The behavioral performance of inbred mouse strains was examined in animal models of anxiety to evaluate the potential contribution of genetic factors to fear-motivated behaviors. The preference that randomly bred mice and rats exhibit for the enclosed as opposed to the open arms of an elevated maze has been considered a fear-motivated behavior. Pronounced differences were observed in this measure among 16 inbred mouse strains. An estimate of the proportion of the variance attributable to between-strain differences, eta 2, revealed that 78% and 69% of the variance in time and number of entries in the open arms of an elevated maze, respectively, can be attributed to genetic factors. In contrast, only 27% and 42% of the variance could be attributed to between-strain differences in ambulatory activity in the open field and elevated maze, respectively. Furthermore, performance in the elevated maze was predictive of behavior in other animal models of anxiety. Thus, significant negative correlations were observed among inbred mouse strains between the percent time spent in the open arms of the elevated maze and amplitude of an acoustic startle response (rs = -0.88m P < 0.01) or latency to initiate chow consumption in a hyponeophagia paradigm (rs = -0.71, P < 0.05). These results indicate that genetic factors substantially contribute to fear motivated behaviors in these animal models of anxiety. The use of such inbred mouse strains may provide a novel approach to investigate the biochemical and genetic bases of fear.
Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires > or =2-4 weeks of treatment and a first course of therapy provides symptom relief to only 60-65% of patients. Roche and Evotec recently announced plans to develop N-methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment-resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.
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