Rodent behavior models

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

The primary approach currently used to detect and characterize potential neurotoxicants involves the use of animal models, particularly rodents. Behavioral and neurophysiological tests, often similar to the ones used in humans, are typically administered. The sensitivity of these measures to neurotoxicant exposure is widely accepted. Although it is often not possible to test toxicant effects on some higher behavioral functions in animals (e.g., verbal ability, cognitive flexibility), there are other neurobehavioral outcomes such as memory loss, motivational defects, somatosensory deficits, and motor dysfunction that can be successfully modeled in rodents. These behaviors are based on the ability of the nervous system to integrate multiple inputs and outputs, thus they cannot be modeled adequately in vitro. Although the bulk of neurotoxicity data has been collected in rodents, birds and primates are also used to model human behavioral outcomes. 

Meredith GE, Kang UJ (2006) Behavioral models of Parkinson s disease in rodents a new look at an old problem. Mov Disord 21 1595-1606... 

The same strategy was applied to lactams with the hope to also increase permeability and brain penetration. Data obtained (not shown) were encouraging but the introduction of the cyclobutoxy linker in that series unfortunately significantly increased human and rodent microsomal clearances resulting in worsened PK profiles (higher clearances, higher volumes) and less consistent results in behavioral models. Efforts were, therefore, focused on cyclobutoxy fused thiazole series for which the overall properties profile seemed much more balanced. 

The NgR antibody can be covalently attached to a HA hydrogel by a hydrolytically unstable hydrazone linkage, and this modified HA hydrogel can serve as an antibody releasing system for grafting into the injured brain [39]. By use of this system in rodent stroke models, the distribution of the antibody and differentiation of neurons in the injured area can be seen, accompanied by certain behavioral recovery [40]. There has been a study by Wei and co-workers [41] showing that HA hydrogels modified with poly(L-lysine) (PLL) and... 

Taken together, this body of work demonstrates that adult behavioral responses to social odors are shaped by early olfactory experience. Indeed, heterospecific or artificial odor cues associated with the rearing environment acquire attractive properties that can last into adulthood in many rodent species. Furthermore, early experience with opposite-sex odors appears to be critical for the normal development of appropriate behavioral responses to sexual odors in mice and hamsters. Importantly, the behavioral plasticity observed using these different experimental approaches may all be mediated by a classical conditioning model of olfactory learning. The experience-dependent development of odor preference in rodents therefore provides a powerful model for understanding how the olfactory system recognizes and learns the salience of social odors, a function that is critical for the appropriate expression of reproductive behavior. 

Attentional or cognitive impairments have also been observed in rodent models of nicotine withdrawal. These include impaired performance of a test of sustained attention (Shoaib and Bizarro 2005), disrupted contextual fear conditioning (Davis and Gould 2007 Davis et al. 2005), disrupted operant behaviors (Vann et al. 2006), and decreased prepulse inhibition, a test of selective attention (Semenova et al. 2003). 

Internal validity of the rodent models involves verifying that withdrawal severity (indicated by numbers of observed behavioral changes) reflects chronic nicotine exposnre followed by termination of that exposure. The rat model involving continnons nicotine infusion has probably been the most extensively validated in this sense (Malin 2001), meeting the following validity criteria ... 

Several natural products have been evaluated in rodent models of nicotine withdrawal. An extract of Hypericum perforatum (St. John s Wort, a putative antidepressant, and inhibitor of serotonin reuptake) reversed somatically expressed withdrawal behaviors and locomotor depression in spontaneous withdrawal (Catania et al. 2003). A benzoflavone compound isolated from Passiflora incarnata, interfered with the induction of physical dependence. Coadministration with chronic nicotine prevented various subsequent indicators of withdrawal syndrome in the mouse, including jumping, locomotor inactivity, immobility in the swim test and naloxone-precipitated escape jumping (Dhawan et al. 2002). 

How rodents smell buried seeds a model based on the behavior of pesticides in soil. Journal of Mammalogy 84,1089-1099. 

Comprehensive studies based on rodent models of anxiety have not only underlined that anxiety in itself represents a complex behavioral system but also that it is determined by both genetic and environmental factors as well as by the interaction between both. The examples used in this section have been selected to illustrate both the potential and the caveats of current models and the emerging possibilities offered by gene technology. These examples are thought to be representative of the different concepts followed in generating animal models. 

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