Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice - PubMed (original) (raw)

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice

W C Griffin 3rd et al. Pharmacol Biochem Behav. 2007 Jun-Jul.

Abstract

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion). Mice trained to lever respond for IV cocaine were given the drug initially on an FR2 schedule and then on a Progressive Ratio 2(PR2) schedule. Hierarchical linear modeling (HLM) techniques were used to examine data generated across four FR2 and four PR2 sessions, as well as within session data when cocaine was delivered on the PR2 schedule. HLM techniques, although uncommon in the animal literature, characterize individual differences in human studies and are likely to be useful in more complex preclinical studies. Analysis established distinct patterns of self-administration both across and within sessions. Responses for cocaine delivered on the FR2 schedule was dose-dependent, but did not differ according to sex. Response output was greater when either dose of cocaine was delivered on the PR2 than the FR2 schedule. Although response output for the more rewarding 1 mg/kg unit dose was similar for the two sexes, males responded more and had greater cocaine intake than females when the less reinforcing 0.3 mg/kg dose was delivered at the more behaviorally challenging PR2 schedule. HLM analysis of response patterns and cocaine intake within the PR2 sessions corroborated this sex difference and also indicated that trajectories differed for individual mice after accounting for the sex and dose factors. The reduced response output by females for cocaine in the present experiment is consistent with previous reports that sex differences in the rewarding effects of either alcohol or food reinforcement were revealed for C57 mice only when delivered on more behaviorally demanding schedules (e.g. PR2 or FR100).

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Figures

Figure 1

Responding for intravenous cocaine delivered on an FR 2 schedule of reinforcement. Open squares and open circles, respectively, represent females and males responding for the 0.3 mg/kg unit dose. Closed squares and closed circles, respectively, represent females and males responding for the 1mg/kg unit dose. (A) The mean ± S.E.M. across sessions for the 4 groups of mice. (B) The predicted values from the 2 level hierarchical model for lever pressing across the 4 sessions by the same mice summarized in Panel A. The hierachical analysis indicated that responding was dose-dependent but did not vary according to sex.

Figure 2

Responding for cocaine delivered on a behaviorally demanding PR2 schedule for the same 4 groups of mice shown in Figure 1. Symbols are as described for Fig 1. (A) The mean ± S.E.M. across 4 sessions on PR2 was elevated in comparison to response output on the FR2 schedule. (B) The 2 level hierarchical model predicted values for lever pressing across sessions for the same mice. The analysis indicated that responses for the 0.3 mg/kg unit dose of cocaine were greater for male than for female mice and responses where similar between the sexes for the 1 mg/kg cocaine unit dose.

Figure 3

Behavioral trajectories across the four sessions for indiviudal mice during the PR2 reinforcement sessions. Curves represent trajectories of individual subjects, grouped according to Sex and Dose. Individual mice had distinct trajectories of lever pressing behavior across sessions while maintained on the PR2 schedule of reinforcement, even after accounting for Sex and Dose.

Figure 4

Within-session lever presses compared to the predicted values derived from the 3 level hierarchical model for 2 representative mice to illustrate the relationship of predicted to actual responses. Open squares are active lever presses and the smoothed dark lines are the responses predicted by the model. (A) A female mouse responding for the 0.3 mg/kg unit dose of cocaine during session 1. (B) A male mouse responding for the 1 mg/kg unit dose of cocaine during session 4. The response estimates accurately represent the behavioral trajectory of each mouse.

Figure 5

Within and across session predicated values (Right panels, A-D) and corresponding cocaine intake estimates (Left panels, E-H) derived from the 3 level hierarchical model for the first four PR2 sessions. (A,E) Males responding for the 0.3 mg/kg unit dose show dynamic changes both within and across sessions, but despite high local rates of responding during the early and middle portions of the sessions, cocaine intake declined because high response rates were not maintained. (B,F) Females responding for the 0.3 mg/kg unit dose generally showed stable responding across and within sessions, but because of the increasing ratio requirements of the PR2 schedule, steady cocaine intake was not maintained. (C,G) Responding for the 1mg/kg unit dose increased steadily within session for males and females, suggesting this dose was more reinforcing than the lower dose. (D,H) In contrast to the the low dose, the steady increases in responding for the high dose within sessions lead to relatively stable periods of intake during the middle of the session. Session symbols are: formula image

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Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice - PubMed (original) (raw)