Reinstatement of cocaine-seeking in remission by cues, drug or a drug/cue combination: an intravenous self-administration study

E. Keogh, J. Slade, D. Heal, S. Smith. RenaSci Ltd, Nottingham, United Kingdom.

Introduction: Relapse is a major factor in treating substance use disorders⁽¹⁾. Drug-seeking can be triggered not only by re-exposure to drug, but also to environmental cues associated with drug-taking⁽²⁾. The relative effects on reinstatement of cocaine-seeking elicited by contingent cues, cocaine and cocaine+cues combined, in cocaine-trained rats after saline extinction(remission) in a model of IVSA were investigated.

Method: Male Sprague Dawley rats (200-225g;Charles River,UK) were mildly food restricted and trained to lever-press for food on fixed ratio (FR) 3 schedule. Rats were implanted with jugular catheters and allowed to lever-press for cocaine (0.36mg/kg/injection[inj]) on a FR5 schedule in 2hr test sessions. Cocaine infusions were paired with contingent cues (tone+/-light). Responding was extinguished on FR5 saline without cues. In 4 once-daily, 2hr reinstatement sessions, rats were presented with (i)Tone/light, (ii)Cocaine(1.0 mg/kg IV), (iii)Tone/light+Cocaine, or (iv)Tone. Active drug-paired lever presses were measured on FR5 with rats receiving saline infusions. Results are mean±sem, n=8-10.

Results: Cocaine was a positive reinforcer in all groups (range:17.8±1.2 to 21.8±1.2 inj/session; 120.9±7.7 to 155.9±12.5 active lever-presses[p<0.001 versus saline]). All rats extinguished on saline (range:2.3±0.4 to 2.8±0.3 inj/session; 15.7±2.2 to 19.3±1.6 active lever-presses). All interventions induced reinstatement in the first session (active lever-presses: Tone/light=61.2±15.0; Cocaine=59.5±11.8; Tone/light+Cocaine=102.5±15.0; Tone=38.4±9.8 [all p<0.001 versus saline]). Tone/light+Cocaine elicited significantly (p<0.001) more active lever-presses than saline extinction in Sessions 1-4 (Session 2:97.8±10.1; 3: 77.6±10.8; 4: 61.6±9.4). Compared with saline, Tone/light or Tone produced more (p<0.05) active lever-presses in Sessions 1 and 4, and Cocaine in Session 1 (p=0.059, Session 3). Reinstatement elicited by Tone/light+Cocaine was not significantly different from Tone/light or Cocaine in Session 1, but was significantly greater (p<0.05) than their effects in Sessions 2-4. Reinstatement by Tone/light+Cocaine was significantly (p<0.05) greater than Tone in all reinstatement sessions (Sessions 1-4). There were no differences between the level of cocaine seeking elicited in the reinstatement sessions by Tone/light, Cocaine or Tone.

Conclusions: Cocaine-seeking in remission was triggered by contingent cues or drug priming. The level of drug-seeking induced by cues was not significantly different from cocaine priming demonstrating their importance as motivators for relapse. The results also revealed the cocaine-seeking effects of drug priming and the presentation of contingent cues were additive when combined.

References:

(1) Litvin et al,.2007, Annu.Rev.Clin.Psychol..3:257-84

(2) Ehrman et al,.1992, Classical conditioning in drug dependent humans. Ann.N.Y. Acad. Sci. 654, 400-415.