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Psychoneuroendocrinology, 19, No. 8, pp. 723-749, 1994 Vol. Copyright 1994ElsevierScience Ltd 0 Printedin the USA.

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0306-4530(94)EOO35-8

REVIEW THE ROLE OF CENTRAL OXYTOCIN IN OBSESSIVE COMPULSIVE DISORDER AND RELATED NORMAL BEHAVIOR
WAYNE K. GOODMAN,~ WILLIAM G. NORTH,~ PHILLIP B. CHAPPELL,~LAWRENCE H. PRICE,~DAVID L. PAULS, GEORGEM. ANDERSON,~MARK A. RIDDLE,~ CHRISTOPHER MCDOUGLE,.~ J. LINDA C. BARR,~ and DONALD J. COHEN JAMES F. LECKMAN, Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA; ?Department of Psychiatry, University of Florida College of Medicine, Gainsville, Florida USA; -Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire USA; 4Connecticut Mental Health Center, New Haven, Connecticut USA; and Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
(Received 12 November 1993; in jinal form 4 February 1994)

SUMMARY
Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells. which project to widely distributed sites in the CNS as well as the neurohypophysis. Central OT affects a variety of cognitive, grooming, affiliative, sexual, and reproductive behaviors in animals. Obsessive Compulsive Disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with OT. Anecdotal data and a recently completed cerebrospinal fluid (CSF) study provide evidence that some forms of OCD are related to OT dysfunction. Based on these findings, we hypothesize: I) that some forms of OCD are at the extreme end of a range of normal behaviors that are mediated by OT and related systems: and that 2) some normal cognitive, affiliative, and sexual behaviors contain elements that are similar to features of OCD. Alternative hypotheses are considered, and a series of predictions are presented concerning the relationship between central OT and the onset, course, treatment response, and response to challenge procedures seen in this form of OCD. Keywords-Oxytocin (OT); CNS administration; disorder (OCD); Pathogenesis; CSF studies. Behavioral effects; Obsessive compulsive

INTRODUCTION have thus far been isolated and sequenced. They are heterogeneously distributed in the CNS and are likely to play some role in the pathobiology of major psychiatric disorders (Nemeroff, 1991). One of the first to be isolated was
MORE THAN 50 neuropeptides

correspondence and reprint requests to: James F. Leckman, MD, Yale Child Study Center, 230 South Frontage Road, PO Box 207900, New Haven, CT 06520-7900 USA.
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oxytocin (OT) (du Vigneaud et al., 1953). Despite 40 years of research, we have only a partial understanding of the role of OT in a range of normal human behaviors and even less knowledge of its role, if any, in the genesis or maintenance of mental disorders (Pedersen, 1991). This review attempts to synthesize the findings of preclinical investigations with clinical studies to develop a set of hypotheses related to the pathogenesis of obsessive compulsive disorder (OCD). GENES TO PEPTIDES Oxytocin OT is a cyclic nonapeptide with cysteine residues at the 1 and 6 positions, which form a disulfide bond. Both OT and its carrier protein, oxytocin- associated neurophysin (OTNP), are synthesized as part of a larger polypeptide precursor (Land et al., 1983). Posttranslational processing of the initial gene product by endoproteases usually yields OT and OT-NP. Incomplete processing of OT during fetal development has been reported, however, yielding a stable but extended form of OT (Alstein & Gainer, 1988). Pathways for the subsequent metabolism of OT have been identified. Acetylation inactivates the peptide (Smyth, 1967), while the action of a specific aminopeptidase may produce metabolites with enhanced potency (Burbach et al., 1983). In humans, the OT gene is located on chromosome 20 (Riddell et al., 1985). It is closely linked to the arginine vasopressin (AVP) gene with only 9 kb separating the two loci. Intriguingly, these two loci are arranged in opposite transcriptional directions. The regulatory elements in the 5-flanking region of the OT gene have not been fully characterized (Grainer & Wray, 1992), but they do include a composite hormone response element for members of the steroid superfamily of receptors (Adan et al., 1993; Burbach et al., 1992). OT Receptors Thus far, only one OT receptor gene has been isolated (Kimura et al., 1992). It encodes for a 388-amino-acid polypeptide with seven transmembrane domains typical of G proteincoupled receptors. It is likely that additional OT receptor genes will be found (de Wied et al., 1993). Studies are currently underway to identify the regulatory elements responsible for the cell-specific expression of OT receptors in the neural axis. NEUROANATOMY AND NEUROPHYSIOLOGY

OT-Containing Neurons OT-producing cells in the hypothalamus include the magnocellular (large) neurons of the supraoptic (SON) and the paraventricular (PVN) nuclei (Rhodes et al., 1981a, 1981b). Their axons terminate in the posterior pituitary and release OT in the peripheral circulation given the appropriate stimuli. In addition, OT synthesized principally by parvocellular (small) neurons in the PVN can be released directly into the CSF from dendrites in the walls of the third ventricle (Dogterom et al., 1977; Mens et al., 1983; Perlow et al., 1982). Based on animal studies as well as postmortem human brain studies, OT-containing neurons in the PVN also project to limbic sites [amygdala, bed nucleus of the stria terminalis (BNST), lateral septum, and portions of the hippocampus] and to autonomic centers in the midbrain (including the locus coeruleus), brainstem, and spinal cord (Buijs, 1978; de Vries & Buijs, 1983; Fliers et al., 1986; Sofroniew & Weindl, 1981; Swanson & Kuypers, 1980; Wagner & Clemens, 1993). In some species, there may be extrahypo-

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thalamic neurons that synthesize OT (Kendrick & Keverne, 1992) with limbic sites such as the bed nucleus of the stria terminalis (BNST) being a prime possibility. However, OT messenger RNA (mRNA) appears to be axonally transported so that in situ hybridization studies which localize OT mRNA in extrahypothalamic sites may be misleading (Richter & Mohr, in press). Remarkably, OT-containing neurons have been found to synapse on other OT-containing neurons (Theodosis, 1985). Although OT receptors have generally not been visualized in the PVN, OT receptor mRNA has been detected in the PVN using in situ techniques (Yoshimura et al., 1993). Under certain physiological conditions but not others, OT has a self-stimulatory excitatory effect on it own release (Kawarabayashi et al., 1993; Kuriyama et al., 1993; Moos et al., 1984; Yamashita et al., 1987). During parturition and lactation and perhaps during other periods of increased demand for OT release (see below), a number of structural changes in OT-containing neurons occur including: large areas of membrane apposition among adjacent OT-containing cell bodies (Hatton & Tweedle, 1982; Montagnese et al., 1987; Theodosis & Poulain, 1984); dendritic bundling (Perlmutter et al., 1984); formation of new multiple synapses both in the somatic and the dendritic zones (Hatton & Tweedle, 1982; Modney & Hatton, 1989; Tweedle & Hatton, 1984); and dye coupling (an indicator of electronic coupling) of OT-containing cells (Hatton et al., 1987; Yang & Hatton, 1987). These structural effects may contribute directly to the synchronous firing of OT neurons (Freund-Mercier & Richard, 1984). Steroids are also likely to contribute to the bundling of neuronal elements and to the other remarkable structural and functional changes in OT-containing neurons during parturition and lactation (Fahrbach et al., 1984a, 1984b; Pedersen et al., 1982; Pedersen & Prange, 1979; Schumacher et al., 1990). The central release of OT can be independent of OT release from the posterior pituitary as the CSF and plasma OT responses to some stimuli are not correlated (Amico et al., 1990; Jones & Robinson, 1982; Kendrick et al., 1986; Perlow et al., 1982). For example, the systemic administration of apomorphine, a potent but nonspecific dopamine agonist, can dramatically increase plasma levels of OT in a dose dependent fashion in both rats (Melis et al., 1990) and nonhuman primates (Cameron et al., 1992). However, in the same experiments, systemic apomorphine had no effect on septal OT concentrations and the concentration of OT in the hypothalamus decreased (Melis et al., 1990). OT-containing neurons in the PVN are very sensitive to the inhibitory effects of opioids, acting via p- and K-type opioid receptors (Clarke et al., 1979; Russell et al., 1988) and the excitatory effects of opioid antagonists (Bicknell et al., 1988; Coombes et al., 1991; Summy-Long et al., 1984). OT-containing cells in the PVN and SON are also quite sensitive to the excitatory effects of serotonergic efferents from the dorsal and median raphe and noradrenergic projections from the locus coeruleus complex (Swanson & Sawchenko, 1983; van de Kar, 1991). Neurons With OT Receptors In animal studies, both the number and distribution of OT receptors undergo major changes over the course of development (Shapiro & Insel, 1989; Tribollet et al., 1989, 1991). Critical periods include the weaning period and puberty. During infancy, the areas of greatest density are: the cingulate cortex, dorsal subiculum, lateral septum, and substantia gelatinosa of the spinal cord with lower densities in the striatum (caudate and putamen), and the hypothalamus. In contrast, the sites of greatest density in adult animals are: the ventral pallidurn, dorsal subiculum, and hypothalamus, with somewhat lower

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levels in the BNST, and central nucleus of the amygdala (de Kloet et al., 1985; Elands et al., 1988; Freund-Mercier et al., 1987). Intriguingly, binding in the cingulate cortex is virtually lost in adult animals (Shapiro & Insel, 1989; Tribollet et al., 1992). The factors that influence these developmental changes are not understood. A variety of gonadal steroids including 17P-estradiol, progesterone, and testosterone influence OT binding in selected brain regions (Insel et al., in press; Johnson et al., 1989; Schumacher et al., 1990; Tribollet et al., 1990). Consistent with these effects, OT binding selectively increases in the ventromedial hypothalamic nucleus during estrus (Insel, 1992a, 1992b) and in the BNST during parturition (Insel, 1992a, 1992b). Despite these effects, however, no systematic sex-related differences have been noted in high affinity OT binding (Tribollet et al., 1990). Species differences in brain OT binding are notable. The distribution of OT binding in the brains of rats, voles, hamsters, mice, guinea pigs, and humans show marked et al., differences (Dubois-Dauphin et al., 1992; Elands et al., 1988; Freund-Mercer 1987; Insel & Shapiro, 1992; Loup et al., 1991; Tribollet et al., 1992; Witt et al., 1992). Correlational analyses have suggested that brain OT receptor distribution may reflect the social organization and mating patterns of voles (Insel et al., 1991; Insel & Shapiro, 1992). In studies of 12 human brains (aged 40-81 years), intense OT binding was observed in the basal nucleus of Meynert, the nucleus of the vertical limb of the diagonal band of Broca, the ventral portion of the lateral septal nucleus and adjacent areas of the BNST, the anterior and posterior areas of the hypothalamus, the pars compacta of the substantia nigra, the substantiae gelatinosa of the caudal trigemmal nucleus, and the dorsal horn of the upper spinal cord (Loup et al., 1989, 1991). Less intense and variable OT binding was observed in the globus pallidus and its subcommissural extension, the ventral pallidum (Loup et al., 1991). Although not observed in animal studies, the binding in the pars compacta of the substantia nigra (where dopaminergic projections to the caudate, putamen and globus pallidus originate) was seen in all of the brains examined. No sex differences were observed. Virtually all of the data presently available on the distribution of OT receptors are based on relatively selective radiolabeled ligands using autoradiographic techniques. Depending on how many OT receptors are eventually isolated and what the nature of their affinities are to the available ligands, a somewhat different and more complex picture may emerge. Indeed, it is unclear whether or not the high affinity binding sites for OT are functional neuronal receptors. However with the cloning of the OT receptor, it has been possible to use in situ hybridization to identify cells which contain the OT receptor mRNA. With few exceptions, the distribution of OT receptor mRNA in rat brain is similar to that observed in the autoradiographic studies using specific OT ligands (Yoshimura et al., 1993). Future immunohistochemical studies using specific antibodies to the OT receptor will add valuable information concerning the distribution of these receptors. The results of iontophoretic studies also suggest that OT affects the excitability of neurons in several brain regions. For example in the CA1 region of rat hippocampus, some neurons were found to be readily excited by low concentrations of OT as well as a number of structural analogues of OT. The pattern of responses was similar to that observed in uterine smooth muscle when these same agents were applied suggesting that the effects on neuronal activity were due to binding of the OT to OT receptors (Muhlethaler et al., 1983).

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BEHAVIORAL EFFECTS OF CENTRALLY ADMINISTERED OXYTOCIN Historically, de Wied and his colleagues were the first to point to the central effects of OT on memory (see de Wied et al., 1993). Other authors have focused on the role of OT in grooming behaviors (see Spruijt et al., 1992). More recently, attention has shifted to role of OT in mediating sexual (see Carter, 1992) and maternal (see Insel, 1992a, 1992b; Pedersen et al., 1992) behaviors. This is a large, and at times contradictory, literature. Differences in dosage, routes of administration, choice of agonists and antagonists, the species studied, as well as differences in outcome measures are likely to account for much of the variance. Some of the effects are bimodal and dose specific including the effects on memory, aggression, and sexual behavior. Limited data are available concerning the central mechanisms that mediate these responses. Barring some other explanation such as the production of potent and highly stable metabolites of OT that readily cross into the CNS, the systemic administration of OT does not appear to be an efficient route for reaching brain centers in view of the blood-brain barrier for such substances (Cornford et al., 1978). Less than 0.003% of peripherally administered OT reaches the CNS in some species (Mens et al., 1983). The extraordinarily short half-life of OT in plasma (1-6 min) (Mens et al., 1983) also argues against putting much weight on studies in which OT was administered systemically via intravenous (IV), intraperitoneal (IP), or intranasal routes. The following section selectively addresses only those studies in which OT, OT analogues, or OT antagonists were administered into the cerebral ventricles ICV or injected directly into specific brain sites. Table I summarizes these data. The CNS effects of OT have also been extensively discussed by Richard et al. (1991) and de Wied et al. (1993). Cognitive Behuviors OT has been called the amnesic neuropeptide because of its action to attenuate memory consolidation and retrieval (Bohus et al., 1987; Schulz et al., 1976). This property has led clinical investigators to use systemically administered OT to treat OCD in the hope that it would facilitate the extinction of avoidance behaviors associated with this disorder (Ansseau et al., 1987; Charles et al., 1989; de Boer & Westenberg et al., 1992). The results of these trials were mixed, with some patients showing a slight worsening of the OC symptoms (Salzberg & Swedo, 1992). Given the systemic administration of OT in these studies, however, their relevance can be challenged. A selective review of the animal data shows that OT effects on memory are bimodal and site dependent. While low doses do appear to attenuate memory consolidation (see de Wied et al., 1993), moderate doses actually improve memory function (Table I). This inverted U-shaped dose-response relationship is well known in neuropeptide research (Kovacs et al., 1985). Although the basis for this pattern of response is unknown, one possible explanation is that the effects of OT on memory function following intracerebral injections vary from site to site in the brain (Table I). It is also possible that active metabolites of OT or AVP contribute to this bimodal response (de Wied et al., 1993). It is also worth noting that virtually all of the data on learning and memory focus on the effects of OT on male animals leaving open questions of possible gender differences in these responses. Grooming The outer body surface of animals is complex and requires attention and care. In most animal species grooming occurs in three general contexts: as a direct reaction to peripheral

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TABLE I. CONGRUENCE

BETWEEN

THE CNS

EFFECTS OF OXYTOCIN

AND

SYMPTOMS

OF OBSESSIVE COMPULSIVE DISORDER

Domains implicated
Cognitive Agonists: OT (rats, ICV):

Effects

Relevant OC symptoms Phenomenology: Normal obsessions. Pathological doubting and other obsessional worries associated with the need to perform harm avoidant rituals such as compulsive checking to ward off potential dangers (injury, contamination).

Bimodal effect: low doses

Grooming

(100 pg to 1 ng) shortens latency of response to noxious stimuli in a conditioned passive avoidance paradigm, and moderate doses (10 ng) increase latency and consolidate memory (Bohus et al., 1978; de Kloet & de Wied, 1980) OT,_h fragment (rats, ICV): Bimodal effect: low doses (100 pg) shorten latency while slightly higher doses (1 ng) facilitates memory consolidation and retrieval (de Kloet & de Wied, 1980) OT (rats, microinjections into specific brain areas): Injection of 25 pg into either the hippocampal dentate gyrus or the dorsal raphe attenmates memory consolidation, the same dose injected into the dorsal septal nucleus facilitates memory consolidation (KovBcs et al., 1979) Agonists: OT (rats and mice, ICV): moderate to high doses (100 ng to 10 gg) induce marked increases in grooming behaviors, particularly grooming of the anogenital area, and scratching (Delanoy et al, 1978; Diamant & de Wied, 1993; Drago et al., 1986; Meisenberg & Simmons, 1982; van Erp et al., 1993a, 1993b; van Wimersma Greidanus et al., 1990) OT (rats, chronic ICV infusion): high doses (100 rig/h x 48 h) induced four-fold increase in duration of upper body autogrooming and a doubling of anogenital autogrooming in males when paired with estrogen-primed females (Diamant & de Wied, 1993) OT (rats, microinjections into specific brain areas): Slow infusion of 100 ng into either the hypothalamic paraventricular nucleus initiates grooming (van Erp et al., 1993a, 1993b) OT (squirrel monkeys, ICV): moderate to high doses increase autogrooming in both dominant and subordinate males (Witt et al., 1992). Antagonists: Squirrel monkeys, ICV: blocks autogrooming behaviors in both dominant and subordinate males (Witt et al., 1992)

Phenomenology: Increased grooming behaviors especially of the head, hands, and anogenital area. Excessive or ritualized showering, bathing, or hand washing. Contamination fears regarding feces and/or urine.

(Continued)

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TABLE I (CONTINUED)
Domains implicated Effects Relevant OC symptoms

Maternal

Affiliative

Aggressive

Agonists: OT (rats, ICV): High doses (400 ng) induce the initiation of maternal behaviors in estrogen-primed virgin females in a novel environment, this effect is not observed in all strains of rats (Bolwerk & Swanson, 1984; Pedersen & Prange, 1979; Rubin et al., 1983) OT (ewes, ICV): Very high doses (5-20 pg) increase maternal behaviors in estrogenprimed females Antagonists: Rats, ICV: Delay in the initiation of maternal behavior (Fahrbach et al., 1985; Pedersen et al., 1985; van Leengoed et al., 1987) Agonists: OT (rats, ICV): dose response (from 10 ng to 10 pg) decrease in distress vocalizations from isolated pups and adult animals (Insel & Winslow, 1991; Panksepp, 1992) OT (rats, chronic ICV infusion): high doses (100 rig/h X 48 h) induced a doubling of direct physical contact between infused males and estrogen-primed females (Witt et al., 1992) OT (squirrel monkeys, ICV): Bimodal effect in males: moderate doses (100 ng) decrease associative behaviors (approach, touch, huddle with partner) and high doses (1 pg) increase associative behavior (Winslow & Insel, 1991) Antagonists: Rats, ICV: slight attenuation of the decrease in distress vocalizations (Insel & Winslow, 1991) Squirrel monkeys, ICV: no intrinsic effect on associative behaviors compared to controls but attenuated the effects of ICV OT (Winslow & Insel, 1991) Agonists: OT (mother hamsters, central nucleus of the amygdala): 2 ng OT injections associated with increased maternal aggression directed towards intruder (Ferris, 1992); (squirrel monkeys, ICV): Dose response increase in aggressive behavior (0, 100 ng, 1 pg) in dominant males only (Winslow & Insel, 1991) Antagonists: OT (squirrel monkeys, ICV): blockade of OT receptors increases in aggressive behavior (Winslow & Insel, 1991)

Phenomenology: Normal parental preoccupations and normal obsessions concerning the safety and well being of their children especially during the early prenatal period. Increased vulnerability to OCD onsets during this period.

Phenomenology: Normal obsessions during courtship, pair bonding, and infant attachment. Pathological obsessions concerning separation.

Phenomenology: Normal obsessional worries about the safety of infants, children, and other loved-ones from external threats. Pathological obsessional worries involving violent or horrific images that suddenly intrude into consciousness. (Continued)

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TABLE I (CONTINUED)
Domains implicated Effects Relevant OC symptoms

Sexual

Reproductive

Agonists: Rats, ICV: Bimodal effects in males: moderate doses (5-90 ng) facilitate penile erections and decrease the postejaculatory interval (PEI) (Argiolas et al., 1986, 1987; Arletti et al., 1992) and high doses (250-500 ng) increase latency to first mount and the length of the (PEI) (Stoneham et al., 1985); moderate to high doses (l-800 ng) increase lordosis in steroidprimed females (Arlette et al., 1992; Caldwell et al., 1987a; Stoneham et al., 1985; Witt & Insel, 1992) Rats, IC: bilateral injections of 30 ng into the CA1 field of the hippocampus induced penile erections (Argiolas et al., 1993) Squirrel monkeys, ICV: bimodal effect in dominant males: moderate doses (100 ng) increase sexual behavior, high doses (1 pg) decrease sexual behavior (Winslow & Insel, 1991) Antagonists: Rats, ICV: In males decreased mounts, eliminated most ejaculations (Argiolas et al., 1987, 1988; Arletti et al., 1992), direct injection of antagonists into PVN prevents OT induced penile erections (Argiolas, 1992) in females decreased lordosis (Arletti et al., 1992; Witt & Insel, 1992) Squirrel monkeys, ICV: decrease in sexual behavior among dominant males (Winslow & Insel, 1991) Agonists: Rats, ICV: Injection of low doses of OT (10 pg to 2.2 ng) has a strong dose dependent facilitation of milk ejection (Freund-Mercier & Richard, 1984; Wakerley et al., 1990) Antagonists: Rats, ICV: decreased milk ejection frequency (Freund-Mercier & Richard, 1984)

Phenomenology: Normal obsessions during courtship and bonding-preoccupations with sexual thoughts. In pathologic states recurrent unwanted, forbidden, or perverse sexual thoughts, images, or impulses. Obsessive worries about semen contamination. Possibly compulsive masturbation or decreased sexual behavior.

Natural history: Heightened period of normal obsessions during gestation and the early postpartum period. Onset or exacerbation of OCD during immediate postpartum period.

stimulation or contamination; as a displacement activity at times of behavioral conflict and indecision; and as a reaction to a recent situation of activation, arousal, or stress

(see Spruijt et al., 1992). Grooming can also be elicited pharmacologically with the administration of neuropeptides such as AVP, OT, corticotrophin releasing factor (CRF), adrenocorticotropic hormone (ACTH), and a host of other peptide fragments. The effect of centrally administered OT is a clear and straight forward dose-response relationship (van Wimersma Greidanus et al., 1990) (Table I). The pattern of OT-related grooming (in both male and female animals) is distinctive and involves autogrooming

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particularly involving the head and the anogenital regions (Table I). While extensive structure function studies have not been performed, it appears that the whole OT molecule is required to produce the grooming behavior (Meisenberg & Simmons, 1983). The possible relevance of these behaviors to OCD is discussed below.
Maternal and Afjliative Behavior

Pederesen, Insel and their co-workers have convincingly demonstrated the importance of OT and related brain sites in the initiation of maternal behavior (see Insel, 1992a, 1992b; Pedersen et al., 1992). Interestingly, this effect is quite sensitive to changes in the external environment (the effect is usually only seen when the animals are in a novel environment), to the perceptual status of the animal (anosmic animals are more likely to show maternal behavior), and to the hormonal status of the animal (steroid priming is necessary for the response to be observed) (Pedersen et al., 1992). Studies of OT antagonists and anti-sera administered ICV, which significantly delays the onset of maternal behaviors, however, provide compelling evidence that OT is crucially involved in the initiation of maternal behaviors. Lesioning studies of the PVN during gestation also support OT having an important role in the initiation of some aspects of maternal behavior (Insel & Harbaugh, 1989). Other nonmaternal, nonsexual affiliative behaviors have not been extensively studied. The limited data in nonhuman primates suggests that the behavioral effects may be bimodal with moderate doses of OT decreasing associative behaviors and higher doses increasing such behaviors (Insel & Winslow, 1991; Witt et al., 1992; Table I).
Sexual and Reproductive Behaviors

Some of the most striking data concerning the bimodal behavioral effects of OT concern its role in sexual behavior (arousal and satiety) in humans (Carmichael et al., 1987; Murphy et al., 1987, 1990) as well as other species (Table I). As suggested by another researcher (Carter, 1992), the picture is consistent with OT participating at several levels of the sexual response: small amounts of OT might facilitate precopulatory events and through positive feedback prime the PVN for more OT to be released; subsequent pulsatile release of OT may lead to orgasmic responses involving activation of limbic and autonomic centers, followed by a refractory period of sexual satiety. Carters speculations concerning the behavioral impact of the OT released during sexual acts taken with Insels work with closely related species of voles, suggest that OT may play a powerful role in the development of pair-bonding and the formation of monogamous relationships (Carter, 1992; Carter et al., 1992; Insel & Shapiro, 1992). It appears that these effects are mediated by the intact OT molecule as either opening of the disulfide bridge or deleting the C-terminal glycinamide abolishes these effects (see Argiolas, 1992). Parturition and lactation might be seen as analogous behaviors in which the pulsatile release of OT leads to climatic events (birth) or a condition of satiety (after nursing) both of which facilitate libidinous attachments.
Aggressive Behavior

Although the central administration of OT can lead to a dose-response increase in aggressive behavior by dominant male monkeys (Winslow & Insel, 1991), relatively little else is known concerning the role of OT in mediating aggressive behavior (Table I). Basic questions such as, whether OT release plays some role in states of heightened arousal prior to or during a fight, are unknown.

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RELEVANT FEATURES OF OBSESSIVE COMPULSIVE DISORDER


Phenomenology

OCD is a chronic disabling condition in which the individual repeatedly experiences the sudden intrusion into consciousness of unwanted thoughts or images and urges to perform seemingly senseless acts over and over again. These intrusive mental images that beseige the consciousness often involve sexual or aggressive ideas that the individual regards as repugnant and morally reprehensible. Compulsions are repetitive acts that are often performed a certain number of times or according to certain private rules that the individual is driven to complete, even though the act is perceived as excessive and/ or senseless. Compulsions are often preceded by an urge that is recognized to be of internal origin that bears some relationship to obsessional worries (Rachman & Hodgson, 1980). The most common compulsions are concerned with fears of contamination leading to hand washing or other grooming behaviors or some pathological doubting, leading to repeatedly checking something to prevent some catastrophe, e.g., repeatedly checking the stove to ensure that a fire would not start inadvertently. Despite potential embarrassment, performance of compulsive washing and checking is frequently associated with a measurable reduction in the subjective discomfort generated by the obsessional worries (Hodgson & Rachman, 1972; Rachman et al., 1976; Roper & Rachman, 1.976; Roper et al., 1973). Both in the case of obsessions and compulsions, patients frequently report their efforts to resist mentally these unwanted ideas, images, and urge to act.
Natural History

The age of onset of OCD is bimodal (Rasmussen & Tsuang, 1986). Prepubertal onsets are associated with a male preponderance and an increased risk for tic disorders including Tourettes syndrome (TS) (Riddle et al., 1990; Swedo et al., 1989). A second peak of OCD onset is associated with puberty and the years following (see Goodwin et al., 1969; Rasmussen & Tsuang, 1986). Pregnancy and the immediate postpartum period is a time of increased risk, with rates among women varying from 11% to 27% (Ingram, 1961; Neziroglu et al., 1992; Pollitt, 1957; Sichel et al., 1993). Two-thirds of these cases begin a few days to 2 weeks after delivery (Sichel et al., 1993). The onset of OC symptoms can be either sudden (as in the case of the postpartum cases) or gradual; patients with compulsive cleaning most frequently report a sudden onset (Rachman & Hodgson, 1980). The subsequent course is variable ranging from unremitting (with or without social role impairment) to episodic to incomplete remissions (Goodwin et al., 1969).
Etiology

The etiology of OCD is unknown. Based on family genetic data, OCD is likely to be an etiologically heterogenous set of conditions. Some forms of OCD are familial and may be associated with a specific genetic vulnerability (Brown, 1942; Lewis, 1935). Others present as sporadic cases. Among the familial cases, a portion appear to be etiologically related to Tourettes syndrome (TS) and other tic disorders (Pauls & Leckman, 1986; Pauls et al., 1991). Data from clinical drug trials offer additional support for the distinction between TS-related OCD and other forms of the disorder (McDougle et al., 1994).
Neurobiology

Neurobiological and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of OCD, TS, and related disorders. The

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strongest available evidence concerns the serotoninergic system and the well-established efficacy of potent serotonin reuptake inhibitors in the treatment of OCD (see Goodman et al., 1989; Zohar et al., 1987). Central dopaminergic and opioid systems have also been implicated (Goodman et al., 1990; Insel & Pickar, 1983; McDougle et al., 1993; McDougle et al., 1994; Senjo, 1989). During the past decade, there has been considerable progress concerning the neuroanatomical substrates involved in OCD. The brain areas most frequently identified by in vivo neuroimaging studies are the orbitofrontal cortex (OFC), the anterior cingulate area (ACA), and the head of the caudate nucleus (Insel, 1992a, 1992b). The OFC, which maintains extensive connections with the amygdala and hypothalamus as well as projecting to the basal forebrain and autonomic centers in the brainstem, has consistently been shown have increased rates of glucose utilization in unmedicated OCD patients (Baxter et al., 1987; Nordahl et al., 1989; Swale et al., 1991; Swedo et al., 1992a, 1992b). The ACA has been strongly implicated in the pathobiology of OCD, because of the encouraging results of neurosurgical procedures directed at this structure and related fiber tracts (Bingley et al., 1977; Fodstad et al., 1982; Jenike et al., 1991). The head of the caudate nucleus and the closely associated nucleus accumbens, which receives input from both the OFC and the ACA, has also been implicated in OCD. Specifically, two in vivo neuroimaging studies have found that changes in the glucose utilization in the head of the caudate nucleus are correlated with treatment (pharmacological or behavioral) response (Baxter et al., 1992; Benkelfat et al., 1990). The OFC, ACA, and the head of the caudate are functionally interrelated limbic structures that are part of cortico-striato-thalamo-cortical (CSTC) circuits, which likely channel and subchannel emotionally laden information (Alexander et al., 1986). They may be critically important in the neuronal encoding of active avoidance behaviors (see Sparenborg & Gabriel, 1990). Baxter et al. (1992) and others (Model1 et al., 1989; Pitman, 1989; Rapoport & Wise, 1988) speculated that these circuits are hyperactive in OCD creating a self-reinforcing loop that is difficult to break. Insel (1992a, 1992b) offers the contrasting view that the hypermetabolic state observed in the OFC may be the product of the individuals resistance to the OC symptoms. CONTINUUM OF NORMAL OBSESSIVE BEHAVIORS COMPULSIVE

Although OCD is seen nosologically as a discrete entity, it clearly bears a relationship to the wide range of normal fears and rituals that are part of everyday life (Leonard et al., 1990; Rachman & de Silva, 1978). Indeed, Rachman and de Silva (1978) report that normal obsessions are a common experience and closely resemble the form and content of abnormal obsessions, which differ from the norm only with respect to their frequency and complexity. As pointed out by Douglas (1970) and King and Noshpitz (1991), many of these concerns transcend the individual and have been incorporated into many religious and cultural practices, as well as civil law, as individuals and groups seek to safeguard themselves from pollution, external disaster, or the effects of unbridled sexual desire or greed. Certain periods of human development are associated with increased levels of compulsiveness. One period of heightened compulsiveness occurs around 30 mo of age. Gesell and Ilg (1943) describe how the bedtime demands of a 2 l/2-year-old have grown into an elaborate and rigid structure that may now take as long as . . . one hour to enact. There

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is a going upstairs ritual, the taking a bath ritual, brushing the teeth ritual, getting into bed, pulling down the shades, kissing, and even a specially worded good-night ritual. A second period of normal obsessional worries is associated with courtship and concerns about potential love relationships and whether ones own feelings are reciprocated. A third period of normally heightened obsessive worries and compulsiveness occurs during gestation and the initial phases of maternal behavior. This is a time of intense concern, superstition, exact feeding schedules, and intrusive thoughts about the well-being of the baby and its need to be protected, fed, and groomed (Jones, 1990; Winnicott, 1975). Within the first 2 weeks, mothers frequently report a near-constant preoccupation with their infants- rarely going more than lo-15 min without thinking about their baby, for example, checking its breathing or being assailed by acute anxieties about the childs well being. EVIDENCE THAT OXYTOCIN IS INVOLVED IN THE PATHOGENESIS OF SOME FORMS OF OBSESSIVE COMPULSIVE DISORDER Based on the cognitive and behavioral effects of AVP and OT and their neuroanatomic distributions, recent interest has focused on their role in the pathobiology of OCD (Altemus et al., 1992; Ansseau et al., 1987; de Boer & Westenberg, 1992; Swedo et al., 1992a, 1992b). Hypothesized relationships have emphasized the role of AVP in promoting repetitive grooming behaviors, possibly analogous to hand washing and cleaning compulsions, and maintaining conditioned responses to aversive stimuli in experimental animals (de Wied, 1971; Doris, 1984; Sahgal, 1984). Elevated levels of CSF AVP in OCD patients (Altemus et al., 1992) and anecdotal clinical reports of OCD among patients with diabetes insipidus, in which central AVP levels are increased (Barton, 1965, 1987), are also consistent with this hypothesis. However, we have recently been unable to replicate the finding of elevated CSF AVP in OCD patients (Leckman et al., in press), and it is likely that central OT levels are also elevated in diabetes insipidus. Other speculations have focused on the possible role of the sexually dimorphic extrahypothalamic AVPprojections in mediating tic symptoms (Peterson et al., 1992). The empirical evidence indicating a role for OT in the pathogenesis of OCD is meager and has mostly focused on systemically administered OTs equivocal value as a therapeutic agent (Ansseau et al., 1987; Charles et al., 1989; de Boer & Westenberg, 1992; Salzberg & Swedo, 1992). In addition, one study reported that the CSF AVP/OT ratio was negatively correlated with OC symptom severity (Swedo et al., 1992a, 1992b). In an effort to examine the role of AVP and OT in TS and OCD, we compared CSF levels of AVP and OT (Leckman et al., in press). We collected CSF at midday in a standardized fashion from a total of 116 individuals (39 patients with OCD, 33 patients with TS [including 14 with OCD as well as TS], and 44 normal controls). We also collected family study data on each of the subjects to determine which subjects had a positive family history for TS, OCD, or related syndromes. In contrast to previous reports, we found similar AVP concentrations for all three groups, but increused OT levels in OCD patients without a personal or family history of tic disorders. A possible role for OT in the neurobiology of an independently defined subtype of OCD (patients without a personal or family history of a tic disorder) was further suggested by the elevated levels of OT in the CSF of these patients and the demonstrated correlation between CSF OT and concurrent clinician ratings of OCD severity (N = 19, r = .47, p < .05). In addition,

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we found positive correlations between CSF OT and CSF levels of 5-hydroxyindole acetic acid (the major metabolite of CNS serotonin) and norepinephrine, and an inverse relationship between CSF OT and dynorphin A1_8. Each of these correlations are in the predicted direction given the available evidence on the factors that influence OT release (see above). Although these data require replication, it is tempting to speculate about the emerging role of central OT in a range of cognitive, grooming, affiliative, and sexual behaviors and how these behaviors are disrupted in some forms of OCD. HYPOTHESIS THAT SOME FORMS OF OBSESSIVE COMPULSIVE DISORDER ARE RELATED TO CENTRAL OXYTOCIN RELEASE Although it may be overly simplistic, the hypothesis is offered that some forms of OCD are directly influenced by OT and related systems. The range of symptomatology seen in OCD is congruent with the range of behavioral effects seen after the central administration of OT (Table I). In steroid-primed (sexually mature) and otherwise vulnerable (see below) individuals, exposure to a provoking situation (or the spontaneous occurrence of an otherwise normal obsessive thought) might lead to or be associated with the initial pulses of OT delivered to central limbic and autonomic centers. The action of OT in these regions would intensify and prolong the unacceptable thoughts. Given the positive feedback properties of this system under certain physiological conditions, the release of OT could further prime the system leading to the synchronous generation of action potentials and increased amounts of OT being released (see Freund-Mercier & Richard, 1984; Hastings, 1991; Lincoln et al., 1985). With the hypothalamus acting as a pulse generator directed at limbic sites, the patient would subjectively experience frequent and intense intrusive worries as well as sexual (and perhaps aggressive) impulses (see above). The discomfort associated with these worries and the increasing levels of central OT would also be associated with onset of the urge to perform compulsive rituals, particularly grooming and checking compulsions. The performance of these rituals or checking behaviors would be relieving of the discomfort and would de-arouse the system. This hypothesis is partially an extension of the anxiety-reduction theory of OCD first posited by Dollard and Miller in 1950 (Dollard & Miller, 1950). The essence of the theory is that the anxiety or discomfort elicited by obsessive thoughts, motivates performance of compulsions or rituals and that these acts are reinforced by the reduction in discomfort that they produce (see Leckman et al., in press; Peterson et al., 1992). This theory is supported by a body of empirical evidence which reports that the subjective discomfort generated by exposure to a provoking situation is markedly diminished with the performance of compulsive acts (Hodgson & Rachman, 1972; Rachmen et al., 1976; Rachman & Hodgson, 1980; RGper & Rachman, 1976; Riiper et al., 1973). It is also consistent with Millers and Mowrers two-process theory of avoidance learning (Miller, 1969; Mineka, 1985; Mowrer, 1960; Teasdale, 1974). Elaborating on this theory, it is suggested that over-active OT projections to limbic sites intensify and prolong normal unacceptable obsessive thoughts leading to markedly increased levels of discomfort and anxiety and the need to perform harm avoidant rituals. Thus far, this hypothesis concerns the maintenance of and persistence of OCD once it is present rather than how the process is established. Although Rachman and Hodgson (Rachman & Hodgson, 1980) are correct to note that evidence of specific traumatic

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learning is lacking in many instances, there are many cases in which overt traumata (including sexually traumatic events) are identified as precipitants (Kringlen, 1965; Pollitt, 1957). In these cases, the traumatic experience may serve to establish (prime) the hypothesized over-activity of the hypothalamic OT projections (Ivanyi et al., 1991). In other cases, the OT system may already be normally overactive (courtship, pregnancy, parturition, lactation), so that the OCD emerges as an extreme version of normal OC behaviors associated with usual obsessive worries and harm avoidance activities seen during these periods. A complete exploration of this line of thought would also involve a consideration of the role emotional trauma (current or remembered) during periods of heightened physiological vulnerability (Capstick & Seldrup, 1977; van der Kolk & van der Hart, 1989) as well as the role of OT in the mediation of self-stimulatory and other rewarded behaviors (Ibragimov et al., 1987; Kovacs et al., 1985; van Ree, 1987). The precise neuroanatomical sites at which OT input might drive the CSTC circuits described above are uncertain but might include the central amygdala, BNST, septum, hippocampus, nucleus accumbens, ventral tegmental area, the pars compacta of the substantia nigra, the locus coeruleus, and possibly even the ACA (if there was a developmentally inappropriate expression of OT receptors in the ACA in OCD). Certain features of the natural history of OCD are also consistent with this hypothesis. Some forms of the disorder appear only during or after puberty. This may be understood in relation to the steroid priming that is necessary for the initiation of sexual and maternal behaviors by OT. The heightened risk of onset or exacerbation of OCD during puberty and the postpartum period may also be a function of steroid priming. Developmental changes in the location and density of OT projections and receptor systems may also underlie the earlier period of normal OC behaviors seen in infancy. A grand corollary of this model is that the behaviors seen in OCD are evolutionarily conserved and are normally part of the behavioral repertoire associated with the formation of interpersonal bonds or group affiliations. The developmentally appropriate initiation of this conserved set of behaviors (possibly via OT-related mechanisms) would facilitate the formation of lasting interpersonal bonds while their overexpression or developmentally inappropriate activation would lead to clinical OCD. This model is also consistent with the successful use of behavioral treatments for OC symptoms such as exposure and response prevention in reducing the discomfort associated with the obsessional worries (or exposure to a provoking situation) and hastening the extinction of the compulsive behaviors (or the phobic avoidance) (see Mineka, 1985). ALTERNATIVE HYPOTHESES AND EXPLANATIONS

There are many other hypotheses that might account for the data reviewed above. It is possible that the elevation in CSF OT is a consequence of having OCD or it could be an epiphenomena. Elevated OT as a Failed Compensatory Response Increased central OT might reflect a failed compensatory effort. Indeed, there is a considerable body of evidence that OT is a stress hormone and may serve as an endogenous anxiolytic (Gibbs, 1986a). Briefly, rat studies have shown that plasma OT shows dramatic increases following tail-hang, immobilization stress, forced swimming, and ether exposure but not to cold stress (Gibbs, 1984, 1986b; Lange et al., 1983; Romero

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et al., 1993). Human studies also indicate that peripheral release of OT can occur following an uncontrollable noise stress while no increase was observed when the stress was controllable (Sanders et al., 1990). The hypothesis that OT can be anxiolytic is based in part on the observations that both IP and ICV (2 and 20 ng) administration of OT reduces exploratory motor behavior in male rats in a way similar to IP diazepam (Uvnas-Moberg et al., 1992a); that IP OT acts as an antidepressant in two animal models of depression (Arletti & Bertolini, 1987); that IP OT elevates the pain threshold in rats (Uvnas-Moberg et al., 1992b); that intracisternal injections of high doses of OT elevates the pain threshold in mice (Caldwell et al., 1987b); and that huge doses of OT (300 pug) induced strong analgesia in a man with intractable pain (Madrazo et al., 1987). It is also interesting to note that in human subjects, peripherally administered OT appears to completely inhibit plasma adrenocorticotrophin (ACTH) responses to corticotrophin releasing hormone (CRH) (Page et al., 1990). As suggested by Pedersen (personal communication, 1993), if OT is a coping or anti-stress factor perhaps some anxiety disorders like nontic related OCD may result from an insensitivity to OT in specific brain regions such as the amygdala or other limbic sites. This receptor insensitivity in turn might result in a compensatory increase in OT levels.
Insensitivity of Lumbar CSF

The measurement of OT in lumbar CSF may be insensitive to OT changes occurring in the telencephalon. This view may be consistent with the finding of caudal-rostra1 gradients OT in the CSF of rhesus and cynomolgus monkeys (Amico et al., 1989), and the observation that the PVN-spinal projections largely arise from the posteriorly positioned lateral parvocellular PVN subnuclei (Wagner & Clemens, 1993). If the five major subdivisions of parvocellular neurons in the PVN are to some extent functionally independent, this might suggest that overactivity in one or more of the remaining parvicellular subdivisions is key to the development of OCD. If this were true then, inappropriate central OT release might be part of the pathophysiology of both tic-related and nonticrelated OCD.
Elevated OT as a Successful Compensatory Response

If the central OT systems involved in both normal obsessions and psychopathological states resemble those in seen in animals, then there may be a bimodality of response so that the heightened initial OT response sets off a flurry of obsessions, but when enough OT is generated a refractory anxiolytic period ensues.
Other Possibilities

Alternatively the elevated OT levels might involve primary alterations in centrally active gonadal or neurosteroids which would secondarily effect OT levels. Another possibility would be that metabolic fragments of OT might induce more positive feedback on the PVN neurons. ETIOLOGICAL HETEROGENEITY OF OBSESSIVE COMPULSIVE DISORDER The CSF data (Leckman et al., 1994) taken with available family genetic data (Pauls & Leckman, 1986; Pauls et al., 1991) and the emerging pharmacological data showing a differential responsiveness of tic-related OCD vs. nontic-related OCD (Hanna

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et al., 1991; McDougle et al., 1993; McDougle et al., 1994) all argue strongly that OCD is a etiologically heterogeneous disorder. It may be that inappropriate activation of central OT systems (as reflected in the lumbar CSF) is important for only a single type of OCD. If true, this would imply that the increase in OT (as reflected in lumbar CSF) are not the immediate or sole cause of OC symptoms as other abnormalities can lead to a very similar clinical picture. Simply stated, this would mean that OT is not part of the final common pathway that leads to all forms of OCD. Further if OCD is etiologically heterogeneous with regard to OT function, then failure to group OCD patients accordingly (ticrelated OCD vs. OT-related OCD) may lead to inclusive or misleading results with regard to treatment response, response to pharmacological challenges, and other neurobiological studies. However (as noted above), the possibility that tic-related OCD is also related to rostra1 OT dysfunction cannot be dismissed. PREDICTIONS Additional work is needed before precise predictions can be formulated. A key issue is whether or not central OT plays an important role in the genesis of tic-related OCD as well as nontic related OCD. If OCD is etiologically heterogenous, with some forms of the disorder associated with a dysregulation of central OT, then it would be expected that OT-related OCD would be distinctive across a number of dimensions. If not, more overlap would be predicted.
Phenomenology

In OT-related OCD, many of the OC symptoms would be experienced as being in the service of harm avoidance. That is the internal experience of what motivates compulsive acts would have more to do with avoiding a catastrophe and maintaining relationships and less to do with the perception of things not looking or feeling just right (Leckman et al., 1994). Prominent obsessive worries might involve separation worries as well as contamination fears (urine, feces, and semen) (Greenberg et al., 1987). Grooming behaviors especially anogenital grooming and other bathroom rituals would be commonplace symptoms (Greenberg et al., 1987).
Natural History

OT-related OCD is predicted to have a later age of onset with most cases beginning with puberty, given the need for steroid priming of the OT system. Males and females with a vulnerability to OCD would be at greater risk during courtship periods. Females with a vulnerability to this form of illness would also be at greater risk during the postpartum period for the sudden onset or exacerbation of OC symptoms.
Etiology

Some forms of nontic-related OCD are familial (Pauls et al., in press) so that it may be worth performing segregation analyses just within the OT-related OCD families.
Neurobiology

Given the hypothesized over-activity of the OT system, the normal circadian rhythm of OT release into the CSF (Amico et al., 1983) may be lost in OCD patients with an OT-related forms of illness, it would be expected that CSF OT will be especially high

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among those individuals who report near constant obsessional worries about contamination and sexual matters. Given the role of serotonin in modulating the activity of OT neurons, patients with OT-related OCD may be more sensitive to the effects of the partial serotonin agonist mchlorophenylpiperazine (m-CPP) than patients with tic-related OCD. If this is the case, it might account for the mixed response to this agent among patients with OCD (Charney et al., 1988; Hollander et al., 1988, 1992). We would also predict that OT-related OCD patients would have an increased sensitivity to high doses of opioid antagonists (Insel & Pickar, 1983). With regard to functional neuroimaging studies, it would be anticipated that the rates of glucose utilization would be elevated in the PVN. However, the small size of the PVN and the likely involvement of just the parvocellular elements may preclude such observations. Separation of existing data sets into subgroups of OCD patients (tic-related OCD vs. OT-related OCD vs. other) might also be informative.
Animal Models

Given the congruence of this model with the predominant anxiety reduction theory of OCD (see Mineka, 1985) and the analogy to Millers and Mowrers two-process theory of avoidance learning (Miller, 1982; Mowrer, 1960), it may be worthwhile to revisit the available animal models of active and passive avoidance learning and examine the central levels of OT in the CSF and in certain brain areas at different points during the learning process (baseline, acquisition, extinction). The study of Ivanyi et al. indicating that OT is released into the CSF following selected types of physical, pharmacological, and emotional stress may be relevant in this regard (Ivanyi et al., 1991). Similarly, studies of peripheral OT release also indicate some selectivity of response to psychological stressors (Gibbs, 1986a, 1986b; Romero et al., 1993). More work is needed to understand the various mechanisms that influence the central release of OT (Kawarabayashi et al., 1993; Kuriyama et al., 1993).
Treatment

Patients with OT-related OCD may be more responsive to serotonin reuptake inhibitors than patients with tic-related OCD (McDougle et al., 1993; McDougle et al., 1994). A recent case series, describing 15 cases of postpartum onset of OCD, also provides circumstantial support of this hypothesis, as virtually all of the patients responded well to 5-HT reuptake inhibitors (Sichel et al., 1993). Changes in clinical severity in response to successful behavioral or pharmacological treatment should also be reflected in changes in the dynamics or pattern of OT release in the CNS. Patients with OT-related OCD might also be expected to benefit from treatment with centrally active OT antagonists (none of which are currently available (Manning et al., 1993). FUTURE DIRECTIONS

The finding of a marked elevation of CSF OT in a subset of OCD patients, independently identified as having a form of OCD unrelated to TS (Leckman et al., in press), if confirmed, may open a new chapter in our understanding of the neurobiological substrates involved with this chronic disabling condition as well as less severe normal variants. Future neurobiological and treatment studies of OCD should address this source of heterogeneity. Restratification of existing data sets, including functional brain imaging

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and pharmacological challenges studies, using either family history or OT-status as a marker may prove worthwhile. A reexamination of animal models of OCD may also be warranted.
This work was supported in part by NIH grants MH44843, MH49351, MH00508, NS16648, HD03008, RROOl25, & RR06022 (General Clinical Research Centers), MH30929 (Mental Health Clinical Research Center), and the Tourette Syndrome Association. The authors would like to thank Ms. Susan Gagnon, Ms. Sharon 1. Ort, Ms. Maureen McSwiggan-Hardin, and Mr. Lawrence Scahill; and Drs. Paul J. Lombroso, Robert A. Makuch. Bradley S. Peterson, and Yanki Yazgan for their assistance in completing the project and their comments on an earlier draft of this report. The close reading of an earlier version of this manuscript and many helpful suggestions made by Drs. Thomas R. Insel, Cort A. Pedersen, and David de Wied are also gratefully acknowledged.
Acknowledgments:

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