Amperometric measurements of cocaine cue and novel context-evoked glutamate and nitric oxide release in the nucleus accumbens core

Abstract

Abbreviations: SA (self-administration), NO (nitric oxide), MSNs (medium spiny neurons), nNOS (neuronal nitric oxide synthase), NAcore (nucleus accumbens core), PL (prelimbic), vSub (ventral subiculum), VTA (ventral tegmental area), GLT-1 (glutamate transporter-1), BLA (basolateral amygdala), DETA (DETA-NONOate), CNO (Clozapine-n-oxide), FR (Fixed ratio), standard error of the mean (SEM), eGFP (enhanced green fluorescent protein), cGMP (cyclic GMP), sGC (soluble guanylyl cyclase), CPP (conditioned place preference), MMPs (matric metallo-proteinases), i.v. (intravenous), LOD (limit of detection), GluOx (glutamate oxidase) AbstractCue-induced reinstatement of cocaine seeking after self-administration (SA) and extinction relies on glutamate release in the nucleus accumbens core (NAcore), which in turn activates neuronal nitric oxide synthase (nNOS) interneurons. Nitric oxide (NO) is required for structural plasticity in NAcore medium spiny neurons (MSNs), as well as cued cocaine seeking. However, NO release in the NAcore during reinstatement has yet to be directly measured. Further, the temporal relationship between glutamate release, and the induction of a NO response also remains unknown. Using wireless amperometric recordings in awake behaving rats, we quantified the magnitude and temporal dynamics of novel context-and cue-induced reinstatement-evoked glutamate and NO release in the NAcore. We found that re-exposure to cocaine-conditioned stimuli following SA and extinction increased extracellular glutamate, leading to release of NO in the NAcore. In contrast, exposing drug-naïve rats to a novel context led to a lower magnitude rise in glutamate in the NAcore relative to cue-induced reinstatement. Interestingly, novel context exposure evoked a higher magnitude NO response relative to cue-induced reinstatement. Despite differences in magnitude, novel context evoked-NO release in the NAcore was also temporally delayed when compared to glutamate. These results demonstrate a dissociation between the magnitude of cocaine cue-and novel context-evoked glutamate and NO release in the NAcore, yet similarity in the temporal dynamics of their release. Together, these data contribute to a greater understanding of the relationship between glutamate and NO, two neurotransmitters implicated in encoding the valence of distinct contextual stimuli.

A Rat Model of Cocaine-Alcohol Polysubstance Use Reveals Altered Cocaine Seeking and Glutamate Levels in the Nucleus Accumbens

“…Glutamate homeostasis refers to the balance between glutamate release and reuptake. This dysregulation includes a decrease in the glutamate transporter GLT-1 expression and function in the NA core and increased synaptic glutamate during reinstatement of cocaine-seeking, regardless of the stimuli priming such reinstatement (e.g., cue, context, cocaine-prime) ( McFarland et al, 2003 ; Knackstedt et al, 2010 ; Fischer et al, 2013 ; LaCrosse et al, 2016 ; Smith et al, 2017 ; Siemsen et al, 2020 ). Basal, extra-synaptic glutamate levels are reduced in the NA core at the time of reinstatement testing, caused by reduction in function of the glutamate antiporter system xc- and protein expression of its catalytic subunit xCT ( Baker et al, 2003 ; Knackstedt et al, 2010 ).…”