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DNA methylation and mRNA expression in the dmPFC are altered after protracted withdrawal from cocaine self‐administration
Author(s) -
Ploense Kyle,
Vieira Philip,
Kippin Tod
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.745.1
Subject(s) - self administration , medicine , drug withdrawal , addiction , saline , drug , anesthesia , pharmacology , psychiatry
Cocaine addiction is a chronic disorder that involves excessive, uncontrolled drug consumption. Both humans and rodents will escalate the amount of cocaine taken when it is readily available indicating that excessive intake is dependent on prior consumption. In rodents, however, escalation is not observed when access is restricted to “limited” (i.e. 1 hr) daily sessions. Here, we investigated whether control over drug intake or drug exposure are the critical factors in escalation by employing a mixed limited‐contingent exposure and prolonged noncontingent exposure model. . Rats were implanted with a permanent jugular catheter and then allowed to lever press to self‐administer (FI20 with a 20 s light cue paired with each infusion) saline vehicle (0.1 ml/infusion) or cocaine (0.25 mg/infusion) under 3 conditions: limited‐access (1 h/ day), extended‐access (6 h/day), and 1 h limited‐access + 5 h non‐contingent exposure (via yoking to extended access rats) to cocaine. Based on the first 10 min and first hour of daily access, we observed rapid escalation of cocaine intake in both the extended‐access and limited‐access + non‐contingent conditions (ps < 0.05). We also observed a delayed escalation of cocaine intake in the limited‐access condition within the first 10 min of self‐administration (p < 0.05), but not across the 1 h of cocaine availability. Interestingly, escalation of cocaine intake was accelerated in the limited + non‐contingent‐access condition relative to the extended‐access condition. However, relative to the other cocaine conditions, the limited‐access + non‐contingent group exhibited markedly more non‐reinforced responses indicating that distinct behavioral mechanisms drive escalation by contingent versus noncontingent drug exposure (ps<0.05). Additionally, post‐mortem quantification of homer2 (a gene implicated in cocaine intake and associated) mRNA expression within the dmPFC indicated elevation only in the extended‐access conditions (p<0.05). Rises in homer2 mRNA were associated with distinct levels of DNA methylation, hydroxymethylation, and transcription factor binding to the Homer2 gene. Together, these findings indicate that either contingent or non‐contingent “excessive” cocaine exposure supports escalation but have differential effects on the temporal patterning of operant responsiveness as well as molecular correlates of escalation. Support or Funding Information This research was supported by NIH grants DA‐027115 and DA‐027525 (TEK) and DA024038 (KKS), as well as funding from and the W.M. Keck Foundation (TEK)