Escalation of cocaine intake with extended access in rats: dysregulated addiction or regulated acquisition?

Abstract

Rationale: Understanding the neurobehavioral mechanisms underlying dysregulated cocaine intake is important for the development of new cocaine abuse therapies.

Objectives: The current study determined if cocaine escalation under extended access conditions (6-h access) is regulated by discrimination learning processes.

Methods: Rats were initially trained on cocaine self-administration (0.1 or 0.25 mg/kg/infusion) using a fixed ratio 1 (FR 1) schedule under 1-h access for 12 sessions. Some rats were then trained to self-administer cocaine under 1-h or 6-h access conditions exclusively for 14 additional sessions, while other rats were trained under both 1- and 6-h access conditions that were cued or noncued for 28 additional sessions (14 sessions for each 1- and 6-h access). Two additional groups of rats were initially trained to self-administer cocaine using an FR 1 schedule under 10-min access for 12 sessions; half of the animals were then switched to 60-min access conditions for 14 additional sessions.

Results: When access conditions were differentially cued, escalation of cocaine intake was evident in animals with both 1- and 6-h access conditions during the escalation phase. Escalation also was evident in animals initially trained with 10-min access and then switched to 60-min access.

Conclusions: The results demonstrate that dysregulated and regulated intakes can be expressed within the same animal, indicating that escalation is context-dependent. Furthermore, escalated cocaine intake can be expressed under 1-h access conditions. Overall, these results suggest that escalated cocaine intake may be representative of discrimination-dependent regulated intake rather than addiction-like, compulsive intake.

Fig 1

(A) Between-subject escalation of total cocaine infusions (Mean ± SEM) at a 0.1 mg/kg/infusion unit dose for 1-hr (n = 7) and 6-hr (n = 8) access groups. Asterisk (*) represents significant difference in session infusions, relative to session 1 (p < 0.05). (B) First-hour total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for 1-hr and 6-hr access groups. Asterisk (*) represents significant differences in total infusions (p < 0.05). (C) Time course (5-min bins) for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the 1-hr access group. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05). (D) Time course for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the 6-hr access group. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05).

Fig 2

(A) Within-subject escalation of total cocaine infusions (Mean ± SEM) at a 0.1 mg/kg/infusion unit dose with differential stimulus cues for 1- and 6-hr access conditions. Asterisk (*) represents significant difference in session infusions, relative to session 1 (p < 0.05). (B) First-hour total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for differentially cued 1-hr and 6-hr access conditions. Asterisk (*) represents significant differences in total infusions (p < 0.05). (C) Time course (5-min bins) for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the cued 1-hr access condition. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05). (D) Time course for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the cued 6-hr access condition. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05). n = 7

Fig 3

(A) Within-subject escalation of total cocaine infusions (Mean ± SEM) at a 0.1 mg/kg/infusion unit dose without differential stimulus cues for 1- and 6-hr access conditions. (B) First-hour total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for non-differentially cued 1-hr and 6-hr access conditions. (C) Time course (5-min bins) for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the non-differentially cued 1-hr access condition. (D) Time course for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the non-differentially cued 6-hr access condition. n = 6.

Fig 4

(A) Within-subject escalation of total cocaine infusions (Mean ± SEM) at a 0.25 mg/kg/infusion unit dose with differential stimulus cues for 1- and 6-hr access conditions. Asterisk (*) represents significant difference in session infusions, relative to session 1 (p < 0.05). (B) First-hour total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for differentially cued 1-hr and 6-hr access conditions at the 0.25 mg/kg/infusion unit dose. Asterisk (*) represents significant differences in total infusions (p < 0.05). (C) Time course (5-min bins) for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the cued 1-hr access condition at the 0.25 mg/kg/infusion unit dose. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05). (D) Time course for cocaine infusions (Mean ± SEM) across the first hour on sessions 1 and 14 for the cued 6-hr access condition at the 0.25 mg/kg/infusion unit dose. Asterisk (*) represents significant differences in total infusions between session 1 and 14 (p < 0.05). n = 6.

Fig 5

(A) Acquisition of cocaine self-administration for 10-min training sessions at a 0.1 mg/kg/infusion unit dose (n = 14). Asterisk (*) represents significant differences between active and inactive lever presses (p < 0.05). (B) Between-subject escalation of total cocaine infusions (Mean ± SEM) at a 0.1 mg/kg/infusion unit dose for 10-min (n = 7) and 60-min (n = 7) access groups. Asterisk (*) represents significant difference in session infusions, relative to session 1 (p < 0.05). (C) First-10 min total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for 110-min and 60-min access groups at the 0.1 mg/kg/infusion unit dose. (D) Acquisition of cocaine self-administration for 10-min training sessions at a 0.25 mg/kg/infusion unit dose (n = 14). Asterisk (*) represents significant differences between active and inactive lever presses (p < 0.05). (E) Between-subject escalation of total cocaine infusions (Mean ± SEM) at 0.25 mg/kg/infusion unit dose for the 10-min (n = 7) and 60-min (n = 7) access groups. Asterisk (*) represents significant difference in session infusions, relative to session 1 (p < 0.05) (F) First-10 min total cocaine infusions (Mean ± SEM) from sessions 1 and 14 for 110-min and 60-min access groups at the 0.25 mg/kg/infusion unit dose.