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G-protein coupled receptors & autism--reflections on a double-edged sword at the example of the oxytocin receptor system.

G-protein coupled receptors (GPCR) tend to desensitize/internalize when exposed to excess agonist. Previously, we have supported the argument that in the case of the oxytocin receptor (OTR), excess agonist (oxytocin, OT) at birth could be implicated with behavioural disorders of the autistic spectrum. In this review, more recent evidence for this hypothesis is summarized, and it is juxtaposed against reports where exogenous OT was found beneficial in alleviating certain undesired behaviours. Facing this dichotomy, we suggest possible in silico drug discovery approaches to mitigate undesired side effect of OT administration/OTR desensitization, especially in the light of potentially emerging agonist therapies. For this, the most important structural features of OTR are reviewed, and we highlight here the need for higher level of theory studies at the easier approachable extracellular receptor side, where loop 3(e3) and the N-terminated strain of OTR appear to offer targets of particular interest for the development of an agent that conditions the action of excess OT. Another approach, based on the development of new agonists with an improved receptor activation to receptor phosphorylation ratio, is also discussed. Finally, the issue of OTR desensitization is put into the broader context of GPCR desensitization and possible implications for behavioural disorders, and the case is made for the usefulness of computational studies in this area.

Key words ASD--autism--GPCR--oxytocin receptor

Oxytocin receptor system and its possible link to autistic spectrum disorders (ASD)

Autism is a neurobiological disorder with no cure, the neurochemistry and pathophysiology of which has been reviewed (1). The neurohypophysial nona-peptide oxytocin (OT) is biosynthesized in magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei (SON, PVN) (2). OT has the sequence [??]Cys(1)-Tyr(2)-Ile(3)-Gln(4)-Asn(5)-Cys(6)[??] -Pro(7)-Leu(8)-Gly(NH2)(9) (3), and has not only been widely implicated with social behaviour and attachment in animal models (4-12) and in humans (13-15), but with autism (16-22). In humans, OT has been found to selectively influence memory performance, impairing deepened information processing during category-cued semantic association tests (23). An altered central OT sensitivity has been encountered when administering OT to men with early-parental-separation (EPS) experience (24), indicating long-term effects of OT/OTR system disturbances that occurred early in life. In the human central nervous system (CNS), OT is most strongly bound by OTR in cortical areas (basal nucleus of Meynert), the limbic system (lateral septal nucleus) and the brain stem (substantia nigra pars compacta, nucleus of solitary tract, substantia gelatinosa of trigeminal nucleus), and, to a lesser extent, in the thalamus and hypothalamus (25). While reports linking OT to social behaviour and autism (26), and OT concentration in urine samples to social experience early in life of humans (27,28), continue to appear, we have previously concluded that an excess-OT-autism connection cannot be ruled out at this time (29). This supported the hypothesis first forwarded by Hollander et al (30) that excess OT, possibly through OT administration at birth for labour induction, could contribute to the development of the autistic spectrum disorders (ASD) by proposed downregulation of the OTR, a member of the class A (rhodopsin-type) G protein-coupled receptor (GPCR) family. Most notably, there is ample evidence in the literature that excess OT leads to OTR-desensitization (31-33), which occurs at the receptor level (34). Gimpl & Fahrenholz (25) reported in a seminal OTR system review that within 5-10 min of agonist stimulation, more than 60 per cent of the human OTR, expressed in human embryonic kidney (HEK) 293 ceils, is internalized. They also reported that the internalized receptor was not recycled back to the cell's surface, which is tentatively ascribed to the existence of two serine clusters in the cytosolic end of the receptor, in analogy to similar phenomena first observed with the V2 vasopressin receptor (35). The molecular underpinnings of this have later been extended to other GPCRs including OTR (36). Recent thinking in GPCR endocytosis has been summarized (37), the dynamics of which, upon agonist stimulation, has recently been imaged in real time in vivo for an opioid GPCR (38). OTR has been observed to form a relatively stable [beta]-arrestin complex (39), which is indicative that OTR belongs to the class B type of GPCRs that tend to internalize with the [beta]-arrestin into endosomes and are only poorly dephosphorylated and retargeted to the cell surface (36,40). Also, OTR desensitization has been able to be inhibited by dynamin and clathrin mutants in human embryonic kidney (HEK) 293 cells (41), as well as by concanavalin A (34), a lectin-type protein that reacts with specific sugar residues. In addition to receptor downregulation, excess OT has been shown to downregulate OTR-mRNA (42), and there appears to be a connection in haploinsufficient reeler mice arid OTR downregulation (43).

The above information seems to show that in the context of autism, in a newborn's brain OTR could become, at least temporarily unavailable for further OT binding due to internalization triggered by excess agonist, and the corresponding natural signal transduction cascades could cease to be in place. Hence OT could be, again at least temporarily, unable to exert its usual biological role.

On the other hand, reports of behaviourally beneficial effects of OT administration have appeared (44), where OT has been delivered for example, through intravenous infusion (45,46). The test subjects (15 adults with autism or Asperger's disorder) received a continued infusion over 4 h of OT or placebo. The initial vial of Pitocin (10[micro]g/ml OT) was combined with a 1 liter bag of saline and administered at an initial low rate of 10 ml/h in an effort to minimize potential side effects. The maximum infusion rate used was 700 ml/h. The behavioral response was reported for 240 min during OT or placebo administration, and a statistically significant reduction in repetitive behavior was found for the autistic subjects after around 60 min and reported until 240 min. Also intranasal administration (14,47,48) intraperintoneally (49), subcutaneous administration (50), and intracerebroventricular administration (51) have been employed. While such beneficial OT action has recently been explained through modulation of amygdala function (15), i.e., averting a flight-fear-response, and while at least two clinical trials for use of OT against autism have been initiated (52), little is known about the long-term effects of excess agonist, especially when the agonist enters the system from exogenous sources. Recently, first evidence around the sexually dimorphic nature of the long-term effects when manipulating OT/OTR system early in life, has appeared, largely through the work of Kramer et al (53) with prairie voles. Their study of the developmental effects of OT injection on the first day of life and the animal's neural responses in adulthood showed that females were affected and males were not. It was also found that excess OT has a down-regulating long-term effect on the structurally very closely related vasopressin receptor system (VRS) (54). New findings by Terenzi and Ingram (55) seem to support this in the following way: in rat central and medial amygdaloid nuclei, administration of OT first increases firing rate, but when repeated, leads to receptor desensitization. Also, most interestingly, Popik et al have already noted more than a decade ago that when OT was administered in lower doses, it facilitated social recognition in rats (50), and when used in higher doses, social memory was disrupted (56,57). For the latter, could it be that a low OTR availability, caused receptor internalization triggered by high OT concentration, was the cause for that? It appears likely that the effects of OT may vary depending on the dose and concentration used, and ultimately its bioavailability at a given time and place (organ, cell, receptor). Notably, there is at least one published case for humans, where GPCR desensitization has been linked to autism: Two week exposure of terbutalene, a selective [[beta].sub.2]-adrenergic receptor agonist used to treat premature labour, to its receptor, as well as increased signaling from genetic receptor polymorphisms, led to prenatal overstimulation, which was associated with affecting cellular responses leading to autism (58). All in all, receptor desensitization is likely to remain an issue to be dealt with when considering therapeutic use of exogenous OT or any other exogenous OTR--or, more broadly speaking, GPCR-agonists. Developing a molecular understanding how this might be prevented seems desirable in terms of rendering potential new therapeutic approaches more effective. Avoiding excess of agonist (OT) at the molecular level at the receptor site in order to prevent receptor desensitization and internalization thus appears the first step toward that direction. And while this review focuses on OTR, VRS might as well be a prime candidate for similar considerations as those outlined here for OTR.

In addition to the molecular/mechanistic argument forwarded so far, recently Glasson et al (59) published a population study in Australia, finding that labour induction is of statistical significance amongst cases with autism. Gerlai & Gerlai (60) included oxytocin as part of a list consisting of candidate pharmacotherapeutic areas for autism research. Evidence for the involvement of OT/OTR system in autism continues to mount, some of which is at the genetic level. For example, recently three studies showed independently a positive evidence for association of the oxytocin receptor gene (OXTR) with autism, one with Chinese Han population (61), the other with a combination of Finnish autism families and U.S. autism genetic resource exchange (AGRE) families (62) and the third using a caucasion sample group (63).

Taken together, there is considerable evidence in the literature that OT and the OTR system could be involved in autism. The key question is how? Hence further studies and trials in connection with autism are recommended; a conclusion that has been reached very recently also by others (64). The excess-agonist-negative-feedback hypothesis (29,30) appears to have notable mechanistic backing from the literature. Also, it provides for the involvement of an exogenous factor in ASD, such as OT administration during childbirth. This is a matter of significance often lacking in other hypotheses, since it could help account for some of the increase in ASD cases over time. The use of labour induction, for which OT is the only drug approved by the FDA, has increased over time as well, for example, in the United States from 9.5 per cent in 1990 to 21.5 per cent in 2004, as a percentage of all births (65), while the number of cases classified as ASD has increased six-fold in the U.S. between 1994 and 2003 (66).

Structural aspects of OTR and recommended work

So far there is no crystal structure of OTR resolved. The most relevant structure elucidated has been that of rhodopsin (67), the impact of which has been reviewed (68). But rhodopsin shares only about 20 per cent of its the primary structure with OTR. Regarding the in silico approaches to OTR, molecular dynamics (MD) at the molecular mechanics (MM) level of theory has been employed. Most notably here has been the work of Ciarkowski et al (68) as well as Fanelli et al (69) and Chini et al (70). In simple terms, three proposed steps are thought to be distinguished: (i) Ligand binding to the extracellular site; (ii) signal transduction along the [alpha]-helical transmembranes to the intracellular site; and (iii) G-protein coupling. OT binding is modeled to occur with its linear portion and Cys(1) mainly to the extracellular receptor regions, with the other residues of the ring penetrating deeper into the transmembrane core. While Ile(3) is deemed essential for receptor stimulation (71), the interaction of Leu(8) with a cluster of hydrophobic residues of eland 2 e2, and the binding of the N-terminal protonated Cys(1) with glutamic acid E307 on e3 appear to be especially important (70). The latter is believed to be of significance in receptor activation. For signal transduction and receptor activation, it is thought that ligand binding might lead to the formation of a network of polar residues in the transmembrane (TM) domains, in particular to rigid body motions of TM3 and TM6. Special attention has been given to the formation of a so-called polar pocket, partially formed by the E/DRY motif of TM3 (D136, R137) and TM7 (Y329). In the inactive receptor state, the highly conserved arginine (R) is constrained in a pocket formed by polar residues N57 (TM1), D85 (TM2) and Y329 (TM7). In the active state, upon OT (agonist) binding, the arginine side chain is shifted outside that pocket. The active/inactive equilibrium depends on the protonation state of the aspartic acid (D) of the polar pocket; the active state has the aspartate protonated, which shifts the arginine out of the polar pocket. The conformation of the inactive state depends on a molecular interaction between E307(e3) and K116 (TM3). This binding of OT to E307 triggers an outward motion of TM3 and TM6. The latter motion shifts W288 towards TM5, and the attractive effect of D85 and D136 on R137 is weakened, this shifting the arginine R137 out of the pocket, which then allows for the formation of a potential G-protein docking site (70).

Thus, while an overall agreement of homology modeled OTR predictions with the rhodopsin structure can be found, at a closer look, significant differences have been noted (68). For example, transmembrane region five (TM5) forks more to the top in the simulation than the experimental one does, with a displacement of up to 6-7 Angstrom, which is very significant from a ligand docking molecular perspective, where only up to 2-3 Angstrom are tolerable for subsequent promising lead identification and optimization. Other differences include the TM6 helix being shifted over a full turn, and only 50 per cent of intra-bundle side chains are in similar conformations and fit the experimental 3D structure. And in vacuo molecular dynamics simulations have been reported to lead to severe distortions of the loop structures, due to formation of artificial H-bonds (72). So even though significant progress including further Refinements (73) have been made, these and other limitations show that many questions remain. For example, why do structurally related agonists and antagonists not bind to the same receptor regions? (74) Most importantly, what is the effect of excess OT on active state geometries, and how does that affect the serine-rich amino acid cluster on the cytosolic end? What governs the dynamics of OT receptor binding, and how can they be changed without affecting the receptor response? How should a potential candidate structure look like in order to prevent excess OT access the receptor's active site, again without influencing the natural OT-OTR response? Probably there has been no structural study examining the effect of excess OT on OTR. In this sense, it is realized that there remains a need for research which differs significantly from the classical quest for OT agonists and antagonists, since one should not want to alter the 'natural' biochemical function of the OT-OTR-G-Protein system, i.e., its time-response-curves should not be affected. Excess OT should simply be prevented from leading to irreversible receptor internalization. The system ought to be cured, not changed.

Interestingly, a possible 2:1 stoichiometry of GPCR to G-Protein for GPCR = rhodopsin has been recently suggested (75), and Park et al advocated possible oligomeric structures for GPCRs in membranes (76). Could this be the case for OTR as well? What would be the influence of a potential "double activation", i.e., the activation of two adjacent receptors by two equivalents of agonist at the same time? Still, a recent article challenges the oligomeric view from a functional perspective (77); a finding that renders the computational study of one receptor at a time, as opposed to a whole agglomerate of them, biologically more meaningful.

As mentioned before, the methods for structure refinement used so far are mainly based on MM and MD simulations, which usually yield reliable results, especially where the receptor is highly restrained and conserved, like at the inner membrane regions and, to a lesser extent, at the cytosolic end, but with the much looser conformations at the extracellular side, and especially when performing ligand docking and active site calculations for lead optimization, MM have their limits. Here, employment of recent semi-empirical or fully quantum chemical methods such as density functional theory (DFT), for example parameterized DFT such as EDF1 or economic Moller-Plesset methods such as RI-MP2, should have significant advantages over MM when optimizing important fragments of potential docking sites. They can also account for possible roles of cation-[pi] interactions (78) in agonist-receptor binding. There appears to be precedence for the use of higher levels of theory in some aspects of GPCR modeling, such as side chain conformer determination and hydrogen bonding in opioid receptors (79). This process is called distance geometry optimization, leading to lowest energy residue to residue contacts. Similar techniques could be applied to OTR. This would take into account learnings from the numerous studies on other GPCRs (80), mostly rhodopsin (81) and vasopressin (82) receptors, which could prove useful to help identify better experimental constraints, especially in terms of influence of exogeneous water molecules (83), the lipid membrane, or, most notably, steroids (25). Learnings from 3D-de novo in silico modeling can also be taken into account, which has been reported for five GPCRs other than OTR (84).

Another approach could build on work that has been carried out on GPCR activation and desensitization using the stochastic Monte Carlo modeling technique (85) by Brinkerhoff et al (86). They calculated the G-protein activation to receptor phosphorylation (GARP) ratio, eventually coming to the important conclusion that drugs, according to their respective receptor binding constants, might be designed not only to enhance receptor activation, but also to minimize receptor desensitization. Thus, agonists that might increase the GARP ratio should be discovered and screened in silico for their ADME as well as blood brain barrier (BBB) crossing properties, possibly leading to safer OTR agonists than OT itself. As support for the idea that such molecules can be found or de novo designed, could serve the case of the newly licensed drug atosiban, which has recently been reported to act as a selective or 'biased' agonist on human OTR while leading to significantly less OTR desensitization. The problem with atosiban is that it is also considered an antagonist, since it activates a different G-protein compared to OTR (87). It is also an effective vasopressin receptor antagonist, which could cause long-term issues when using atosiban. In terms of labour management, it is thus used for treatment of preterm labour since it reduces rather than enhances contraction of the uterus. Given the lower desensitization profile, it has also fewer side effects (88). Therefore, one aim of future research could be to achieve atosiban activity while maintaining OT signal transduction characteristics in the receptor. Thus an OT/OTR 'conditioner' would be needed. This conditioner would most likely interact with the extracellular loops of the activated OT-OTR complex. The structures to be tested could be of peptide and non-peptide nature, as a molecular recognition study with the Via vasopressin receptor has shown, where the concept of 'initial capture' before the final docking has been proposed by the authors (89). Since the extracellular loops are flexible and therefore difficult to model, very little has been done in terms of molecular recognition at these loops. It will be important that molecular recognition sites identified do not interfere with normal OT activity. Two first candidate regions in the extracellular side could be the extracellular loop 3 (e3) and the extracellular N-terminal domain of OTR. The latter has been reported to affect OTR activation, but only a small- 1 2-residue part of it (90), which leaves the neighbouring residues as prime candidates for conditioner targets. Also e3 provides good candidates for conditioner targets, since only three residues, including E307, have been reported to interact with OT. Therefore, one aim could be to identify molecules that would dock to the candidate extracellular regions just described, and that would alter OT-OTR kinetics in a way that the GARP ratio of OT would shift towards lower receptor phosphorylation while maintaining similar activation.

In general, today, GPCRs are thought to be promising targets for future drug discovery efforts, but there is common agreement that structural elucidation of the individual subtypes is of paramount importance for Success (91), because if a molecule acts on many GPCR receptor types rather than one specifically (OTR), it is likely to have too many side effects, and it might fail during clinical trials. Also, the greatest variations in structure between GPCRs lie in their extracellular ends of the helix bundles, hence where excess ligand binding is more likely to occur.

Summary--A broader view

GPCR research, including drug discovery (92-95), is at the core of many research areas, some of which are likely related to autism. Besides behaviour (e.g., OTR), it concerns vision (through rhodopsin). Also it concerns the olfactory system, where the genetic and molecular model for odour recognition has been elucidated (96), where binding sites have been proposed through homology modeling (97), and where for example, the pituitary adenylate cyclase-activating polypeptide type I receptor (PAC 1) receptor has been shown to modulate animal behaviour (98). It also concerns opioid excess theory (through the [mu], [delta] and [kappa] opioid receptors) (99-102), and it concerns neurotransmitting, and it includes GPCR families such as serotonergic (103-104), may be dopaminergic (105) or cholinergic (106,107) systems, and of course the much related vasopressin receptor system (VRS). The latter has around 80 per cent homology to OTR and has been associated with social impairment such as autism (108). There may be interconnections. An emerging theory starts linking OTR and VRS to the dopaminergic receptor region as a 'reward center' (109). OT and VP are sexually dimorphic, and possible interaction of both systems could account for a 4:1 male prevalence over females in ASD (110). Also, one should consider that the elucidation of the human genome suggests that over 950 genes encode for GPCRs, hence, many more therapeutic targets are unexplored today and might become available in the future. Moreover, published studies on OTR are relatively rare and appear underrepresented given the large body of overall work on GPCRs other than OTR.

While much structural knowledge has been gained about membrane proteins including GPCRs through innovative techniques such as atomic force microscopy, where the cytoplasmic conformational space of bacteriorhodopsin has been sampled (111), computational approaches are increasingly successful and considered full partners to experimental approaches (112). Using an in silico approach as the first stage of a discovery programme for manipulation of GPCR-activity appears therefore appropriate. Very recently Bonacci et al used a computer-based screening method to discover small molecules to selectively modulate G-protein subunits and their protein targets (113). In other words, the feasibility of the approach suggested here has support from the literature. In the meantime, GPCR ligand discovery is being routinely carried out and continuously improved by in silico methods (114). The detailed understanding of GPCR activation is continuously being advanced by aid of in silico methods (115). In general, GPCRs have recently enjoyed renewed interest in the pharmaceutical industry (91,116), but unfortunately hardly in the explicit context of autism.

In conclusion, the effect of OT on behaviour appears to be dose dependent. At low doses, behavioural benefits appear to prevail, and at higher doses, caution is warranted to the extent that literature suggests behavioral disorders such as autism could develop. For the latter case, computational studies at higher level of theory building on many of the previous findings described herein should enable researchers to devise lead candidates for new therapeutic approaches through GPCR agonist conditioning, preventing undesired receptor downregulation by excess agonist, and thereby potentially alleviating a plausible cause for ASD.

Finally, GPCRs, notably rhodopsin, but also the OT and VP system, also play a role in vision. Here, it has been noted that OT and VP do occur in the retina (117), and that fine eye movements are important in recognizing faces (118). It has also been found that if during early childhood vision is impaired, but cured later on, difficulties will remain when trying to put the right meaning behind what is seen (119). Recently, a single dose of OT administration was found to enhance performance in the reading the mind in the eyes test (RMET) with 30 healthy men (47). Hence, there remains the possibility for a causal GPCR function/malfunction--face recognition--ASD connection.


The author thanks Ms. Doris Haire, American Foundation for Maternal and Child Health, Prof. Piotr Popik, Laboratory of Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, Dr Markus Heinrichs, Ph.D., Department of Clinical Psychology and Psychotherapy, University of Zurich, as well as Prof. C. Sue Carter, Brain Body Center, Department of Psychiatry, University of Illinois at Chicago, for support, helpful discussion and for providing relevant references.

Received September 6, 2006


(1.) McDougle CJ, Erickson CA, Stigler KA, Posey DJ. Neurochemistry and pathophysiology of autism. J Clin Psychiatry 2005; 66: 9-18.

(2.) Brownstein MJ, Russell JT, Gainer H. Synthesis transport and release of posterior pituitary hormones. Science 1980; 207: 373-8.

(3.) Du Vigneaud V, Ressler C, Tripett S. The sequence of amino acids in oxytocin with a proposal for the structure of oxytocin. J Biol Chem 1953; 205 : 949-57.

(4.) Insel T, Young L. The neurobiology of attachment. Nat Rev Neurosci 2001; 2 : 129-36.

(5.) Ferguson J, Young L, Insel T. The neuroendocrine basis of social recognition. Front Neuroendocrinol 2002; 23 : 200-24.

(6.) Winslow J, Insel T. The social effects of the oxytocin knockout mouse. Neuropeptides 2002; 36: 221-9.

(7.) Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet 2000; 25 : 284-8.

(8.) Henderson C. Oxytocin gene necessary for social memory. Pain Central Nervous System Week 2000; July 8.

(9.) Cushing B, Yamamoto Y, Hoffman G, Carter C. Central expression of c-Fos in neonatal male and female prairie voles in response to treatment with oxytocin. Brain Res Dev Brain Res 2003; 143 : 129-36.

(10.) Young L, Pitkow L, Ferguson J. Neuropeptides and social behavior: Animal models relevant to autism. Mol Psychiatry 2002; 7: S38-9.

(11.) Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA 2005; 102 : 16096-101.

(12.) Lim MM, Bielsky IF, Young LJ. Neuropeptides and the social brain: potential rodent models of autism. Int J Dev Neurosci 2005; 23 : 235-43.

(13.) Zak PJ, Kurzban R, Matzner WT. The neurobiology of trust. Ann N Y Acad Sci 2004; 1032 : 224-7.

(14.) Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature 2005; 435 : 673-6.

(15.) Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005; 25 : 11489-93.

(16.) Modahl C, Fein D, Waterhouse L, Newton N. Does oxytocin deficiency mediate social deficits in autism? J Autism Dev Disord 1992; 22 : 449-51.

(17.) Panksepp J. Commentary on the possible role of oxytocin in autism. J Autism Dev Disord 1993; 23 : 567-9.

(18.) Freemann W. Neurohormonal brain dynamics of social group formation: Implications for autism. Ann N Y Acad Sci 1997; 807 : 501-3.

(19.) Modahl C, Fein D, Morris M, Waterhouse L, Feinstein C, Levin H. Plasma oxytocin levels in autistic children. Biol Psychiatry. 1998; 43 : 270-7.

(20.) Insel T, O'Brien D, Leckman J. Oxytocin vasopressin and autism--Is there a connection? Biol Psychiatry 1999; 45 : 145-57.

(21.) Stokstad E. New hints into the biological basis of autism. Science 2001; 294 : 34-7.

(22.) Hammock EA, Young LJ. Oxytocin, vasopressin and pair bonding: Implications for autism. Philos Trans R Soc Lond B Biol Sci 2006; 361 : 2187-98.

(23.) Heinrichs M, Meinlschmidt G, Wippich W, Ehlert U, Hellhammer DH. Selective amnesic effects of oxytocin on human memory. Physiol Behav 2004; 83 : 31-8.

(24.) Meinlschmidt G, Heim C. Sensitivity to intranasal oxytocin in adult men with early parental separation. Biol Psychiatry 2006; 61 : 1109-11.

(25.) Gimpl G, Fahrenholz F. The oxytocin receptor system-structure function and regulation. Physiol Rev 2001; 81 : 629-83.

(26.) Kendrick KM. The neurobiology of social bonds. J Neuroendocrinol 2004; 16 : 1007-8.

(27.) Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci USA 2005; 102 : 17237-40.

(28.) Carter CS. The chemistry of child neglect: Do oxytocin and vasopressin mediate the effects of early experience? Proc Natl Acad Sci USA 2005; 102: 18247-8.

(29.) Wahl RU. Could oxytocin administration during labor contribute to autism and related behavioral disorders? Med Hypotheses 2004; 63 : 456-60.

(30.) Hollander E, Cartwright C, Wong C, DeCaria C, DelGuidiceAsch G, Buchsbaum M, et al. A dimensional approach to the autism spectrum. CNS Spectrums 1998; 3 : 22-39.

(31.) Robinson C, Schumann R, Zhang P, Young R. Oxytocin-induced desensitization of the oxytocin receptor. Am J Obstet Gynecol 2003; 188 : 497-502.

(32.) Phaneuf S, Rodriguez Linares B, TambyRaja R, MacKenzie I, Bernal A. Loss of myometrical oxytocin receptors during oxytocin-induced and oxytocin augmented labour. J Reprod Fertil 2000; 120 : 91-7.

(33.) Phaneuf S, Asboth G, Carrasco M, Lineares B, Kimura T, Harris A, et al. Desensitization of oxytocin receptors in human myometrium. Hum Reprod Update 1998; 4 : 625-33.

(34.) Adachi S, Oku M. The regulation of oxytocin receptor expression in human myometrial monolayer culture. J Smooth Muscle Res 1995; 31 : 175-87.

(35.) Innamorati G, Sadeghi H, Tran N. Birnbaumer M. A serine cluster prevents recycling of the V2 vasopressin receptor. Proc Natl Acad Sci USA 1998; 95 : 2222-6.

(36.) Oakley R, Laporte SA, Holt J, Barak LS, Caron MG. Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-[beta]-arrestin complexes after receptor endocytosis. J Biol Chem 2001; 276 : 19452-60.

(37.) Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: The role of in receptor desensitization and signaling. Pharmacol Rev 2001; 53 : 1-24.

(38.) Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Laustriat D, Cao YQ, et al. Knockin mice expressing fluorescent {delta}opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proc Natl Acad Sci USA 2006; 103 : 9691-6.

(39.) Hasbi A, Devost D, Laporte SA, Zingg H. Real-time detection of interactions between the human oxytocin receptor and G protein coupled receptor kinase-2. Mol Endocrinol 2004; 18 : 1277-86.

(40.) Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, et al. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem 2003; 278 : 6258-67.

(41.) Smith MP, Ayad VJ, Mundell SJ, McArdle CA, Kelly E, Lopez Bernal A. Internalization and desensitization of the oxytocin receptor is inhibited by dynamin and clathrin mutants in human embryonic kidney 293 cells. Mol Endricrinol 2006; 20 : 379-88.

(42.) Phaneuf S, Asboth G, Carrasco M, Europe-Finner G, Saji F, Kimura T, et al. The desensitization of oxytocin receptors in human myometrial cells is accompanied by down-regulation of oxytocin receptor messenger RNA. J Endocrinol 1997; 154 : 7-18.

(43.) Lui W, Pappas GD, Carter CS. Oxytocin receptors in brain cortical regions are reduced in haploinsufficient (+/-) reeler mice. Neurol Res 2005; 27 : 339-45.

(44.) Bartz JA, Hollander E. The neuroscience of affiliation: forging links between basic and clinical research on neuropeptides and social behavior Horm Behav 2006; 50 : 518-28.

(45.) Hollander E, Novotny S, Hanratty M, Yaffe Rdecaria C, Aronowitz B, et al. Oxytocin infusion reduces repetitive behaviours in adults with autistic and Asperger's disorder. Neuropsychopharmacology 2003; 28 : 193-80.

(46.) Hollander E, Bartz J, Chalpin W, Phillips A, Summer J, Soorya L, et al. Oxytocin increases social cognition in autism. Biol Psychiatry 2007; 61 : 498-503.

(47.) Domes G, Heinrichs M, Michel A, Berger C, Herpetz SC. Oxytocin improves "mind-reading" in humans. Biol Psychiatry 2007; 61 : 731-3.

(48.) Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychological stress. Biol Psychiatry 2003; 54 : 1389-98.

(49.) Arletti R, Benelli A, Poggioli R, Luppi P, Menozzi B, Bertoloni A. Aged rats are still responsive to the anti-depressant and memory improving effects of oxytocin. Neuropeptides 1995; 29 : 177-82.

(50.) Popik P, Vetulani J, van Ree JM. Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology (Berlin) 1992; 106 : 71-4.

(51.) Pedersen CA, Ascher JA, Monroe JL, Prange AJ Jr. Oxytocin induces maternal behavior in virgin female rats. Science 1982; 216 : 648-50.

(52.) NCT00263796: An fMRI study of the effect of intravenous oxytocin vs. placebo on response inhibtion and face processing in autism. Phase I, recruiting adults only: See: http//; NCT00490802: Intransal oxytocin in the treatment of autism, Phase II, recruiting adults only. See: http// (Both sites originally accessed on May 15th, 2007).

(53.) Kramer KM, Choe C, Carter CS, Cushing BS. Developmental effects of oxytocin on neural activation and neuropeptide release in response to social stimuli. Horm Behav 2006; 49 : 206-14.

(54.) Bales KL, Plotsky PM, Young LJ, Lim MM, Grotte N, Ferrer E, et al. Neonatal oxytocin manipulations have long-lasting sexually dimorphic effects on vasopressin receptors. Neuroscience 2007; 144 : 38-45.

(55.) Terenzi MG, Ingram CD. Oxytocin-induced excitation of neurones in the rat central and medial amygdaloid nuclei. Neuroscience 2005; 134 : 345-54.

(56.) Popik P, Vetulani J. Opposite action of oxytocin and its peptide antagonists on social memories in rats. Neuropeptides 1991; 18 : 23-7.

(57.) Dantzer R, Bluthe RM, Koob GF, Le Moal M. Modulation of social memories in male rats by neurohypophyseal peptides. Psychopharmacology (Berlin) 1987; 91 : 363-8.

(58.) Connors SL, Crowell DE, Eberhart CG, Copeland J, Newschaffer C J, Spence S J, et al. [beta]2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizogotic twins. J Child Neurol 2005; 20 : 876-84.

(59.) Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism--a population study. Arch Gen Psychiatry 2004; 61 : 618-27.

(60.) Gerlai R, Gedai J. Autism--a target of pharmacotherapies? Drug Discov Today 2004; 9 : 366-74.

(61.) Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 2005; 58 : 74-7.

(62.) Ylisaukko-oja T, Alarcon M, Cantor RM, Auranen M, Vanhala R, Kempas E, et al. Search for autism loci by combined data analysis of autism genetic resource exchange and Finnish families. Ann Neurol 2006; 59 : 145-55.

(63.) Jacob S, Brune CW, Carter CS, Leventhal BL, Lord C, Cook EH. Association of the oxytocin receptor gene (OXTR) in caucasian childern and adolescents with autism. Neurosci Lett 2007; 417 : 6-9.

(64.) Lam KS, Aman MG, Arnold LE. Neurochemical correlates of autistic disorder: A review of the literature. Res Dev Disabil 2006; 27 : 254-89.

(65.) Martin JA, Hamilton BE, Sutton PD, Ventura S J, Menacker F, Kirmeyer S. Births: Final Data for 2004. National Vital Statistics Report, Sept 29 2006, Vol. 55, No. 1. Available at : http:// See "highlights"; Accessed on December 26, 2006.

(66.) How comman are autism spectrum disorders? NCBDD, CDC. Department of Health and Human Services-Center for Disease Control and Prevention, November 10, 2006. See: http:// original accessed on December 26, 2006.

(67.) Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al Crystal structure of rhodopsin--A G-protein-coupled receptor. Science 2000; 289 : 739-45.

(68.) Ciarkowski J, Drabik P, Gieldon A, Kazmierkiewicz R, Slusarz R. Signal transduction via G protein coupled receptors in the light of rhodopsin structure determination. Acta Biochim Pol 2001; 48 : 1203-7.

(69.) Fanelli F; Barbier P, Zanchetta D, de Benedetti PG, Chini B. Activation mechanism of human oxytocin receptor--A combined study of experimental and computer-simulated mutagenesis. Mol Pharmacol 1999; 56 : 214-25.

(70.) Chini B, Franelli F. Molecular basis of ligand and receptor activation in the oxytocin and vasopressin receptor family. Exp Physiol 2000; 85S : 59S-66.

(71.) Barberis C, Mouillac B, Durroux T. Structural basis of vasopressin/oxytocin receptor function. J Endocrinol 1996; 10 : 119-54.

(72.) Mehler EL, Petiole X, Hassan SA, Weinstein H. Key issues in computational simulation of GPCR function representation of loop domains. J Comput Aided Mol Des 2002; 16 : 841-53.

(73.) Bissantz C, Bernard P, Hibert M, Rognan D. Protein-based virtual screening of chemical databases II. Are homology models of G-protein coupled receptors suitable targets? Proteins 2003; 50 : 5-25.

(74.) Postina R, Kojro E, Fahrenholz F. Identification of neurohypophysical hormone receptor domains involved in ligand binding and G protein coupling. Adv Exp Med Biol 1998; 449 : 371-85.

(75.) Slusarz R, Ciarkowski J. Interaction of class A G protein-coupled receptors with G proteins. Acta Biochim Pol 2004; 51 : 129-36.

(76.) Park PSH, Filipek S, Wells JW, Palczewski K. Oligomerization of G-protein-coupled receptors-past present and future Biochemistry 2004; 43 : 15643-56.

(77.) Chabre M, le Maire M. Monomeric G-protein-coupled receptor as a functional unit. Biochemistry 2005; 44 : 9395-403.

(78.) Everts S. Neuron activation--Scientists crack how a family of brain receptors receives and responds to chemical signals. Chem Eng News 2006; 84 : 44-5.

(79.) Pogozheva ID, Lomize AL, Mosberg HI. Opioid receptor three dimensional structures from distance geometry calculations with hydrogen bonding constraints. Biophys J 1998; 75 : 612-34.

(80.) Bissantz C. Conformational changes of G protein-coupled receptors during their activation by agonist binding. J Recept Signal Transduct Res 2003; 23 : 123-53.

(81.) Becker OM, Shacham OS, Marantz Y, Moiman S. Modeling the 3D structure of GPCRs advances and application to drug discovery. Curr Opin Drug Discov Devel 2003; 6 : 353-61.

(82.) Gieldon A, Kazmierkiewicz R, Slusarz R, Pasenkiewicz-Gierula M, Ciarkowski J. Molecular dynamics study of 4-OH-phenylD-Y(Me)FQNRPR-NH2 selectivity to Via receptor. J Mol Model 2003; 9 : 372-8.

(83.) Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y. Functional role of internal water molecules revealed by x-ray crystallography Proc Natl Acad Sci USA 2002; 99 : 5982-7.

(84.) Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, et al. G protein-coupled receptors: In silico drug discovery in 3D. Proc Natl Acad Sci USA 2004; 101 : 11304-9.

(85.) Computational Chemistry List (CCL). Labanowski JK. Molecular Dynamics and Monte Carlo [updated Dec 1996]. Available from: Accessed on September 9, 2003.

(86.) Brinkerhoff CJ, Woolf PJ, Linderman JJ. Monte Carlo simulations of receptor dynamics: Insights into cell signaling. J Mol Histol 2004; 35 : 667-77.

(87.) Reversi A, Rimoldi V, Marrocco T, Cassoni P, Bussolati G, Parenti M, et al. The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J Biol Chem 2005; 280 : 16311-8.

(88.) Coomarasamy A, Knox EM, Gee H, Khan KS. Oxytocin antagonists for tocolysis in preterm labor--a systematic review. Med Sci Monit 2002; 8 : RA268-73.

(89.) Howl J, Wheatley M. Molecular recognition of peptide and non-peptide ligands by extracellular domains of neurohypophysial hormone receptors. Biochem J 1996; 317 : 577-82.

(90.) Hawtin SR, Howard HC, Wheatley M. Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes. Biochem J 2001; 354 : 465-72.

(91.) Filmore D. It's a GPCR world. Mod Drug Discov 2004; 7 : 24-8.

(92.) Lundstrom KH, Chin ML, editors. G protein-coupled receptors in drug discovery. Boca Raton: Taylor & Francis; 2006.

(93.) Ishiguro M. Modeling of G protein-coupled receptors for drug design. In: Haga T, Takeda S, editors. G protein coupled receptors--structure, function, and ligand screening. Boca Raton: CRC Publishing; 2006 p. 283-302.

(94.) Seifert R, Wieland T, editors. G protein-coupled receptors as drug targets: Analysis of activation and constitutive activity. Mannhold R, Kubinyi H, Folkers G. Series Editors. Methods and principles in medicinal chemistry. Vol. 24. Weinheim: Wiley-VCH; 2006.

(95.) Rognan D, editor. Ligand design for G protein-coupled receptors. Mannhold R, Kubinyi H, Folkers G, Series Editors. Methods and principles in medicinal chemistry. Vol 30. Weinheim: Wiley-VCH; 2006.

(96.) Buck L, Axel R. A novel multi gene family may encode odorant receptors: A molecular basis for odor recognition. Cell 1991; 65 : 175-87.

(97.) Man O, Gilad Y, Lancet D. Prediction of odorant binding site of olfactory receptor proteins by human--mouse comparisons. Protein Sci 2004; 13 : 240-54.

(98.) Nicot A, Otto T, Brabet P, DiCicco-Bloom E. Altered social behavior in pituary adenylate cyclase activating polypeptide type I receptor deficient mice. J Neurosci 2004; 24 : 8786-95.

(99.) Seroussi K. Unraveling the mystery of autism and pervasive development disorder. New York: Simon & Schuster; 2000.

(100.) Bell SJ, Grochoski GT, Clarke AJ. Health implications of milk containing beta-casein with the A2 genetic variant. Crit Rev Food Sci Nutr 2006; 46 : 93-100.

(101.) Shattock P, Whiteley P. Biochemical aspects in autism spectrum disorders: Updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets 2002; 6 : 175-83.

(102.) Moles A, Kieffer BL, D'Amato FR. Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 2004; 304 : 1983-6.

(103.) Murphy DG, Daly E, Schmitz N, Toal F, Murphy K, Curran S, et al. Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study. Am J Psychiatry 2006; 163 : 934-6.

(104.) Marek GJ, Carpenter LL, McDougle C J, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 2003; 28 : 402-12.

(105.) Nieoullon A. Dopamine and the regulation of cognition and attention. Prog Neurobiol 2002; 67 : 53-83.

(106.) Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses 2006; 66 : 985-90.

(107.) Ray MA, Graham AJ, Lee M, Perry RH, Court JA, Perry EK. Neuronal nicotinic acetylcholine receptor subunits in autism: an immunohistochemical investigation in the thalamus. Neurobiol Dis 2005; 19 : 366-77.

(108.) Bielsky HF, Hu SB, Szegda KL, Westphal H, Young LJ. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin Via receptor knockout mice. Neuropsychopharmacology 2004; 29 : 483-93.

(109.) Lucentini J. Love is like an addiction. The Scientist 2005; 19 : 20-1.

(110.) Carter CS. Sex differences in oxytocin and vasopressin: Implications for autism spectrum disorders? Behav Brain Res 2007; 176 : 170-86.

(111.) Scheuring S, Muller D J, Stahlberg H, Engel HA, Engel A. Sampling the conformational space of membrane proteins with the AFM. Eur Biophys J 2002; 31 : 172-8.

(112.) Ma B, Nussinov R. From computational quantum chemistry to computational biology experiments and computations are (full) partners. Phys Biol 2004; 1 : 23-6.

(113.) Bonacci TM, Mathews JL, Yuan C, Lehmann DM, Malik S, Wu D, et al. Differential targeting of G-[beta]-[gamma]-subunit signalling with small molecules. Science 2006; 312 : 443-6.

(114.) Seizer P, Ertl P. Identification and classification of GPCR ligands using self-organizing neural networks. QSAR Comb Sci 2005; 24 : 270-6.

(115.) Jongejan A, Bruysters M, Ballesteros JA, Haaksma E, Bakker RA, Pardo L, et al. Linking agonist binding to histamine H1 receptor activation. Nature Chem Biol 2005; 1 : 98-103.

(116.) Sakmar TP. Twenty years of the magnificient seven. The Scientist 2005; 19 : 22-3.

(117.) Gauquelin G, Geelen G, Louis F, Allevard AM, Meunier C, Cuisinaud G, et al. Presence of vasopressin, oxytocin and neurophysin in the retina of mammals, effect of light and darkness, comparison with the neuropeptide content of the neurohypophysis and the pineal gland. Peptides 1983; 4 : 509-15.

(118.) Birnbaumer N, Schmidt RF. Biologische Psychologic, 6th Auflage. Heidelberg: Springer Medizin Verlag; 2006 p. 384.

(119.) Birnbaumer N, Schmidt RE Biologische Psychologic, 6th Auflage. Heidelberg: Springer Medizin Verlag; 2006 p. 382.

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Roy U. Rojas Wahl

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