Mouse Strain Differences in Opiate Reward Learning Are Explained by Differences in Anxiety, Not Reward or Learning

Abstract

Gene-targeting techniques to produce null mutations provide a powerful method for evaluating the contribution of particular candidate genes involved in motivation. The embryonic stem cell lines in which homologous recombination is undertaken are derived from 129 mice, but because of the impoverished performance of 129 mice on a number of behavioral tasks, mice chimeric for the mutation are often bred with a C57BL/6 mouse strain. Thus, an examination of both parental strains is important in the study of the knock-out mice. Although the C57BL/6 behavioral phenotype is well documented, details of the 129 phenotype have not been the focus of study until recently. We investigated opiate motivation in both 129/SvJ and C57BL/6J mouse strains to determine whether, and under what circumstances, the 129/SvJ mouse exhibited motivated behavior toward opiates. 129/SvJ mice required both drug and contextual cues to demonstrate morphine conditioned place preferences on test day, whereas C57BL/6J mice required only contextual cues to express opiate place conditioning. Pentobarbital and diazepam but not saline, cocaine, or naloxone could substitute for morphine on test day in 129/SvJ mice, demonstrating that morphine indeed has rewarding motivational valence in the 129/SvJ mouse strain. This critical, interoceptive cue in 129/SvJ mice on test day may be the anxiolytic properties of the effective drugs. Therefore, some deficits observed in 129 mice and mice harboring this genetic background may be attributed to high levels of anxiety during the retrieval period rather than to sensory, learning, or motivational deficits.

Heroin-induced locomotor activity and conditioned place preference in C57BL/6J and 129P3/J mice

“…This is in partial agreement with studies reporting that both C57BL/6J mice and substrains of 129 mice develop conditioned place preference and locomotor activation in response to morphine, although with significant strain differences in the response (e.g. [6,20]), and a study showing that C57BL/6J mice developed conditioned place preference to a very low dose of heroin (100 μg/kg; [31]). Interestingly, the same dose of heroin was reported to produce conditioned place aversion in 129X1/sVJ mice [31].…”

“…Strain differences in basal anxiety level may also be important determinants in the expression of conditioned place preference. 129/SvJ mice showed greater levels of anxiety-like behaviors than did C57BL/6J mice [10] and anxiety has been shown to attenuate the expression of conditioned place preference [6]. We found that during the preconditioning baseline day 129P3/J, mice spent significantly more time in the black side of the conditioning chamber than on the white side,which may indicate higher levels of basal anxiety.…”

“…Furthermore, differences in behavioral response to drugs of abuse have been reported in many strains of mice (e.g. [5,6,14,15,18,28,29,31,36]). …”

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

“…Cumulative dose-response curve studies before and after mE7M-B6 homozygous mice exhibited significantly lower preference for the drug-paired compartment than the mE7M WT control mice ( Figure 2B), suggesting that exon 7-associated variants are involved in morphine reward behavior in B6 mice. Morphine CPP in WT and homozygous 129 mice at the same dose was not robust and was not significant (Supplemental Figure 4), consistent with previous findings (36).…”

Corticotropin-Releasing Factor Receptors Couple to Multiple G-Proteins to Activate Diverse Intracellular Signaling Pathways in Mouse Hippocampus: Role in Neuronal Excitability and Associative Learning

“…Our results add to the existing data showing that the genetic background can affect the behavioral phenotypes of genetically modified mice generated for elucidating the molecular basis of learning and memory (McNamara et al, 1998;Dobkin et al, 2000;Dockstader and van der Kooy, 2001). In view of the contribution of the hippocampus to numerous forms of learning (for review, see Kesner et al, 2000;Kim and Baxter, 2001;Maren, 2001) and the fact that h/rCRF represents an early signal in the neuroendocrine response to stress (Koob and Bloom, 1985), our present findings may represent an important step toward understanding the cellular and molecular processes underlying interstrain variability concerning the impact of stress on learning and memory (Brush et al, 1988;Francis et al, 1995;Palmer and Prinz, 1999).…”