Investigating social anxiety disorder with animal models is more problematic than investigating the conditioned-fear paradigm in rodents, which we used to understand panic disorder (1), largely because the interactional nature of the disorder is less amenable to laboratory study. Nevertheless, we review three nonhuman primate models that seem particularly relevant.
Subordination Stress Model
Like man, primates are particularly dependent on social relationships, and laboratory-based behavioral observations can be readily conducted. Shively (2) conducted informative nonhuman primate studies in social subordination and dominance in laboratory-housed female cynomolgus monkeys. Behavioral observations revealed that subordinates spent more time alone, fearfully scanning their social environment, than dominants. Biological studies of these subordinates revealed evidence of hyperactive hypothalamic-pituitary-adrenal (HPA) axis activity, impaired serotonergic functioning, and impaired dopaminergic neurotransmission. In a challenge study with ACTH, social subordinates hypersecreted cortisol, reflecting HPA axis activation. When investigators carried out the fenfluramine challenge test (which causes release of serotonin), laboratory-housed cynomolgus macaques exhibited a blunted prolactin response, which suggests reduced central serotonergic activity. These monkeys were more socially withdrawn and spent less time in passive body contact than those who showed a high prolactin response (3). When investigators carried out a haloperidol challenge test with a dopamine antagonist that enhances prolactin secretion through tubero-infundibular dopamine pathways, reduced prolactin responses were observed in subordinates (2). This result suggested a lowering of the sensitivity of postsynaptic dopamine receptors in this pathway in the subordinates. Consistent with the neuroendocrine data, a positron emission tomography (PET) study (4) of subordinates showed decreased striatal dopamine D2 receptor binding, which suggests abnormal central dopaminergic neurotransmission, a finding that mimics the results of a single photon emission computerized tomography (SPECT) study (5) in humans with social anxiety disorder.
Studies of socially subordinate baboons in the wild have revealed other neuroendocrine abnormalities that mimic findings in certain anxious and depressed human subjects. Hypercortisolemia, as well as resistance to feedback inhibition by dexamethasone, was reported by Sapolsky et al. (6) in baboons. Another interesting finding is that subordinate male baboons have lower insulin-like growth factor I levels than dominants (7). This finding might explain the observed association between short stature and social anxiety disorder found in one study (8).
There are several important limitations of this model as it applies to patients with social anxiety disorder. First, there is no evidence of an HPA axis disturbance in social anxiety disorder as measured by the degree of dexamethasone nonsuppression (9). Second, the prolactin response to fenfluramine differs in subordinate models versus patients with social anxiety disorder (10). Another important limitation of this and the other animal models is that humans with social anxiety disorder tend to be "hard wired" to act avoidant, submissive, and anxious in social settings, whereas nonhuman primates, because of environmental manipulations in dominance and submission, display a certain plasticity in response to environmental stresses. For example, dominant vervet monkeys have higher blood serotonin levels than subordinates, but their serotonin levels significantly decrease when they are removed from the group (11). Thus, it appears that the major correlative finding in the primate subordination stress model with social anxiety disorder is striatal dopaminergic dysfunction. Whether this dysfunction is a byproduct of social stress or a feature of social subordinance per se is not clear.
Variable-Foraging-Demand Model
Another model of potential use is the variable-foraging-demand model in nonhuman primates. Rosenblum and Paully (12) developed this model for social timidity and nonassertiveness by exposing nursing mothers to unpredictable foraging-demand conditions and experimentally inducing unstable attachment patterns to their infants. Grown animals raised under variable-foraging-demand conditions, in comparison to predictably reared comparison subjects, showed stable increases in levels of social timidity—e.g., social subordination, avoidance of antagonistic encounters—and decreased species-typical huddling, in comparison to predictably reared comparison subjects (13). From a biological standpoint, subjects reared under the variable-foraging-demand model exhibited longstanding increases in levels of CSF corticotropin-releasing factor (CRF) (14), the dopamine metabolite homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Only in subjects reared under the variable-foraging-demand model did CRF levels correlate positively with HVA and 5-HIAA levels, which suggests a functional linkage between CRF level and both dopaminergic and serotonergic systems (15). Moreover, within the variable-foraging-demand group, relative increases in CRF levels were correlated with relative reductions in growth hormone (GH) response to the 
2 adrenergic agonist clonidine (16), as well as exaggerated anxiety responses to yohimbine, an 2 antagonist (17).
Neurochemically, what appeared to be most relevant for social anxiety disorder is the finding of altered dopaminergic metabolites in CSF in primates reared under the variable-foraging-demand condition, which parallels the numerous dopaminergic abnormalities observed in patients with social anxiety disorder. Behaviorally, the primates reared under the variable-foraging-demand condition resembled what Kagan et al. (18) described in a group of young children who manifested characteristics of "behavioral inhibition to the unfamiliar." These children exhibited an exaggerated heart rate acceleration to stress, high early-morning salivary cortisol levels, and levels of behavioral inhibition correlated with high total norepinephrine activity. Thus, the variable-foraging-demand model is useful in its suggestion that early environmental stress, particularly of an affective nature, may shift behavior and neurobiology toward a trait-like socially anxious profile. Clinically, however, the neuroendocrine findings of dissociation between increased CRF levels and decreased cortisol levels most closely resembled the profile of patients with posttraumatic stress disorder (PTSD) (19, 20).
Animal Attachment Models
Historically, deficits in attachment behavior have been most closely associated conceptually with autistic disorders and schizoid personality disorders. In fact, an often-noted clinical distinction between patients with social anxiety disorder and those with autism and schizoid personality disorder is in the degree of desire for relatedness and attachment to others. Because patients with social anxiety disorder (and its closely related axis II variant avoidant personality disorder) have been generally regarded as persons who desire connections and attachments with others but are fearful of the negative consequences of such interactions, whereas autistic and schizoid persons generally do not desire these attachments and lack affiliative behaviors, attachment models have not been considered important in understanding social anxiety disorder. However, emerging genetic links between autism and social anxiety disorder suggest a reexamination of attachment neurobiology. For example, Smalley et al. (21) found that the first-degree relatives of autistic probands had an increase in social anxiety disorder relative to comparison subjects. A recent study (22) showed that the parents of autistic probands had significantly higher rates of social phobia than the parents of Down’s syndrome probands, although there was no evidence of an association within individuals between social anxiety disorder and the broad autism phenotype (defined as milder aspects of autism, including social and communication deficits and stereotypical repetitive behaviors). These studies point to a shared biology of attachment, which makes the neurobiology of animal attachment potentially more relevant to social anxiety disorder than previously acknowledged.
Numerous neurotransmitter systems have been investigated clinically in subjects with autism and preclinically in primate models of attachment and affiliation. Raleigh and colleagues (23) showed that enhancement of serotonergic function resulted in improved social affiliativeness in primates, whereas low serotonin levels promoted avoidance. In separate but related work, free-ranging primates with low levels of CSF 5-HIAA showed less social competence and were more likely to emigrate at a younger age from their social groups than primates with higher levels of CSF 5-HIAA (24).
The brain opioid system was the first neurochemical system to be implicated as a regulator of attachment behaviors in primates and other species. In one study of nonhuman primates (25), 10 juvenile macaques living in a stable social group with their mothers and other group companion subjects were administered naloxone, an opiate antagonist. The primates receiving naloxone made more grooming solicitations and received more grooming and increased their proximity with their mothers. Kalin et al. (26) studied reunions of nonhuman primate infants after separations from their mothers and demonstrated that both infants and mothers who were administered morphine showed a significant reduction in clinging behaviors, whereas those given naltrexone increased their clinging. Finally, there was evidence of complex interrelationships between endogenous opioid activity and other affiliative neurotransmitter systems, as it was suggested that opiate activity was increased by oxytocin injections in the rat (27). Clinically, there is some evidence that opioid abusers have high rates of social avoidance and anxiety (28).
The neurohormone oxytocin is well established in the initiation but not the maintenance of maternal behavior and pair bonding (29), as well as in social interactions in nonhuman primates (30). Recent data from Insel and Winslow (29) demonstrated that a genetically engineered mouse lacking oxytocin emitted few isolation calls and had reduced social interactions. They hypothesized that the neural substrates of attachment are "those pathways which couple social recognition (olfactory, auditory, and visual stimuli) to the neural pathways for reinforcement, such as the [dopaminergic] mesolimbic projections from the ventral tegmental area to the nucleus accumbens and prefrontal cortex" (p. 888). It is known that dopaminergic neurotransmission is implicated in brain reward pathway projections. Social anxiety disorder, as Stein (31) suggested, might therefore be an illness "characterized by dysfunction within the system(s) that evaluate(s) the risks and benefits of social affiliation" (p. 1280) by employment of brain reward pathways. Anatomically, many of these disparate attachment pathways traverse the anterior cingulate, a region recently implicated by functional magnetic resonance imaging (fMRI) in an aspect of the human maternal-infant bond: the response to infant cries (32). In summary, animal attachment models implicate not only oxytocin, but varied serotonergic, opioid, and dopaminergic pathways.
Although they are incomplete in explaining the varied cognitive misappraisals observed in patients with social anxiety disorder, preclinical attachment models provide a useful construct for understanding the aberrant social affiliativeness seen in subjects with social anxiety disorder and provide guides for future investigations of the clinical neurobiology of the disorder. Unfortunately, the amount of replicated data in primate attachment neurobiology is extremely sparse, particularly in neuroimaging. Thus, the direct applicability of these animal models to social anxiety disorder is necessarily limited at this time. (See Table 1 for a summary of preclinical models of social anxiety disorder.)
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