The rat maternal deprivation model has been suggested to constitute a valid model of early life stress in humans. In different separation paradigms, rat pups are subjected to various intervals of separation from their mothers during the first 2–3 weeks after birth. Maternally de- prived rats may be compared with so-called handled rats, which are subjected to daily handling during the same period, or with facility-reared animals. As adults, maternally deprived rats show several signs of increased anxiety, including decreased exploration in a novel open field, increased defensive withdrawal behavior, increased novelty-induced suppression of feeding, increased startle response, and a distinct preference for alcohol, cocaine, and morphine, compared with handled rats (Caldji et al. 2000; Moffett et al. 2007). Maternally deprived rats also show an enhanced neuroendocrine response to an acute psychological, but not somatic, stressor, as evidenced by a larger rise in plasma ACTH and corticosterone con- centrations than in nondeprived rats (Ladd et al. 2000).
The hyperresponsiveness to stress may be related to the observed hypersecretion of hypothalamic CRF, coupled with the decrease in glucocorticoid receptor binding and expression in the hippocampus and medial prefrontal cortex, in maternally deprived rats. Moreover, changes in extrahypothalamic CRF systems have been observed in maternally deprived rats. Notably, CRF binding sites are increased in both the dorsal raphe nucleus, the major site of origin of the widespread serotonergic innervation of the forebrain, and the LC, the origin of the nor- adrenergic innervation. In addition, maternally deprived rats show an increased release of hypothalamic nor- epinephrine in response to restraint stress and decreased α2-adrenoceptor binding in the LC, compared with handled rats. These findings are of particular interest in view of the possible involvement of these monoaminer- gic pathways in the pathogenesis of human anxiety. De- creased binding of GABAA receptors and reduced ben- zodiazepine binding sites also have been found in several different brain regions, including the LC, in maternally deprived rats, which may contribute to the increased anxiety observed in such animals. In the central nucleus of the amygdala, a brain region presumably involved in fear and anxiety, benzodiazepine binding sites are de- creased and CRF mRNA expression is increased in ma- ternally deprived rats (Caldji et al. 2000; Ladd et al. 2000). The effects of benzodiazepines have not yet been studied in maternally deprived rats. However, chronic treatment with the SSRI paroxetine, effective in the treatment of several anxiety disorders, almost completely normalizes stress-induced neuroendocrine hyperrespon- siveness, reduces anxiety behaviors in the elevated plus- maze test and the defensive withdrawal test, and reduces alcohol preference in such animals (Ladd et al. 2000; Moffett et al. 2007; Plotsky et al. 2005).
Although study of negative early life experiences is much more widespread, good maternal care has also been shown to have a profound and long-lasting effect on anxiety state. As would be expected, many of the characteristics of maternally deprived animals are re- versed in animals exposed to an exceptionally high level of maternal attention (e.g., decreased stress responsivity and increased negative feedback of the HPA axis [Champagne and Meaney 2001]).
Conclusion
Our purpose in this chapter was to present a selection of different types of animal models of anxiety (i.e., condi- tioned models, ethologically based models, genetic models, and etiologically based models). Overall, it is clear that the different types of animal models can serve various purposes to increase our understanding of anxi- ety disorders. Because human anxiety disorders are be- lieved to result from genetic and environmental factors (one such factor being adverse early life experiences), and such disorders are often chronic in nature, the ge- netically and etiologically based models in which the an- imals showed permanently increased anxiety may serve as better models to study the pathophysiology of anxiety disorders than the conditioned and ethologically based models. However, a more complete pharmacological validation is needed for the genetic and etiologically based models, because the effects of only a few of the clinically effective anxiolytic drugs have been studied. Further, the conditioned and ethologically based models are important tools for studying “state” anxiety, and these paradigms are necessary to evaluate the level of anxiety of animals in the genetic and etiologically based models. Whether the inconsistent results of chronic treatment with partial 5-HT1A receptor agonists and various antidepressants in these anxiety models are due to pharmacological factors, confounding factors, species differences, or the fact that the models do not really model human anxiety remains to be elucidated.
Interestingly, in the genetic models of anxiety, the animals showing high levels of anxiety respond with helpless behavior in certain situations, suggesting that these animals may also be at increased risk to develop depression. Moreover, because adverse early life experi- ence is associated with increased risk for developing de- pression in humans, the etiologically based animal models have also been used to study the pathophysiol- ogy of depression. The results parallel observations made in studies of humans, in whom comorbid anxiety disorders and depression are common. The findings suggest that the genetic and etiologically based models may also be valid models for studying mixed anxiety- depression in animals.
Key Clinical Points
• When considering the clinical impact of the information presented in this chap- ter, it is important to first note that animal models must be considered to merely mimic many behaviors associated with anxiety, rather than to present a true anx- iety syndrome. The key characteristic of generalized anxiety disorder—excessive worry—is something that cannot be measured in a nonhuman, even if one were to argue for its existence.
• Most animal models of anxiety were developed (and are currently utilized) as screening tests for anxiolytic properties of drugs.
Implications for pharmacotherapy: Drugs that decrease what we call “anxious
characteristics” in animals are likely to decrease the severity of anxiety disorders in patients.
• Models derived from genetic manipulations and models derived from environ- mental manipulations can display very similar behavioral phenotypes, suggest- ing that the pathogenesis of clinical anxiety disorders may likewise be either ge- netic or environmental (or, more likely, a combination of both).
Implications for genetics-based interventions: As new anxiety-related genes
are identified, new treatments can be developed to target the specific products of these genes in preclinical models. Likewise, polymorphisms identified in clin- ical populations can be explored by using transgenic mouse models.
Implications for environment-based interventions: The prevalence of early life
stress in anxiety models suggests that a clinical emphasis on preventative mea- sures in children at risk for developing anxiety would be appropriate.
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