Role of the agranular insular cortex in contextual control
over cocaine-seeking behavior in rats
Amy A. Arguello
Carey M. Lyons
Jessica A. Higginbotham
Matthew A. Hodges
Rita A. Fuchs
Received: 2 November 2016 /Accepted: 15 April 2017 /Published online: 2 May 2017
Springer-Verlag Berlin Heidelberg 2017
Rationale Environmental stimulus control over drug relapse
requires the retrieval of context-response-cocaine associa-
tions, maintained in long-term memory through active
reconsolidation processes. Identifying the neural substrates
of these phenomena is important from a drug addiction treat-
Objectives The present study evaluated whether the agranular
insular cortex (AI) plays a role in drug context-induced co-
caine-seeking behavior and cocaine memory reconsolidation.
Methods Rats were trained to lever press for cocaine infusions
in a distinctive context, followed by extinction training in a
different context. Rats in experiment 1 received bilateral
microinfusions of vehicle or a GABA agonist cocktail (baclo-
fen and muscimol (BM)) into the AI or the overlying somato-
sensory cortex (SSJ, anatomical control region) immediately
before a test of drug-seeking behavior (i.e., non-reinforced
lever presses) in the previously cocaine-paired context. The
effects of these manipulations on locomotor activity were also
assessed in a novel context. Rats in experiment 2 received
vehicle or BM into the AI after a 15-min reexposure to the
cocaine-paired context, intended to reactivate context-
response-cocaine memories and initiate their reconsolidation.
The effects of these manipulations on drug context-induced
cocaine-seeking behavior were assessed 72 h later.
Results BM-induced pharmacological inactivation of the AI,
but not the SSJ, attenuated drug context-induced reinstatement
of cocaine-seeking behavior without altering locomotor activ-
ity. Conversely, AI inactivation after memory reactivation
failed to impair subsequent drug-seeking behavior and thus
cocaine memory reconsolidation.
Conclusions These findings suggest that the AI is a critical
element of the neural circuitry that mediates contextual control
over cocaine-seeking behavior.
Keywords Memory reconsolidation
Agranular insular cortex
Relapse triggered by exposure to drug-associated environ-
mental contexts is a major challenge for the successful treat-
ment of cocaine use disorder (Rohsenow et al. 1990; Ehrman
et al. 1992; Childress et al. 1999; Foltin and Haney 2000).
Following retrieval, which can be induced by exposure to a
previously drug-paired context, drug-associated memories
produce cocaine craving and promote drug-seeking behavior.
At the same time, these memories can become unstable and
must undergo protein synthesis-dependent reconsolidation in
order to be updated or maintained over time (Taylor et al.
2009). Thus, manipulations that disrupt the motivational ef-
fects of drug-associated stimuli may interfere with an acute
relapse episode, while manipulations that interfere with the
reconsolidation of labile drug-associated memories may pre-
empt future relapse to drug-seeking and drug-taking behaviors
(Lee et al. 2005; Miller and Marshall 2005; Milekic et al.
2006; Tronson and Taylor 2007). Accordingly, identifying
the neural substrates involved in drug-seeking behavior and
* Rita A. Fuchs
Department of Psychology, Michigan State University, East
Lansing, MI 48824, USA
Integrative Physiology and Neuroscience, College of Veterinary
Medicine, Washington State University, P.O. Box 647620,
Pullman, WA 99164-7620, USA
Psychopharmacology (2017) 234:2431–2441