Elsevier

Biological Psychiatry

Volume 76, Issue 10, 15 November 2014, Pages 810-815
Biological Psychiatry

Archival Report
A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core With the Development of an Addicted Phenotype

https://doi.org/10.1016/j.biopsych.2014.02.005Get rights and content

Background

While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype.

Methods

Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration.

Results

Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group.

Conclusions

These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed.

Section snippets

Subjects

Adult male (n = 38) and female (n = 48) Sprague-Dawley rats were used in this study. Both male and female rats were included to increase the power of detecting a shift in the mechanisms of cocaine reinforcement by stage of addiction. Importantly, we recently showed that motivation for cocaine, measured following the same short-access and extended-access conditions used here, does not differ between male and female rats [(38); also, see Figure 1]. To facilitate rapid acquisition of cocaine

Effect of Short-Access Versus Extended-Access Cocaine Self-Administration on Subsequent Motivation for Cocaine and Cocaine Seeking

During the 10 days of cocaine self-administration under the extended-access discrete trials procedure, rats self-administered a high level of cocaine (average number of infusions was 68.9 ± 2.0 versus the set 20 infusions/day limit in the short-access group), and as expected, female rats self-administered a greater number of infusions than did male rats (71.8 ± 2.0 versus 64.2 ± 4.3, respectively; t11 = 4.2, p < .05). As expected, extended-access rats maintained a markedly higher level of PR

Discussion

The goal of this study was to examine the role of glutamatergic receptor signaling in the NAc in the motivation for cocaine using conditions known to produce an addicted versus a nonaddicted phenotype. As expected, rats in the extended-access group showed a markedly higher level of motivation for cocaine, as well as higher levels of cocaine seeking under both extinction and reinstatement conditions, following abstinence as compared with short-access control rats, thus confirming the development

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