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

Abstract

Background While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early “non-addicted” 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 “non-addicted” or an “addicted” phenotype. Methods Following acquisition, male and female Sprague Dawley rats were given either short access (3 fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hr access (10 days; 4 trials/hr; 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 AMPA/KA receptor antagonist CNQX (0.0, 0.01, 0.03, 0.1 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 versus extended access self-administration. Results Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended 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 “non-addicted” stages, becomes critical once addiction has developed.

The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens

“…Despite greater cocaine intake, vehicle-treated females reinstated cocaine-seeking at a similar degree as vehicle-treated males. This finding is supported by previous work utilizing the same dose of self-administered cocaine (0.5 mg/kg/infusion; Kerstetter et al 2008; Feltenstein et al 2011; Doyle et al 2014). However, when estrous cycle was considered, ceftriaxone only attenuated reinstatement in female rats that were not in estrus at the time of testing.…”

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

“…These results are in line with the findings of Doyle et al (2014) indicating that glutamatergic signaling in the nucleus accumbens of Sprague-Dawley rats, although not essential for modifying initial cocaine use in non-addicted stages, becomes critical for post withdrawal relapse after the addiction has developed.…”

Dopamine increases NMDA‐stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase‐dependent mechanism

“…In more recent work, it has been shown that MMP‐2 and ‐9 are involved in synaptic changes occurring in the striatum of cocaine‐extinguished and ‐reinstated animals (Smith et al ., ). In particular, the number and/or size of postsynaptic processes for glutamatergic synapses is increased with cocaine‐related plasticity, a finding consistent with accumulating evidence that glutamatergic signalling becomes critical in the addicted state (Doyle et al ., ; Gipson & Kalivas, ).…”