Figure 4

<p>Influence of nicotine dose on nicotine self-administration and total nicotine intake per session under the FR 10 schedule. Number of fixed ratios completed on the active and inactive levers per session (A) and total nicotine intake per session (B) are presented as a function of injection dose of nicotine (n = 5). Each <i>symbol</i> represents the mean (±SEM) of at least three sessions under each nicotine injection dose condition *<i>P</i><0.05, **<i>P</i><0.01 post-hoc comparisons with the saline vehicle (0 µg/kg per injection) conditions.</p

Figure 1

<p>A. Monkeys sat in chambers equipped with two levers and distinctly colored light stimuli above the levers. Completion of the response requirement (the ratio) on the active lever produced a brief two-sec presentation of a light stimulus and an intravenous injection of nicotine followed by a timeout (TO) period of 5 to 60 sec. Completion of the ratio requirement on the inactive lever resulted in presentation of a brief two-sec light stimulus of a different color but no injection. The fixed-ratio (FR) response requirement was gradually increased over successive sessions from one to ten (FR 1 to FR 10). B. Mean percentage choice for responding on the active lever by monkeys when they were experimentally naive (first week under a FR 1 schedule) and when they had learned to self-administer nicotine under the FR 10, TO 60 sec schedule (first week under the FR 10 schedule). *<i>P</i><0.01, compared to first week of training.</p

Figure 5

<p>Influence of nicotine dose on nicotine self-administration and total nicotine intake per session under the progressive-ratio schedule. Number of nicotine injections per session and corresponding breaking-point values (highest ratio completed) under the progressive-ratio schedule (A) and total nicotine intake per session (B) are presented as a function of injection dose of nicotine (n = 5). Each <i>symbol</i> represents the mean (±SEM) of at least three sessions under each nicotine injection dose condition *<i>P</i><0.05, **<i>P</i><0.01 post-hoc comparisons with saline vehicle (0 µg/kg per injection) conditions.</p

Figure 2

<p>Maintenance of self-administration behavior under the FR 10 schedule during the first experience with saline substitution. Mean number (±SEM) of ratios completed on the active lever during three consecutive session with access to nicotine followed by an additional three sessions with saline substituted for nicotine are shown. The brief 2-sec light stimuli were presented following each ratio completion during both the nicotine and saline sessions. Self-administration behavior was not reduced by the substitution of saline injections for nicotine injections during this first exposure to extinction conditions.</p

Summary of previous studies evaluating intravenous nicotine self-administration behavior in non-human primates.

<p>Summary of previous studies evaluating intravenous nicotine self-administration behavior in non-human primates.</p

Figure 3

<p>Maintenance, extinction and reacquisition of self-administration behavior over consecutive sessions under the FR 10 schedule of reinforcement. Numbers of injections per session during consecutive nicotine (10 µg/kg per injection, filled symbols) and saline self-administration sessions (open symbols) are presented. <i>Symbols</i> represent the mean (±SEM) number of ratios completed on the active (circle) or inactive (triangle) levers per session from five squirrel monkeys. *<i>P</i><0.05, compared to nicotine sessions.</p

Effect of AM630 on nicotine self administration under FR5 and PR schedules of reinforcement.

<p><b>A</b>. Effects of pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP, H 30) on nicotine (30 µg/kg/infusion) self administration under the FR5 schedule. Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 60-min session. AM630 did not affect responding vs. vehicle (0 mg/kg) pretreatment (N = 12); P = 0.67. <b>B</b>. Effects of pretreatment with AM630 (5 mg/kg, IP) on nicotine (30 ug/kg/infusion) self administration under PR schedule. <b>A</b>, Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 4-hr sessions. AM630 did not affect break point P>0.05 vs. vehicle (0 mg/kg) pretreatment. (N = 7) P = 0.73.</p

Effects of AM630 on reinstatement of nicotine-seeking behavior induced by presentation of nicotine associated cues and by Nicotine priming.

<p><b>A</b>. Effects of pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP H 30 min) on cue-induced reinstatement of nicotine-seeking behavior. A significant reinstatement of nicotine-seeking behavior was produced by presentation of nicotine-associated cues alone (* P<0.001). ANOVA showed that pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP, H 30 min) did not modify cue induced reinstatement of nicotine-seeking behavior compared to vehicle (0 mg/kg) pretreatment (P>0.05). Data are expressed as means (±SEM) of the number of active and inactive lever presses during extinction (Ext); vehicle (0 mg/kg) pre-treatment and after pretreatment with AM630 (1.25, 2.5 and 5 mg). <b>B</b>. A significant reinstatement of nicotine-seeking was also produced by pretreatment with nicotine (0.15 mg/kg) (* P<0.001). ANOVA showed that AM630 (1.25, 2.5, 5 mg/kg, IP, H 30 min) did not modify reinstatement of nicotine-seeking behavior induced by a priming injection of 0.15 mg/kg nicotine administered 1 min before the session (P>0.05). Data are expressed as means (±SEM) of the number of active and inactive lever presses during extinction (Ext); vehicle (0 mg/kg) pre-treatment and after pretreatment with AM630 (1.25, 2.5 and 5 mg).</p

Pattern of respondinng during acquisition and extinction phases.

<p>A. Acquisition of nicotine self-administration (30 µg/kg/infusion). The total number of active (•) and inactive(▪) lever presses (means ± SEM) received in each session (during time in and time out periods) under the different schedules of reinforcement (FR- 1, FR-2, FR-5,). B. Number of nicotine infusions (means ± SEM) earned during acquisition phase in the same group of animals represented as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029900#pone-0029900-g001" target="_blank">fig. 1A</a>. C. The number of active (•) and inactive(▪) lever presses (means ± SEM) received in each extinction session in the same group of animals represented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029900#pone-0029900-g001" target="_blank">figures 1A & 1B</a>.</p

Effects of AM1241 on nicotine self-administration under FR5 and PR schedules of reinforcement.

<p><b>A</b>. Effects of pretreatment with AM1241 (1, 3 and 10 mg/kg, IP H 30) on nicotine (30 µg/kg/infusion) self-administration under the FR5 schedule. Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 60-min session. All doses of AM1241 did not affect responding vs. vehicle (0 mg/kg) pretreatment (N = 10); P = 0.35. <b>B</b>. Effects of pretreatment with AM1241 (1, 3 and 10 mg/kg) on nicotine (30 ug/kg/infusion) self- administration under PR schedule. <b>A</b>, Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 4-hr sessions. AM1241 did not affect break point P>0.05 compared to vehicle (0 mg/kg) pretreatment. (N = 8) P = 0.89.</p