Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence

Abstract

One of the most insidious features of cocaine addiction is a high rate of relapse even after extended periods of abstinence. A wide variety of drug-associated stimuli, including the context in which a drug is taken, can gain incentive motivational properties that trigger drug desire and relapse to drug-seeking. Both animal and clinical studies suggest that extensive cocaine exposure may induce a transition from cortical to striatal control over decision-making as compulsive drugseeking emerges. Using an animal model of relapse to cocaine-seeking, the present study investigated the expression patterns of three different activity-related genes (c-fos, zif/268, and arc) in cortical and striatal brain regions implicated in compulsive drug-seeking in order to determine the neuroadaptations that occur during context-induced relapse following brief or prolonged abstinence from cocaine self-administration. Re-exposure to the environment previously associated with cocaine self-administration following 22 h or 15 days of abstinence produced a significant increase in zif/268 and arc, but not c-fos mRNA, in the caudate-putamen and nucleus accumbens. With the exception of arc mRNA levels following 15 days of abstinence, all three genes were increased in the anterior cingulate cortex of animals with a cocaine history when they were re-exposed to the operant chamber. Additionally, c-fos, zif/268, and arc expression was differentially affected in the motor and sensory cortices at both timepoints. Together, these results support convergent evidence that drug-seeking induced by a cocaine-paired context changes the activity of corticostriatal circuits.

Contextual encoding by ensembles of medial prefrontal cortex neurons

“…In addition, the mPFC plays a key role in context-based cognitive tasks (2, 3) and context-induced drug relapse (6)(7)(8), and is believed to be an important node in the "context" network (1, 9-12). However, despite numerous attempts, studies have consistently failed to find any clear location-specific mPFC firing patterns that are independent of behavior (i.e., place cells) (31)(32)(33)(34).…”

“…Context can also help to inform the subject about potential changes in the meaning of stimuli and actions. The medial prefrontal cortex (mPFC) is involved in various forms of cognition that depend on spatial and contextual information, including context-based cognitive tasks (2-4), contextual fear conditioning (5), and context-induced drug relapse (6)(7)(8), and is believed to be an important node in the "context" network (1,(9)(10)(11)(12). These functions likely depend on reciprocal interactions with the hippocampus (13,14), an area that has a well-established role in spatial and contextual processing (15)(16)(17)(18)(19)(20).…”

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…For example, activity-regulated cytoskeletal associated (Arc) protein is synthesized within dendrites in an activity-and group I mGluR-dependent manner where it associates with components of AMPAR endocytosis machinery and has been shown to actively maintain LTD (Park et al, 2008;Waung et al, 2008). Within striatal regions, Arc protein expression is robustly induced following re-exposure to cocaine-paired stimuli and modulates extinction of drugseeking behavior (Hearing et al, 2011;Hearing et al, 2008). In addition, mGluR activation has been shown to induce rapid translation of striatal-enriched protein tyrosine phosphatase (STEP), which also downregulates AMPAR surface expression and may actively maintain endocytosis rates (Luscher and Huber, 2010;Zhang et al, 2008).…”

Cocaine Modulation of Frontostriatal Expression of Zif268, D2, and 5-HT2c Receptors in High and Low Impulsive Rats

“…We therefore also investigated whether the duration of cocaine self-administration differentially recruited this marker of neural plasticity within the corticostriatal networks (Hearing et al, 2008;Unal et al, 2009) of HI and LI rats.…”