Novel animal models of affective disorders.

Is there an appropriate animal model for human affective disorders? The traditional difficulties in accepting animal models for psychopathology stem from the argument that there is no evidence for concluding that what occurs in the brain of the animal is equivalent to what occurs in the brain of a human. However, if one models any or some core aspects of affective disorder, this model can become an invaluable tool in the analysis of the multitude of causes, genetic, environmental, or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Animal models can also allow the study of the mechanisms of specific behaviors, their pathophysiology, and can aid in developing and predicting therapeutic responses to pharmacologic agents. Although animals exhibit complex and varied social and emotional behaviors for which well-validated and standardized measures exist, an understanding that a precise replica of human affective disorders cannot be expected in a single animal model is crucial. Instead, a good animal model of a human disorder should fulfill as many of the four main criteria as possible: (1) strong behavioral similarities, (2) common cause, (3) similar pathophysiology, and (4) common treatment. An animal model fulfilling any or most of these criteria can be used to elucidate the mechanisms of the specific aspect of the model that is homologous to the human disorder. A wide range of animal models of affective disorders, primarily depression, has been developed to date. They include models in which "depressive behavior" is the result of genetic selection or manipulation, environmental stressors during development or in adulthood, or pharmacologic treatments. The assessment of these animal models is based either on behavioral tests measuring traits that are homologous to symptoms of the human disorder they model, or behavioral tests responsive to appropriate pharmacologic treatments. The goal of this review is to focus on relatively recent developments of selected models, to aid in understanding their strengths and weaknesses, and to help those choosing the difficult task of developing novel animal models of affective disorders. The ideal animal model of affective disorders of the future would be an endogenous, genetic model that reiterates the essential, core aspects of the human disease and responds to the standard regimens of therapy. Because complex diseases have been approached from the genetic startpoint by using rodent models, a genetic model of affective disorder would open up possibilities for genetic analysis of polygenic traits that seem to underlie these disorders.

[3H]Rauwolscine: an antagonist radioligand for the cloned human 5-hydroxytryptamine2b (5-HT2B) receptor.

In previous reports, [3H]5-HT has been used to characterize the pharmacology of the rat and human 5-HT2B receptors. 5-HT, the native agonist for the 5-HT2B receptor, has a limitation in its usefulness as a radioligand since it is difficult to study the agonist low-affinity state of a G protein-coupled receptor using an agonist radioligand. When using [3H]5-HT as a radioligand, rauwolscine was determined to have relatively high affinity for the human receptor (Ki human = 14.3+/-1.2 nM, compared to Ki rat = 35.8+/-3.8 nM). Since no known high affinity antagonist was available as a radioligand, these studies were performed to characterize [3H]rauwolscine as a radioligand for the cloned human 5-HT2B receptor expressed in AV12 cells. When [3H]rauwolscine was initially tested for its usefulness as a radioligand, complex competition curves were obtained. After testing several alpha2-adrenergic ligands, it was determined that there was a component of [3H]rauwolscine binding in the AV12 cell that was due to the presence of an endogenous alpha2-adrenergic receptor. The alpha2-adrenergic ligand efaroxan was found to block [3H]rauwolscine binding to the alpha2-adrenergic receptor without significantly affecting binding to the 5-HT2B receptor and was therefore included in all subsequent studies. In saturation studies at 37 degrees C, [3H]rauwolscine labeled a single population of binding sites, Kd = 3.75+/-0.23 nM. In simultaneous experiments using identical tissue samples, [3H]rauwolscine labeled 783+/-10 fmol of 5-HT2B receptors/mg of protein, as compared to 733+/-14 fmol of 5-HT2B receptors/mg of protein for [3H]5-HT binding. At 0 degrees C, where the conditions for [3H]5-HT binding should label mostly the agonist high affinity state of the human 5-HT2B receptor, [3H]rauwolscine (Bmax = 951+/-136 fmol/mg), again labeled significantly more receptors than [3H]5-HT (Bmax = 615+/-34 fmol/mg). The affinity of [3H]rauwolscine for the human 5-HT2B receptor at 0 degrees C did not change, Kd = 4.93+/-1.27 nM, while that for [3H]5-HT increased greatly (Kd at 37 degrees C = 7.76+/-1.06 nM; Kd at 0 degrees C = 0.0735+/-0.0081 nM). When using [3H]rauwolscine as the radioligand, competition curves for antagonist structures modeled to a single binding site, while agonist competition typically resulted in curves that best fit a two site binding model. In addition, many of the compounds with antagonist structures displayed higher affinity for the 5-HT2B receptor when [3H]rauwolscine was the radioligand. Typically, approximately 85% of [3H]rauwolscine binding was specific binding. These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. This should provide a good tool for the study of both the agonist high- and low-affinity states of the human cloned 5-HT2B receptor.