Acute Cocaine-Induced Seizures Differential Sensitivity of Six Inbred Mouse Strains

Abstract

Mature male and female mice from six inbred stains were tested for susceptibility to behavioral seizures induced by a single injection of cocaine. Cocaine was injected ip over a range of doses (50-100 mg/kg) Animal models provide fundamental information regarding seizure mechanisms (Jobe et al. 1973;Taylor 1976;Seyfried and Glaser 1985;Golden et al. 1991Golden et al. , 1995 and studies of inbred murine strains in particular (Engstrom and Woodbury 1988;Kosobud and Crabbe 1990;Kosobud et al. 1992;Ferraro et al. 1993Ferraro et al. , 1997Frankel et al. 1995b) have yielded considerable information regarding genetic influences on seizure susceptibility. Paralleling this are studies documenting substantial genetic influences in human epilepsy Leppert et al. 1991;Weissbecker et al. 1991;Greenberg et al. 1992).Cocaine abuse is associated with multiple forms of toxicity and seizures represent a major source of cocaine-induced fatalities (Jonosson et al. 1983;Myers and Earnest 1984;Alldredge, Lowenstein et al. 1989;Choy-Kwong and Lipton 1989;Ernst and Sanders 1989;Ogunyemi et al. 1989;Schwartz 1989; Albertson 1989a, 1989b;Dhuna and Pascual-Leone 1990;Dhuna et al. 1991;Holland et al. 1992;Tseng et al. 1992) with eleven percent of substance abusers reporting seizures related to cocaine use (Washton and Tatarsky 1983). As the number of users of cocaine in the U.S.A. exceeds 1.5 million (Park 1997) it can be estimated that approximately 100,000 individuals have experienced cocaine-induced seizures.The present study represents a systematic strain investigation of acute cocaine-induced seizure sensitivity, a complex trait having genetic and environmental influences. By testing a number of mouse inbred strains for susceptibility to acute cocaine-induced seizures, this study lays the foundation for genetic mapping of specific genes involved in the expression of this complex trait. Because seizure phenomena show striking parallels between mice and humans, and because extensive NO . 3 genetic homology exists between these two species, localization of genes involved in sensitivity to cocaine induced seizures will provide an inroad for studying genetic influence in human drug abuse. The results of this study identify A/J and SJL strains of mice as sensitive to the acute seizure-inducing effect of cocaine whereas C57 mice are significantly more resistant suggesting that these strains may be particularly useful for genetic dissection of this complex trait. MATERIALS AND METHODS AnimalsMature male and female mice from six inbred strains (The Jackson Laboratory, Bar Harbor, ME) were housed by gender (5-6/cage). All mice were housed separately in the Coatesville, VA, animal facility for a least one week prior to use. Mice were tested for susceptibility to seizures induced by an acute injection of cocaine. A total of 519 mice (C57BL/6J n ϭ 124, DBA/2J n ϭ 48, BALB/ n ϭ 48, SJ/L n ϭ 141, NZW/ n ϭ 37, A/J n ϭ 121) were tested for acute cocaine-induced seizures using ip injection of 50, 60, 70, 75, 80, 90 and 100 mg/kg of cocaine HCl. So...

How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

“…Loss of function of this gene in mice induces tremors and seizures (Xie et al, 2005). It is well known that acute, high doses of several classical stimulants including amphetamines cause seizures in mice, rats, and humans (Golden et al, 2001;Hanson et al, 1999;Zagnoni and Albano, 2002). As a cautionary note we like to point out that the analyses presented here are based on microarray data, and the changes in expression for specific genes were not independently confirmed with, for example, qRT-PCR.…”

Repeated maternal separation: differences in cocaine-induced behavioral sensitization in adult male and female mice

“…Behaviorally, female rats demonstrate more robust behavioral sensitization to cocaine and faster acquisition of cocaine self-administration and conditioned place preference (Van Haaren and Meyer 1991;Lynch and Carroll 1999;Chin et al 2001;Lynch et al 2002;Hu and Becker 2003;Russo et al 2003). Murine strains do not demonstrate sex differences in the metabolism of and locomotor response to cocaine although C57BL/6 females appear to be more susceptible to cocaine-induced seizures (Morse et al 1995;Jones et al 1996;Cook et al 1998;Azar et al 1998;Golden et al 2001). In the present experiments, with the exception of maternally separated female mice, we confirm that there does not appear to be a robust sex difference in the locomotor response to cocaine.…”

“Higher order” addiction molecular genetics: Convergent data from genome-wide association in humans and mice

“…Inbred mouse strains do differ in a number of drug related phenotypes [43][44][45][46][47][48]. Many of these phenotypes have now been studied in "quantitative trait locus" paradigms.…”

“…There is thus some rationale for seeking addiction-associated variants in murine genes that have survived selection pressures on mice as potential models for common addiction-associated human variants that have also survived evolutionary selection pressures on humans. If there are a limited number of genes that can contain variants likely to influence vulnerability to addiction, not provide lethality and not provide strong negative selection, some of these genes from such a group may be more likely than a random group of genes to contain both murine strain differences and common human allelic variants that influence addiction phenotypes.Inbred mouse strains do differ in a number of drug related phenotypes [43][44][45][46][47][48]. Many of these phenotypes have now been studied in "quantitative trait locus" paradigms.…”