Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking

Abstract

BACKGROUND Relapse is a two-component process consisting of a highly motivated drug-seeking phase that, if successful, is followed by a drug-using phase resulting in temporary satiation. In rodents, cue-induced drug-seeking requires transient synaptic potentiation (t-SP) of cortical glutamatergic synapses on nucleus accumbens core medium spiny neurons, but it is unknown how achieving drug use affects this plasticity. We modeled the two phases of relapse after extinction from cocaine self-administration to assess how cocaine use affects t-SP associated with cue-induced drug seeking. METHODS Rats were trained to self-administer cocaine (n=96) or used as yoked-saline controls (n=21). After extinction, reinstatement was initiated by 10 min of cue-induced drug seeking, followed by 45 min with contingent cocaine access, after which cocaine was discontinued and unreinforced lever pressing ensued. Three measures of t-SP were assayed during reinstatement: dendritic spine morphology, AMPA:NMDA ratios, and matrix metalloproteinase activity. RESULTS We found that cocaine use for 10 min collapsed all three measures of cue-potentiated t-SP back to baseline. Moreover, when cocaine use was discontinued 45 min later, dendritic spine morphology and AMPA:NMDA were restored as animals became motivated to engage unrewarded lever pressing. Non-reinforced drug seeking was positively correlated with changes in spine morphology and cocaine access reversed this relationship. CONCLUSIONS Using a novel modification of the reinstatement paradigm we show that achieving cocaine use reversed the synaptic plasticity underpinning the motivation to seek drug.

Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration

“…These actions might reduce SRCIN1 inhibition of SRC and promote actin depolymerization, although additional proteins are likely involved, as noted above. This would fit with the current model according to which a cocaine challenge rapidly induces spine destabilization and the re-emergence of thin spines from mushroom spines (Shen et al, 2009;Russo et al, 2010;Huang et al, 2015;Spencer et al, 2017), and a similar mechanism could be at play when relapse is triggered by re-exposure to a drug-paired context (Stankeviciute et al, 2014). Overall, this mechanism could explain how supposedly stable mushroom spines remain labile to certain stimuli, and is consistent with the proposed mechanisms of memory reconsolidation (Sorg, 2012).…”

Restoration of Kv7 channel mediated inhibition reduces cued-reinstatement of cocaine seeking

“…Rats were anaesthetized using a ketamine HCl / xylazine mixture (0.57 / 0.87 mg/kg, respectively, IP) followed by ketorolac (2.0 mg/kg, IP) and Cefazolin (40 mg, IP or 10 mg / 0.1 ml, IV). Subsequently, intrajugular catheters were implanted as described elsewhere (Spencer et al, 2017). Catheter patency was maintained by daily flushing with cefazolin (1 g / 5 ml during surgery and 1 g / 10 ml daily for 1 week) and then with heparin for the remainder of the behavioral paradigms.…”

The importance of data structure in statistical analysis of dendritic spine morphology

“…cluster randomized control trials and in fields outside of biomedicine, such as social sciences, yet inferior statistical analyses are still commonly applied when studying dendritic spine morphology. In our review, only 1 paper corrected for data structure using a two-level nested ANOVA (Spencer et al, 2017). Likewise, in a recent paper that did not match the search term in our restricted review Kondratiuk et al employed nested Gaussian mixed models to analyze dendritic spine morphology parameters while correcting for the data structure (Kondratiuk et al, 2017).…”