Intravenous cocaine self-administration in a panel of inbred mouse strains differing in acute locomotor sensitivity to cocaine

Abstract

We conclude that acute cocaine-induced locomotor activation does predict self-administration behavior, but in a strain-specific manner. These data support the idea that genetic background influences the relationship among addiction-related behaviors.

Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

“…In acquisition sessions, mice progressively learned active vs. inactive lever discrimination and selfadministered drugs paired with a cue light on FR1, FR2, and FR4 schedules. The extent of self-administration during this training period was consistent with publications for the dose, time frame and reinforcement requirements in mice for cocaine [16,26] and remifentanil [50]. The observed increase in total response output with increased response requirement is a hallmark of drug selfadministration across species and drug class [34], and it was not observed in mice given access to saline vehicle rather than cocaine or remifentanil.…”

“…For factor loadings, see Table S7. As documented in multiple species, including mice [17,33], lever responding in our paradigm decreased with successive extinction sessions in a manner that was best fit by a two-phase model: rapidly at first (i.e., sessions 1-4) and then more slowly (i.e., sessions [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. At the time mice met final extinction criterion, active lever responding was not only reduced, but active vs. inactive lever discrimination was lost for cocaine and it was significantly reduced for remifentanil.…”

“…Advances in materials, surgical techniques, and operant protocols have, however, recently led to unprecedented success in mouse self-administration approaches. While studies utilizing genetic techniques and evaluating genetically modified mice are becoming more prevalent [14][15][16][17][18][19][20], self-administration in mice continues to be plagued by a low rate of study completion (e.g., 20-30% of trained mice), limited data collection (e.g., evaluation of a single drug dose on a single delivery schedule), and abbreviated study length [16,21,22].…”

Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains

“…Studying panels of genetically diverse inbred mouse strains is a powerful method for probing genetic and environmental variance that contribute to complex behaviors. We previously examined initial locomotor sensitivity in response to acute COC administration in 45 inbred mouse strains, and observed significant phenotypic variation across strains that could be partially (~50%) attributed to genetics 11,17 . Brain concentrations of COC and norcocaine (NOR) were heritable, varied across strains and were significantly correlated with locomotor activation 11 .…”

“…In the current study, we characterized the PK of COC, its active metabolite, NOR and major inactive metabolite, benzoylecgonine (BZE), at four different doses and five‐time points across a set of six inbred mouse strains that previously showed either high‐ or low‐locomotor response to acute COC 11,17 . Our experimental design allows us to more fully investigate the relationship between genetic background, PK and behavior.…”