Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

Abstract

Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.

Perirhinal Cortex mGlu5 Receptor Activation Reduces Relapse to Methamphetamine Seeking by Restoring Novelty Salience

“…In the absence of this dopaminergic challenge, short-access meth rats respond equally for the novel vs meth cue on the novel cue relapse test. This finding is consistent with a study by Bastle et al, (2012), who reported that short-access (2 h daily self-administration sessions for 2 weeks) cocaine rats respond equally for novel and cocaine cues on a reinstatement test conducted after two weeks of extinction training. In the latter study, however, the novel and cocaine cues were tested in separate animals, so this model did not address the ability of novel cues to compete with conditioned drug cues in a choice setting.…”

What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders

“…For example, electric footshock increases Fos expression in several stress- and reward-related brain regions to significantly greater levels in rats with a history of ethanol self-administration than in ethanol-naïve rats ( Zhao et al, 2006 ). This is further supported by studies examining cue-induced reinstatement, in which animals with a history of cocaine SA display higher cue reactivity, as assessed by greater Fos activation, in several key brain regions, than drug-naïve animals ( Bastle et al, 2012 ; Kufahl et al, 2009 ). The effects of prior drug exposure on stressor-induced Fos responses also appears to be brain region-dependent.…”

Chemogenetic activation of the perirhinal cortex reverses methamphetamine-induced memory deficits and reduces relapse

“…perirhinal cortex may integrate emotional and sensory information before it is conveyed to the hippocampus (Kajiwara et al 2003). Interestingly, novel cues were found to be as effective at triggering reinstatement as cocaine conditioned cues, and both types of cues activated a common neural circuit, measured by Fos expression (Bastle et al 2012). Given that our relapse model incorporates competition between novel cues and conditioned meth cues, the BLA could provide a critical input to the perirhinal cortex conveying the emotional significance of the meth cues, allowing the competition between meth and novel cues within the perirhinal cortex to be computed at a synaptic level before the outcome is relayed to the hippocampus.…”