Behavioral and Neurochemical Studies in Diazepam-Sensitive and Resistant Mice

Abstract

Benzodiazepine (BZ) effects include anxiolyis, sedation, seizure protection, and muscle relaxation; the mechanisms underlying these various effects are not understood. We have recently used the rotarod test in conjunction with selective breeding techniques to develop lines of mice which are diazepam-sensitive (DS) and diazepam-resistant (DR). We review the general methods of selective breeding, along with a description of the DS/DR selection study, and then describe a variety of behavioral and neurochemical studies which have been conducted in an attempt to characterize these mice. We have investigated the effects of other sedative drugs believed to interact with the BZ receptor, including ethanol, pentobarbital, and phenobarbital. We have also tested these mice for seizure threshold and open-field activity. DS and DR mice do not differ in diazepam-induced seizure protection, suggesting that different mechanisms underlie rotarod performance and the anti-convulsant effect. These results provide evidence to support the search for nonsedating anti-convulsants. To determine the neurochemical basis for observed differences, BZ receptor density and chloride flux have been measured. We discuss the interaction between behavioral and neurochemical approaches, and describe a conceptual framework to guide future studies with these unique new animals.

Mice behavioral phenotype changes after administration of Anani (Symphonia globulifera, clusiaceae), an alternative Latin American and African medicine

“…The lack of differences between the blank group and the vehicle group indicates that the saline injection did not influence our results. The positive control group confirms the quality of our model because the data are in according to the previous results[ 43 ] observed in the literature.…”

Selective breeding for negative contrast in consummatory behavior.

“…Thus, the data suggest that insensitivity to at least some of the effects of benzodiazepines may be coselected when breeding for psychological properties, but the logic of these effects is elusive. It has been demonstrated that insensitivity (and sensitivity) to at least one benzodiazepine, diazepam, can itself be selectively bred for in mice (Gallaher & Gionet, 1988; Gallaher, Gionet, & Feller, 1991; Gallaher, Hollister, Gionet, & Crabbe, 1987). The diazepam-resistant mice were also more resistant to sedative effects of ethanol, phenobarbital, lorazepam, and alprazolam than the diazepam-sensitive mice.…”

Contribution of α1 subunit-containing γ-aminobutyric acidA (GABAA) receptors to motor-impairing effects of benzodiazepines in squirrel monkeys

“…Therefore, understanding the GABA A receptor mechanisms underlying specific motor-impairing effects such as ataxia and myorelaxation would clearly benefit drug discovery efforts geared toward anxiolytic development. In rodents, BZ-induced ataxia is often measured using the rotarod test (Gallaher et al 1991; Griebel et al 1999b), while the myorelaxant effects of BZs are typically assessed using a test of grip strength (Griebel et al 1999a; Crestani et al 2001; Bach-Rojecky and Samarzija 2005). In non-human primates, observational procedures have been used to evaluate the effects of BZs on these measures.…”