Accumbens Mechanisms for Cued Sucrose Seeking

Abstract

Many studies support a perspective that addictive drugs usurp brain circuits used by natural rewards, especially for the dopamine-dependent reinforcing qualities of both drugs and natural rewards. Reinstated drug seeking in animal models of relapse relies on glutamate spillover from cortical terminals synapsing in the nucleus accumbens core (NAcore) to stimulate metabotropic glutamate receptor5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons. Contrasting the release of dopamine that is shared by sucrose and drugs of abuse, reinstated sucrose seeking does not induce glutamate spillover. We hypothesized that pharmacologically promoting glutamate spillover in the NAcore would mimic cocaine-induced adaptations and potentiate cued reinstatement of sucrose seeking. Inducing glutamate spillover by blocking astroglial glutamate transporters (GLT-1) had no effect on reinstated sucrose seeking. However, glutamate release probability is negatively regulated by presynaptic mGluR2/3, and sucrose reinstatement was potentiated following mGluR2/3 blockade. Potentiated sucrose reinstatement by mGluR2/3 blockade was reversed by antagonizing mGluR5, but reinstated sucrose seeking in the absence of mGluR2/3 blockade was not affected by blocking mGluR5. In cocaine-trained rodents mGluR5 stimulation reinstates drug seeking by activating nNOS, but activating mGluR5 did not promote reinstated sucrose seeking, nor was potentiated reinstatement after mGluR2/3 blockade reduced by blocking nNOS. However, chemogenetic activation of nNOS interneurons in the NAcore reinstated sucrose seeking. These data indicate that dysregulated presynaptic mGluR2/3 signaling is a possible site of shared signaling in drug seeking and potentiated reinstated sucrose seeking, but that downregulated glutamate transport and subsequent activation of nNOS by synaptic glutamate spillover is not shared.

Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats

“…Our present data are in agreement with previous findings using adult rats wherein EtOH or NIC exposure did not cause any changes in GLT-1 expression in the PFC (Knackstedt et al, 2009, Goodwani et al, 2015). In addition, a recent study found that blocking GLT-1 in the NAc did not attenuate reinstatement of SUC seeking (Bobadilla et al, 2017). It is noteworthy that the present study provided some corroboration for the latter finding, such that chronic exposure to SUC did not affect GLT-1 expression in the NAc, HIP, or PFC.…”

HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors

“…Rats that completed 15–20 days of FR training and were stable on the FR5 schedule for at least 3 days, continued on to subsequent studies. Mouse self-administration sessions (2hr) were performed at the same time each day during the dark phase as described previously (Bobadilla et al, 2017). Briefly, drug or sucrose availability was signaled both by the house light and a light above the active nose poke hole.…”

The Opioid-Addicted Tetrapartite Synapse

“…Self-administration models can also include measures of use escalation, withdrawal, extinction learning, and relapse, thus incorporating many features of OUD (28,29). In addition, rodents can be trained to self-administer natural rewards, such as sucrose, and neuroadaptations occurring during self-administration, extinction, or reinstated seeking of natural rewards can be compared with neuroadaptations observed in animals trained to self-administer opioids (30). In this review, we focus on the pathophysiology induced by noncontingent and self-administered opioids and cue-induced opioid seeking, where the neurobiological adaptations are not confounded by acute drug pharmacology.…”