Conditioned place preference after single doses or “binge” cocaine in C57BL/6J and 129/J mice
Introduction
Cocaine is a commonly abused stimulant drug that produces conditioned place preference and locomotor activity in rodents. The mesolimbic dopamine systems are postulated to be involved in rewarding and locomotor stimulating effects of cocaine, since both effects have been shown to be blocked either by lesions of the nucleus accumbens or by systemic administrations of D1 dopamine receptor antagonists Kelley et al., 1980, Kalivas et al., 1983, Shippenberg and Herz, 1987, Cervo and Samanin, 1995, Pruitt et al., 1995.
Substrains of C57BL and 129 mice are among the most commonly used background strains in the production of transgenic mice. Several studies report that substrains of C57BL and 129 mice differ significantly in their behavioral response to cocaine Miner, 1997, Schlussman et al., 1998. C57BL/6J mice were found to develop conditioned place preference to environments associated with cocaine Seale and Carney, 1991, Miner, 1997, Cunningham et al., 1999, whereas129/SvJ mice did not (Miner, 1997). Kuzmin and Johansson (2000) found that C57BL/6J mice self-administered cocaine, but 129/OlaHsd mice did not. Both strains have been found to show hyperlocomotor activity in response to a single injection of cocaine Womer et al., 1994, Miner, 1997, Kuzmin et al., 2000. However, we found that C57BL/6J mice show significant increases in both locomotor activity and stereotypic behavior in response to acute “binge” pattern cocaine administration, while 129/J mice show only increases in stereotypic behavior following acute “binge” pattern cocaine administration, and the amount of stereotypy was significantly lower than that of the C57BL/6J mice (Schlussman et al., 1998).
The behavioral and neurochemical responses to “binge” pattern cocaine administration, a paradigm used to mimic the abuse pattern of cocaine in humans, have been studied extensively in rodents (e.g. Branch et al., 1992, Daunais and McGinty, 1995, Daunais and McGinty, 1996, Maisonneuve and Kreek, 1994, Unterwald et al., 1994, Maisonneuve and Kreek, 1995, Schlussman et al., 1998). However, conditioned place preference in response to “binge” pattern cocaine administration has not yet been studied.
It has been shown that different cocaine administration regimens can lead to different neurochemical outcomes. For example, single daily cocaine injections resulted in a significant increase of mu opioid receptors in the nucleus accumbens only, whereas two and three daily cocaine injections increased mu opioid receptors in the nucleus accumbens, caudate–putamen and Layer I of the rostral cingulate cortex (Unterwald et al., 2001). Thus, both the dose and pattern of administration may be crucial determinants of the effects of cocaine.
Studies using the technique of in vivo microdialysis have shown that significant increases in dopamine levels in the nucleus accumbens and caudate–putamen are induced by cocaine in both the C57BL/6J and 129 mice He and Shippenberg, 2000, Zhang et al., 2001. The reported failure of 129 mice to develop conditioned place preference with cocaine (Miner, 1997) and to show locomotor stimulating effects after cocaine (Schlussman et al., 1998) led to the systematic studies of both single doses of cocaine and “binge” cocaine-induced place preference in both strains reported below. First, we conducted a dose–response study of single daily injections of cocaine (0, 2.5, 5, 10 and 20 mg/kg) in each strain. Then, in the second study, we examined whether daily “binge” pattern cocaine (15 mg/kg ip ×3 at hourly intervals) would induce conditioned place preference in each strain.
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Animals
Male C57BL/6J and 129/J inbred mice (Jackson Laboratory) weighing 22–25 g were individually housed with free access to food and water in a light (12:12 h light/dark cycle, lights on at 7:00 AM)- and temperature (25 °C)-controlled room. All animal care and experimental procedures were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The experimental protocols were approved by the Institutional Animal Care and Use Committee of The
Results
A preliminary analysis was made for each study of the amount of time spent during the preconditioning session in the compartment that was later paired with cocaine versus the side that would be paired with saline. ANOVAs (Strain×Side) showed that in neither study was there a significant main effect of strain or side, nor was there a significant interaction effect (means±S.E.M. are shown in Table 2).
Discussion
These studies demonstrate that both C57BL/6J and 129/J mice develop conditioned place preference to cocaine. Each strain developed conditioned place preference to single injections of 5, 10 and 20 mg/kg of cocaine. In contrast, “binge” pattern cocaine administration (three injections for a total of 45 mg/kg over 2 h) produced conditioned place preference only in C57BL/6J mice, and not in 129/J mice.
The single-dose cocaine-induced conditioned place preference found in the C57 BL/6J mice in this
Acknowledgements
The authors would like to thank Campbell Stewart and Saul Kane for their assistance in performing these studies.
This work was supported by the National Institute of Health—National Institute on Drug Abuse Research Center Grant P50-05130 and DA-K05-00049 to Dr. Mary Jeanne Kreek.
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