OXYTOCIN - A Deep Dive

Oxytocin is derived by enzymatic splitting from the peptide precursor encoded by the human OXT gene. The deduced structure of the active nonapeptide is:

Cys– Tyr – Ile– Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2.

HIGHLIGHTS:

Sexual Behavior in Men
Sexual Behavior in Women
Social behavior
Maternal and Paternal Behaviors
Autism
Schizophrenia
Pain perception

Social Behavior

The ability to recognize a conspecific is imperative in determining the proper response to that individual, and formation of a ‘social memory’ of individuals is vital for display of appropriate behaviors within a social group. For inter-sex interactions, the appropriate behaviors are often affiliative in nature, which allows for reproduction, pair-bonding, and parental behaviors. For same-sex interactions, particularly male-male interactions, the appropriate behaviors are often aggressive in nature and center around competition for mates and other resources. Across species, Oxt is important in regulating the formation of social memories, as well as displays of affiliative and aggressive behaviors. The next three sections will delve into the particular roles that Oxt has in regulating social behaviors (social recognition; affiliation; aggression); these sections are summarized in Table 1. For recent reviews of Oxt effects on social behaviors, see (Neumann, 2008; Neumann and Landgraf, 2008). [1]

Recognition of individuals is important for everyday life. Without the ability to determine friend from foe, it is difficult to display the appropriate behaviors (either affiliative or aggressive, respectively). The formation of a social memory of individuals is therefore vital, and in rodents relies primarily on volatile and pheremonal olfactory cues. This differs from primates, which rely primarily on both visual and auditory cues. In rodents, Oxt influences social memories by affecting the processing of these olfactory cues (for a recent review, see Sanchez-Andrade and Kendrick, 2008). [1]

Social memory is commonly examined in rodents through three paradigms: habituation-dishabituation, social recognition, and social discrimination. In the first, a subject animal is exposed to the same “stimulus” animal over repeated trials, and decreases investigation through habituation. Following habituation, a novel animal is presented, which typically results in an increase in investigation time, or dishabituation (Winslow and Camacho, 1995). In the social recognition paradigm, a subject animal is exposed to a stimulus animal and after a predetermined period of time is either re-exposed to the same stimulus animal or to a novel stimulus animal. Typically, the subject spends a greater amount of time investigating the novel animal (Dantzer et al., 1987). The third paradigm, social discrimination, is similar to social recognition, except that on the re-exposure trial both the same and novel stimulus animals are presented simultaneously, forcing the subject animal to choose between the two (Engelmann et al., 1995). For detailed protocols, see (Winslow, 2003).

Choleris and coworkers have suggested a gene micronet involving the four genes coding ERα, ERβ, Oxt and Oxtr as the regulatory basis of social recognition in the brain (Choleris et al., 2004). The interactions between the E and Oxt systems are quite intricate. For example, neonatal manipulations of Oxtr stimulation lead to changes in brain ER and Oxt levels in both juveniles and adults (Cushing et al., 2003; Kramer et al., 2007). Even this proposed micronet can only be part of the basis of social recognition, as it is known that other substances (e.g., vasopressin (Bielsky et al., 2004; Wersinger et al., 2002)) are necessary.

Social memory/recognition in males

In males, a great body of evidence indicates that both neuropeptides Avp and Oxt influence social memory. The role of Avp in social memory/recognition has been described previously (Caldwell et al., 2008); this review will focus on the role of Oxt in social memory/recognition. Early work by Dluzen and colleagues indicates that Oxt likely influences social recognition responses in males by affecting the ability to process odors. Infusion of Oxt into the OB facilitates social recognition at both a 30-min and 120-min delay compared to vehicle-treated animals, but infusion of the Oxt antagonist desGly-NH2,d(CH2)5[Try(Me)2,Thr4,Orn8]vasotocin (AOVT) into the same region of the OB fails to block social recognition at either time delay (Dluzen et al., 1998a). Retrodialysis of Oxt into the OB increases norepinephrine (NE) release (Dluzen et al., 2000). Infusion of 6-hydroxydopamine, which destroys NE terminals, directly into the OB results in a complete lack of social recognition, even with co-infusion of Oxt (Dluzen et al., 1998b). Specifically, the actions of NE on the α-adrenoceptors in the OB are necessary, as infusion of clonidine (an alpha-adrenoceptor agonist) preserves social recognition, while phentolamine (an alpha-adrenoceptor antagonist) prevents social recognition, even in the presence of Oxt (Dluzen et al., 2000).

Oxt also facilitates social recognition when administered in other regions. Infusion into the lateral ventricles significantly enhances social recognition 120 minutes later at doses of 1fg – 10 ng/rat when injected after the first encounter (Benelli et al., 1995), indicating a role for Oxt in the acquisition phase of social memory (see (Ferguson et al., 2002) for review). Similarly, infusion of the Oxt antagonist d(CH2)5[Tyr(Me)2-Orn8]vasotocin (CPOVT) 5 minutes before Oxt injection abolishes the memory-enhancing effect (Benelli et al., 1995). Social recognition is facilitated by Oxt injection into the medial preoptic area of the hypothalamus (mPOA) with a wide range of doses (0.3–1000pg), but not when injected into the septum (Popik and van Ree, 1991). Interestingly, Avp facilitates social recognition when injected into the septum (Engelmann and Landgraf, 1994), but not the mPOA (Popik and van Ree, 1991); see (Caldwell et al., 2008) for review), indicating that these two neuropeptides influence social recognition in different brain regions. Finally, subcutaneous administration of Oxt and related peptides containing the C-terminal glycinamide (i.e., Oxt-(1–9), Oxt-(7–9), and Oxt-(8–9)) have been shown to facilitate social recognition at low doses (Popik et al., 1996). Access to the CNS by this route of administration is problematical, as is the site of action.

The development of Oxt and Oxt receptor KO mice has led to the further characterization of Oxt’s role in social recognition responses. Male Oxt KO mice fail to develop social memory on both the habituation-dishabituation test (Ferguson et al., 2000; Lee et al., 2008) and the social recognition test (Ferguson et al., 2001). Oxt in the medial amygdala is necessary to facilitate social recognition, as demonstrated by c-fos activation in the medial amygdala of wildtype (WT) but not Oxt KO mice during the initial exposure (Ferguson et al., 2001). Interestingly, two independently derived lines of Oxt KO mice fail to show any deficits in general sociability (as measured by the social approach task; (Crawley et al., 2007), indicating that Oxt is primarily involved in the memory component of social recognition (see Section 2.2.1 for the role Oxt plays in learning and memory).

Recently, a similar impairment in social recognition in two lines of Oxtr KO mice was described. Specifically, unlike WT controls, Oxtr KO mice continue to investigate a ‘familiar’ female as if she were ‘novel’ (Takayanagi et al., 2005). Furthermore, we generated a line of conditional Oxtr KO mice to reduce Oxtr expression in parts of the forebrain (OxtrFB/FB). Compared to WT littermate controls, OxtrFB/FBmice also have a social recognition impairment but in a different manner, with decreased investigation of both ‘familiar’ and ‘novel’ females on the second trial, but at intermediate levels (Figure 3) (Lee et al., 2008). As OxtrFB/FB mice can distinguish between familiar and novel stimulus females on the habituation-dishabituation task, it is unlikely that the decreased investigation is due to a loss of interest in the social recognition tasks. Why the Oxtr KO and OxtrFB/FB mice should differ in social recognition performance is unclear, and is currently being investigated. [1]

Sex behavior in males

Acute administration of Oxt enhances male sexual behavior, while intravenous Oxt injections accelerate time to ejaculation and number of ejaculations in rabbits (Melin and Kihlstroem, 1963) and the number of intromissions prior to ejaculation in rats, although only at low doses (Stoneham et al., 1985). Similarly, both i.c.v. and i.p. Oxt injections accelerate time to ejaculation and decrease time between mating attempts in rats (Arletti et al., 1985). Oxt facilitates erections in an inverted U-shaped manner, with high doses inhibiting erection frequency (Argiolas et al., 1987) as well as decreasing mounting bouts and increasing intromission latencies in male rats (Stoneham et al., 1985).

One hypothesis is that Oxt, at high levels, contributes to feelings of sexual satiety and therefore inhibits male sexual behavior. During mating bouts with a receptive female, Oxt is released within the PVN of male rats and is accompanied by reduced anxiety-like behavior up to 30 minutes after mating (Waldherr and Neumann, 2007). The release of Oxt during mating could contribute to sexual satiety. Indeed, acute i.c.v. Oxt can inhibit sexual behavior in male prairie voles (Mahalati et al., 1991). Unlike acute administration, chronic i.c.v. Oxt infusion has no long-term effects on number of mounts, intromissions, or ejaculations in male rats (Witt et al., 1992), perhaps due to decreased Oxt receptor density throughout the brain (Insel et al., 1992). However, chronic Oxt infusion does increase interaction time with the female without increasing sexual behavior (Witt et al., 1992), further implicating Oxt in sexual satiety (for review see (Carter, 1992) and general male social behavior (see Section 2.1.1.1).

Oxt does not act alone to bring about penile erections. Oxt is unable to induce erections without testosterone, as castration eliminates erections even with administration of Oxt and apomorphine; erections can later be re-established with co-administration of testosterone (Melis et al., 1994). Additionally, Oxt interacts with the dopamine and serotonin systems. The dopamine agonist apomorphine injected s.c. induces penile erections in a manner similar to that of Oxt injections into the lateral ventricles (Melis et al., 1989). More recently, Melis and coworkers (Melis et al., 2007) found that: (1) injections of both the Oxt receptor antagonist CPOVT and the dopamine receptor antagonist haloperidol into the shell of the NAcc or the PVN abolishes Oxt-induced penile erections; (2) injections of Oxt into the ventral tegmental area (VTA) increases extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the NAcc, which occurs concomitant with penile erection; and (3) Oxt-containing axons from the PVN to the VTA closely contact dopaminergic neurons in the shell of the NAcc, providing evidence that both dopamine and Oxt influence sexual behavior. Furthermore, i.c.v. injections of CPOVT dose-dependently inhibit the sexual response (erection) normally occurring in response to the dopamine D3 receptor agonist 7-OH-DPAT (Clement et al., 2008).

Serotonin depletion is an underlying factor in premature ejaculation in rats (Olivier et al., 2006) and humans (reviewed in (Giuliano and Clement, 2006). Pharmacological studies indicate that treatment with selective serotonin reuptake inhibitors induce serotonin and Oxt release, which may help to maintain erections and delay ejaculation (reviewed in (de Jong et al., 2007).

Potential interactions between Oxt and nitric oxide (NO) systems in mediating penile erections have been the subject of investigation. Administration of NO synthesis inhibitors (NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine), and the oxytocin antagonist CPOVT into the PVN all prevent Oxt-induced erections (Argiolas & Melis, 1995). However, subsequent studies indicate that the same antagonist only prevents erections when injected into the lateral ventricles (Melis et al., 1999). Injections of Oxt into the VTA stimulate dopaminergic neurons that aid in production of NO and ultimately induce penile erection (Succu et al., 2008). However, not all studies agree that the Oxt-NO interaction is necessary for penile erection. Although Oxt i.c.v. increases both the number of erections and the concentration of NO2– and NO3– in the PVN (Melis et al., 1997), administration of oxytocin antagonist CPOVT into the lateral ventricles reduces non-contact erections without modifying NO2– and NO3– concentrations (Melis et al., 2000).

Finally, Oxt KO males produce normal litters when mated (Nishimori et al., 1996; Young et al., 1996b), indicating apparent normal sexual behavior, and the KOs are still potent sexual triggers to hormone-primed females (Agmo et al., 2008). Therefore, other hormones and mechanisms are more critically involved in sexual behavior in males. For review, see (Argiolas and Melis, 2004, 2005; Carter, 1992). [1]

Sex behavior in females

Oxt acts in females to coordinate the onset of sexual maturity through interactions with gonadatropin-releasing hormone (GnRH): treatment with the Oxt antagonist desGly-NH2-d(CH2)2[D-Tyr2,Thr4]-vasotocin for 6 days significantly decreases GnRH pulse frequency, as well as age of vaginal opening and first estrus (Parent et al., 2008). Upon entering sexual maturity, female sexual behavior is examined in rodents primarily via examining the lordosis response. Lordosis is a reflexive posture displayed by receptive females in response to male mounting, and is primarily under control of E (see (Kow and Pfaff, 1998) for review).

Oxitocin also induces female sexual behavior, primarily by actions in the mPOA of the hypothalamus and the VMH (both regions underlie lordosis display; see Kow & Pfaff, 1998). Oxt immunoreactivity is enhanced by E (Caldwell et al., 1989a), and E increases affinity for Oxtr in the mPOA (Caldwell et al., 1994b). Similarly, Oxt release in the VMH due to mounting by males occurs only in females pretreated with E and P (Caldwell et al., 1989b). In females pretreated with E and P, Oxt injection into the mPOA significantly increases sexual receptivity as measured by the lordosis quotient (LQ: number of lordosis postures/100 mounts), while Oxt injection into the VMH increases lordosis duration only (Schulze and Gorzalka, 1991). Oxt injection into the mesencephalic central gray, or ventral tegmental area (other regions implicated in lordosis behavior) is not shown to alter LQ (Caldwell et al., 1989b).

Oxt facilitates sexual receptivity as measured by an increase in lordosis behavior, but only when the females have been pretreated with either E alone (Caldwell et al., 1986b), P alone (Gorzalka and Lester, 1987), or E and P (Arletti et al., 1985; Caldwell et al., 1989a). In intact, non-ovariectomized females, Oxt significantly increases lordosis quotient (LQ) and duration during estrus, when P levels are highest, while the Oxt antagonist CPOVT decreases LQ and duration (Benelli et al., 1994). Similarly, administration of the Oxt antagonist OVTA prior to treatment with P significantly decreases lordosis posturing, and increases duration of fighting with males (Caldwell et al., 1994a), but only when the Oxt antagonist is injected into the mPOA.

Early work indicates that Oxt may primarily affect facilitation of sexual behavior by P. The selective Oxtr antagonist OVTA reduces female sexual behavior in females primed with E and P, but not in females primed with E alone (Witt and Insel, 1991). In contrast, a later study indicates that E (conjugated to bovine serum albumin at position 6) and Oxt infusion to mPOA and medial basal hypothalamus significantly increases sexual receptivity (LQ), whereas E and P with Oxt does not (Caldwell and Moe, 1999). However, the Oxtr antagonist used by Witt and Insel is also an Avpr1a receptor antagonist (see (Pedersen and Boccia, 2006) for a recent study investigating Avp and Oxt interactions in controlling female sexual behavior). Treatment with the more selective Oxtr antagonist AOVT to ovariectomized (OVX) females primed with E significantly decreases LQ, and increases male-directed antagonistic behavior prior to P injection (Pedersen and Boccia, 2002). This Oxt antagonist does not decrease female sexual behavior at 4 and 6 hours after P injection, but does decrease lordosis 8–12 hours after P (Pedersen and Boccia, 2002). It is likely, therefore, that shortly after P injection, Oxtr activation facilitates the onset of female sexual behavior, and contributes to maintaining sexual behavior for up to 8 hours.

Prolactin (see Section 1.5) is released in the presence of Oxt (Egli et al., 2004; Samson et al., 1986) and with vagino-cervical stimulation (Erskine and Kornberg, 1992). Prolactin is released with mating in a twice-daily surge termed pseudopregnancy; females infused with the Oxtr antagonist OVTA into the VMH show only a 22% induction of pseudopregnancy, compared with 100% in females infused with control or an Avpr1a antagonist (Northrop and Erskine, 2008).

Oxt regulates female sexual behavior in other rodent species as well. In a manner similar to rats, Oxt infused into the VMH and mPOA induces sexual receptivity (increased duration of lordosis) in female Syrian hamsters (Whitman and Albers, 1995), while the Oxt antagonist OVTA reduces sexual receptivity. As in rats, female hamsters require pretreatment with some combination of E and P for Oxt to exert an effect (Whitman and Albers, 1995).

Unlike rats, prairie voles do not have a spontaneous estrus cycle. Female voles require social interactions with unfamiliar males for sexual behavior to be displayed (Carter et al., 1987). Accordingly, simple injections of Oxt (i.c.v. or i.p.) do not facilitate sexual receptivity in female prairie voles pretreated with E (Witt et al., 1990), and treatment with an Oxt antagonist does not inhibit sexual behavior (Witt et al., 1991). However, in sexually-naïve females (no exposure to males after weaning), daily Oxt injection (s.c.) for 5 days increases the likelihood of mating (compared to saline treated females), and treatment of Oxt with E increases sexual receptivity greater than E alone (Cushing and Carter, 1999). Therefore, prior exposure to Oxt can mimic the effects of social contact on female sexual behavior. Treatment with the Oxt antagonist CPOVT increases the likelihood of carrying a litter to term when the father is removed (a manipulation that ordinarily leaves a 50:50 chance of producing a litter; (Cushing et al., 2005). [1]

Non-social Behavior

In addition to its effects on social behaviors, oxytocin also impacts non-social behaviors such as non-social memory, anxiety, depression, and stress. The following sections will describe the role that Oxt is believed to play in these behaviors in both non-humans (primarily rodents) and humans via clinical studies. The results are summarized in Table 1.

Learning and Memory

Memory processes are highly influenced by neuropeptides. Generally, Avp seems to enhance both non-spatial and spatial memory, likely through connections between the hippocampus and septum (see (Caldwell et al., 2008) for review). In contrast, Oxt seems to attenuate memory processes. Pioneering work by De Wied and colleagues (Bohus et al., 1978; De Wied, 1971; Kovacs et al., 1978) consistently demonstrated that passive avoidance behavior is either unaffected (Bohus et al., 1978; De Wied, 1971), or impaired by administration of Oxt (Kovacs et al., 1978), even when administered at doses equivalent to effective doses of Avp. Specifically, Oxt decreases “step-down latency” (latency to jump off of a platform onto a floor with which the animals had been trained to associate a shock; (Kovacs et al., 1978) and passive-avoidance behavior (latency to enter a dark chamber in which a shock had previously been given (Kovacs et al., 1979). Region-specific effects of Oxt on passive-avoidance behavior are discussed below. For a complete review of this early work see (Kovacs and Telegdy, 1982). Recently, de Oliveria and colleagues also showed that i.p. Oxt administered prior to testing impairs inhibitory avoidance measuring “step-down latency”, without causing increases in anxiety alone (tested on EPM), and with an accompanying decrease in corticosterone levels (de Oliveira et al., 2007). Stress hormones and effects on the hypothalamic-pituitary-adrenal (HPA) axis may, therefore, mediate the amnesic effects of Oxt.

Stress, Anxiety and Depression

All creatures engage in allostatic defense in response to stressors, be they physiological or psychogenic. Myriad neural systems are engaged in this complicated process, and a complete description is beyond the scope of this review. Oxt can modulate the physiological and behavioral responses to stress by direct and indirect modulation of the HPA axis at the level of the hypothalamus, amygdala, BNST and septum. As discussed in this section, Oxt appears to have a dampening effect on stress responses. The circuits involved and the mechanisms by which they achieve their coordinated effect still remain to be elucidated.

Hypothalamic-pituitary-adrenal Axis and Oxytocin

Oxt plays a role in HPA activity, both in terms of basal function and stress induced activation (Neumann et al., 2000). Two excellent reviews detail Oxt’s effects on HPA functioning (Engelmann et al., 2004; Neumann, 2002), but we will highlight the salient points here. In general, plasma concentrations of Oxt are increased following physiological and psychological stresses, including forced swim, restraint, cold stress, shaker stress, hyperosmolarity and social stress (Engelmann et al., 1999; Gibbs, 1984; Hashiguchi et al., 1997; Jezova et al., 1995; Lang et al., 1983; Neumann et al., 2000).

Oxt was originally thought to have an agonistic effect on adrenocorticotropin hormone (ACTH) release and a facilitative effect on corticotropin-releasing factor (CRF)-mediated ACTH release at the level of the pituitary: Oxt administered to superfused hemipituitaries or pituitary cells in vitro causes the release of ACTH (Link et al., 1992) and potentiates ACTH release in response to CRF (Antoni et al., 1983; Gibbs et al., 1984; Link et al., 1992). This potentiation of ACTH release is due to Oxt’s action at the Avpr1b receptor in the pituitary (Schlosser et al., 1994). I.c.v. Oxt administration decreases plasma ACTH levels in anesthetized rats, possibly by affecting catecholamine levels (Gibbs, 1986). Infusion of the Oxt antagonist AOVT into either the lateral ventricles or directly into the PVN increases basal levels of ACTH, as well as stress induced (e.g., after forced swim or EPM) secretion of ACTH and corticosterone (Neumann et al., 2000).

Oxytocin and Anxiety

Oxytocin is thought to work as an anxiolytic as it decreases release of stress hormones in both humans (reviewed in Legros, 2001) and rats (Stachowiak et al., 1995). As stated above (section 2.1.3.1), endogenous release of Oxt in males during mating can reduce anxiety-like behaviors (Waldherr and Neumann, 2007). In male rats, Oxt administration reduces anxiety-like behaviors in a number of behavioral tests (e.g., EPM); in mice, this effect is blocked in some tests by the Oxt antagonist WAY-162720 (Ring et al., 2006). Bilateral Oxt infusions to the PVN produce anxiolytic effects in both the EPM and the light-dark box, likely through activation of the extracellular signal-regulated kinase 1/2 cascade (Blume et al., 2008). However, as mentioned above (section 2.1.4.1), inducing subordination in males through use of a chronic subordinate housing condition increases anxiety but does not result in a change in hypothalamic Oxt mRNA levels (Reber and Neumann, 2008).

Oxt has anxiolytic effects in females as well. Ovariectomized female rats show a dose dependent decrease in plasma corticosterone levels following an auditory stressor after chronic i.c.v. injection of Oxt (Windle et al., 1997). An anxiolytic effect of Oxt is also found when female rats are exposed to a novel environment (Windle et al., 1997). Oxt also has an anxiolytic effect on EPM behavior in female ovariectomized mice, but only with combined E + Oxt treatment (McCarthy et al., 1996). Oxt seems to mediate postpartum reductions in anxiety, as delivery of the Oxtr antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT in the ventrocaudal periaqueductal gray reduces the percentage of time lactating dams spend in open arms of the EPM, but does not affect virgin females’ performance (Figueira et al., 2008).

The anxiolytic properties of Oxt may be mediated, at least in part, via action at the Oxtr in the amygdala. Oxt infusion into the amygdala, but not the VMH, has an anxiolytic effect on ovariectomized female rats in an open field (Bale et al., 2001). The amygdala is well known for its role in the acquisition, modulation and storage of emotional memory (Davis and Whalen, 2001; LeDoux, 2007; Pare et al., 2004; Schulkin et al., 2003). Projections from the septum and the amygdala may modulate the HPA axis via connections to Oxt neurons in the PVN and SON (Oldfield et al., 1985). Within the extended amygdala there are many regions with binding sites for Oxt (Veinante and Freund-Mercier, 1997). This includes a population of neurons with Oxtr in the lateral portion of the CeA that have inhibitory connections to neurons that excite brainstem areas associated with species-specific defensive responses (Huber et al., 2005). Whether this population of neurons plays a functional role in learned fear behavior has yet to be established, but it is clear that Oxt neurons within the CeA modulate some behaviors such as maternal aggression (Bosch et al., 2005; Consiglio et al., 2005; Ferris et al., 1992; Lubin et al., 2003). A recent study (Yoshida, et al., 2009) in mice indicates that many serotonergic raphe neurons express Oxtr and that infusion of Oxt into the median raphe results in serotonin release. Further, i.c.v. Oxt reduces anxiety that is prevented by i.p. administration of a serotonin 5-HT2A/2C receptor antagonist (Yoshida, et al., 2009). [1]

In terms of trait anxiety, results are mixed. Wistar rats bred for high or low levels of anxiety behavior have similar plasma levels of ACTH, corticosterone and Oxt following an EPM stressor (Landgraf et al., 1999). This suggests that Oxt does not play a role in the anxiety displayed by the high anxiety group. However, transgenic female mice lacking endogenous Oxt do show an anxious behavioral. Virgin female Oxt KO mice tested on the EPM make fewer open arm entries than WT, an effect that is reversed by i.c.v. Oxt administration (Mantella et al., 2003). Corticosterone levels are also higher in KO females following acute and chronic shaker stress, though basal levels remain unaffected (Amico et al., 2004a). In a follow-up study, a similar stressor (insertion of rectal probe to record body temperature) also results in higher levels of plasma corticosterone in female Oxt KO mice compared with WT mice (Amico et al., 2008). Interestingly, a physical stressor (insulin-induced hypoglycemia) does not cause female Oxt KO mice to release greater amounts of corticosterone (Amico et al., 2008), implicating the central Oxt pathways in modulating different types of stressors.

Oxytocin and Appetitive Control

Oxt regulates intake of food and various other solutions, such as NaCl and sucrose. Generally, Oxt suppresses food intake, while at the same time facilitating the onset of sexual behavior. Appetitive control may occur, in part, in the VMH through hormonal like actions after Oxt release from PVN and SON magnocellular dendrites and possibly by yet-to-be-discovered synaptic contact from PVN parvocellular fibers (reviewed in (Leng et al., 2008b; Sabatier et al., 2007). Oxt parvocellular fibers project to the nucleus of the solitary tract as well where regulation of feeding may occur (Blevins, et al., 2003). Oxytocin is also co-expressed with the satiety factor nesfatin-1 in about a quarter of PVN Oxt neurons and 35% of SON Oxt neurons (Kohno et al., 2008). Centrally-administered Oxt and Oxt agonists i.c.v. strongly inhibit feeding (Olson et al., 1991), as does i.p. Oxt, albeit in a dose-dependent manner, with the highest doses most strongly inhibiting food intake (Arletti et al., 1989, 1990). Oxt antagonists prevent this inhibition (Arletti et al., 1989, 1990; Olson et al., 1991). Furthermore, Oxt dose-dependently inhibits water intake in freely-drinking animals, as well as induces thirst (Arletti et al., 1990). During pregnancy, activity of magnocellular Oxt neurons is reduced and Oxt release is inhibited, which may contribute to hyperphagia during pregnancy (Douglas et al., 2007). [1]

Oxytocin and pain perception

Pain perception is generally measured in rodents through the tail flick test, in which heat is applied to the tail and latency to remove the tail from the heat source is measured. The hot plate test is also used and the latency for the animal to lick his paw, vocalize or jump is measured. Oxt lowers the pain threshold in rats, after either i.c.v. or intra-spinal administration (Yang et al., 2007a, b). Specifically, Oxt increases latency to remove the tail from heat, while the Oxt antagonist CPOVT prevents the antinociceptive properties of Oxt (Arletti et al., 1993; Lundeberg et al., 1994; Uvnas-Moberg et al., 1992). Oxt KO mice have significantly reduced antinociception following stress compared to WT mice, and the Oxt antagonist CPOVT given to WT mice attenuates antinociception (Robinson et al., 2002). Recent research indicates that central Oxt (i.c.v. or intra-spinal) combined with acupuncture treatment significantly increases the pain threshold in compared to non-treated controls (Yang et al., 2007b). Oxt seems to mediate antinociception by connections from Oxt neurons in the PVN to the dorsal horn of the spinal cord (Robinson et al., 2002), specifically by acting upon a subpopulation of lamina II glutamatergic interneurons in the dorsal horn. This generally elevates inhibition at the level of the spinal cord (Breton et al., 2008). Furthermore, pain stimulation decreases Oxt concentration throughout the brain, particularly in hypothalamic regions, although notably not in the PVN (Yang et al., 2007a, b). [1]

Autism

Autism is a neuropsychological disorder characterized by abnormal social relationships, including impaired interaction and communication, as well as repetitive and stereotyped behaviors. Autism spectrum disorders (ASD; includes autism) are labeled as pervasive developmental disorders, and can include other medical disorders, such as retardation and seizures, and psychological problems, such as heightened anxiety (Fombonne, 2005). Recently, much effort has gone into determining the underlying causes of autism and related disorders. The positive relationship between Oxt and formation of social bonds in animal studies (reviewed in (Hammock and Young, 2006) has led many to believe that Oxt abnormalities may play a part in autism. Indeed, several studies indicate that single nucleotide polymorphisms (SNPs) in the Oxt(Yrigollen et al., 2008) and Oxtr genes (Jacob et al., 2007; Lerer et al., 2008; Wu et al., 2005) are linked with ASD. Intravenous infusion of Oxt into adults with autism and Asperger’s disorder significantly reduces both number and severity of repetitive behaviors (such as repeating, self-injury, touching; (Hollander et al., 2003), and increases ability to comprehend and remember the affective component of spoken words (happy, indifferent, angry, or sad; (Hollander et al., 2007).

However promising the link between Oxt and autism may be, it is important to remember that many gene systems, in many combinations, contribute to any observable phenotype, and that many systems are currently being explored in relation to autism (Abu-Elneel et al., 2008; McCauley et al., 2005; Morrow et al., 2008; Yan et al., 2008). For a recent review of the possible link beween Oxt and autism, as well as other neuropsychiatric disorders, see (Marazziti and Dell’osso, 2008). [1]

Oxytocin and schizophrenia

Prepulse inhibition (PPI) of the startle reflex is a form of sensorimotor gating displayed across a variety of species in which the reflexive reaction to a sudden, intense sensory stimulus is reduced by a preceding, weaker sensory stimulus. This gating process is an attentional mechanism that filters potentially distracting stimuli so that attention can be focused on relevant information. Deficits in sensorimotor gating are a feature of many psychiatric and neurological disorders including schizophrenia (Braff et al., 2001; Braff et al., 1992; Grillon et al., 1992; Light and Braff, 1999). Using animal models, PPI has been disrupted in a manner similar to that seen in schizophrenics by the administration of psychotomimetic drugs (Davis et al., 1990; Mansbach et al., 1989; Mansbach and Geyer, 1989; Mansbach et al., 1988), particularly those that affect the dopamine and glutamate/NMDA receptors (Martinez et al., 2000).

Oxt levels may be elevated in patients with psychiatric disorders such as schizophrenia (Beckmann et al., 1985) and OCD (Leckman et al., 1994b), although not all studies find such a difference (Glovinsky et al., 1994). Also, a recent study reports lower levels of Oxt in hyponatremic schizophrenics who display altered HPA activity (Goldman et al., 2008). However, use of antipsychotics such as amperozide (serotonin antagonist) and clozapine (dopamine and partial serotonin agonist) significantly increases plasma Oxt levels (Uvnas-Moberg et al., 1992), indicating that Oxt may act as a natural antipsychotic. Indeed, Oxt restores PPI that is disrupted by dizocilpine (non-competitive NMDA antagonist) and amphetamine (indirect dopamine agonist(Feifel and Reza, 1999). Furthermore, Oxt KO mice exhibit greater PPI deficits with treatment of phencyclidine (PCP, an NMDA antagonist) than do WT mice (Caldwell et al., 2009), indicating that Oxt in particular affects the glutamatergic component of PPI, and likely underlies disruptions in sensory gating observed in schizophrenic patients (Swerdlow et al., 2006).

In addition to disrupting PPI, chronic PCP (14 days) causes social deficits and decreased Oxt binding in the hypothalamus, but increases Oxt binding in the CeA; bilateral Oxt administered to the CeA reverses the social deficits from PCP (Lee et al., 2005). Interestingly, levels of plasma Oxt in schizophrenics positively predicts their ability to identify facial emotions (Goldman et al., 2008), further implicating Oxt in the social aspects of schizophrenia. [1]

Lee, Heon-Jin et al. “Oxytocin: the great facilitator of life.” Progress in neurobiology 88,2 (2009): 127-51. doi:10.1016/j.pneurobio.2009.04.001