Optogenetic activation of basolateral amygdala projections to nucleus accumbens core promotes cue-induced expectation of reward but not instrumental pursuit of cues

Reward-associated conditioned stimuli (CS) can acquire predictive value, evoking conditioned approach behaviors that prepare animals to engage with forthcoming rewards. Such CS can also acquire conditioned reinforcing value, becoming attractive and pursued. Through their predictive and conditioned reinforcing properties, CS can promote adaptive (e.g., locating food) but also maladaptive responses (e.g., drug use). Basolateral amygdala neurons projecting to the nucleus accumbens core (BLA→NAc core neurons) mediate the response to appetitive CS, but the extent to which this involves effects on the predictive and/or conditioned reinforcing properties of CS is unclear. Thus, we examined the effects of optogenetic stimulation of BLA→NAc core neurons on conditioned approach behavior and on the instrumental pursuit of a CS, the latter a measure of conditioned reinforcement. Water-restricted, adult male rats learned that a light-tone compound cue (CS) predicts water delivery. Pairing optogenetic stimulation of BLA→NAc core neurons with CS presentation potentiated conditioned approach behavior, and did so even under extinction conditions, when water was omitted. This suggests that BLA→NAc core neurons promote cue-induced expectation of rewards. Rats also received instrumental conditioning sessions during which they could lever press for CS presentations, without water delivery. Optogenetic stimulation of BLA→NAc core neurons either during these instrumental test sessions or during prior CS-water conditioning did not influence lever responding for the CS. This suggests that BLA→NAc core neurons do not influence the conditioned reinforcing effects of CS. We conclude that BLA→NAc core neurons promote cue-induced control over behavior by increasing cue-triggered anticipation of rewards, without influencing cue 'wanting'.

∆9-Tetrahydrocannabinol Self-Administration Induces Cell-Type Specific Adaptations and cFOS Expression in the Nucleus Accumbens Core

Given that 30% of chronic cannabis users develop cannabis use disorder (CUD), it is critical to identify neuroadaptations that contribute to this disease. The nucleus accumbens core (NAcore) is important for drug seeking and ~ 90% of all NAcore neurons are divided into D1- and D2-medium spiny neurons (MSNs) that serve opposing roles in drug seeking. Drugs of abuse induce D1- and D2-MSN specific adaptations but whether ∆9-tetrahydrocannabinol (THC) use initiates similar neuroadaptations is unknown. D1- and D2-Cre transgenic rats were transfected with Cre-dependent reporters and trained to self-administer THC + cannabidiol (THC + CBD). After extinction training dendritic spine morphology, glutamate transmission, CB1R function and cFOS expression were quantified. We found that extinction from THC + CBD induced a loss of large spine heads in D1- but not D2-MSNs and a commensurate reduction in glutamate synaptic transmission. Also, CB1R function was impaired on glutamatergic synapses onto D1-MSNs and this was paralleled by an augmented capacity to potentiate glutamate transmission in D1-MSNs. CB1R function and glutamate synaptic transmission on D2-MSN synapses were unaffected by THC + CBD use. Using cFOS expression as an activity marker, we found that D1-MSNs activity remained unchanged after extinction from THC + CBD but significantly increased after 60 minutes cue-induced drug seeking. Surprisingly, the percentage of D2-MSNs expressing cFOS decreased after extinction from THC + CBD and this decrease was restored by drug cues. Thus, glutamatergic adaptations in D1-MSNs partially predict activity changes and pose modulating CB1R function that is down-regulated selectively at D1-MSN synapses as a potential treatment strategy for CUD.

Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder, but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.

A subset of nucleus accumbens neurons receiving dense and functional prelimbic cortical input are required for cocaine seeking

BackgroundPrelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown.MethodsMale Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, in vivo electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking.ResultsChemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines.ConclusionsWe identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.