinoid receptor. Small amounts of anandamide were also detected in human heart and rat skin. Only trace quantities were detected in pooled human serum, plasma, and CSF. The distribution of anandamide in human brain and spleen supports its potential role as an endogenous agonist in central and peripheral tissues. The low levels found in serum, plasma, and CSF suggest that it is metabolized in tissues where it is synthesized, and that its action is probably not hormonal in nature.Key words: Anandamide; Cannabis; Cannabinoid receptor; Marijuana porcine brain and found to be a lipid of novel structure [7]. Anandamide displayed specific binding to the CBI receptor and inhibited a prototypical twitch response in mouse vas deferens. Anandamide has also been shown to induce similar behavioral [8,9], pharmacological [10,11], and signal transduction effects [12] as classical cannabinoid agonists, but high concentrations were required to induce these effects. Levels of anandamide were first estimated to occur at 0.4 pmol/g (133 pg/g) in whole porcine brain [7], and recently quantitated in porcine and bovine brain at 173 pmol/g (60 ng/g) and 101 pmol/g (35 ng/g) respectively [13]. A recent study reports levels of anandamide in rat testis to be considerably lower (6 pmol/ g, 2.1 ng/g) [14]. However, anandamide has never been isolated from human tissue or fluids. Furthermore, levels of anandamide have not been measured in regions of rat brain or in tissues such as spleen where CB2 receptors have been shown to be expressed at high levels. Studies of anandamide distribution should help elucidate the physiologic role of anandamide as a cannabimimetic eicosanoid and possibly broader functions. In this study we report the isolation and quantitation of anandamide by liquid chromatography/mass spectrometry in various tissues and fluids from postmortem human and rat.

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The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC 50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with K i values < 1 nM and brain levels after oral dosing ~100-fold higher than receptor affinities.The neurohypophysial hormones vasopressin 1 and oxytocin exert a wide range of physiological effects through binding to specific membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. To date, three vasopressin receptor subtypes and one oxytocin receptor have been pharmacologically and functionally described 1 . V1a, V1b, and oxytocin receptors activate phospholipase C, resulting in the production of inositol 1,4,5-trisphosphate and diacylglycerol, mobilization of intracellular calcium, and activation of protein kinase C. V2 receptors stimulate adenylyl cyclase, resulting in the accumulation of cyclic AMP and activation of protein kinase A. All four receptor subtypes from several mammalian species have been recently cloned 2-5 , as well as closely related receptors from bony fishes and invertebrates 6, 7 . Although vasopressin is perhaps best-known for its role in the cardiovascular system, it also has actions in the central nervous system (CNS), and several CNS applications of vasopressin receptor antagonists have been suggested (reviewed in references 8 and 9 ). A number of research groups have prepared antagonists directed at the vasopressin V1 receptor 10-15 . While V1a antagonists have been made, none of these have been reported to penetrate the CNS efficiently. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOur vasopressin antagonist program was initiated to identify a CNS-active V1a antagonist: one with potent affinity for the human V1a receptor (IC 50 < 10 nM), good oral availability, and ability to penetrate the blood brain barrier -in short, a candidate for human clinical development targeting CNS disorders. The program began at Lilly in 1990 with the selection of a 1,500-compound "Neuropeptide Cassette" -a library intended to identify nonpeptide ligands for neuropeptide receptors. The library applied the concept of receptor crosstalk -previously well...

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