Stress decreases serotonin tone in the nucleus accumbens to promote aversion and potentiate cocaine preference via decreased stimulation of 5-HT1B receptors

Stress-induced release of dynorphins (Dyn) activates kappa opioid receptors (KOR) in monoaminergic neurons to produce dysphoria and potentiate drug reward; however, the circuit mechanisms responsible for this effect are not known. We found that conditional deletion of KOR from Slc6a4 (SERT)-expressing neurons blocked stress-induced potentiation of cocaine conditioned place preference (CPP). Within the dorsal raphe nucleus (DRN), two overlapping populations of KOR-expressing neurons: Slc17a8 (VGluT3) and SERT, were distinguished functionally and anatomically. Optogenetic inhibition of these SERT+ neurons potentiated subsequent cocaine CPP, whereas optical inhibition of the VGluT3+ neurons blocked subsequent cocaine CPP. SERT+/VGluT3- expressing neurons were concentrated in the lateral aspect of the DRN. SERT projections from the DRN were observed in the medial nucleus accumbens (mNAc), but VGluT3 projections were not. Optical inhibition of SERT+ neurons produced place aversion, whereas optical stimulation of SERT+ terminals in the mNAc attenuated stress-induced increases in forced swim immobility and subsequent cocaine CPP. KOR neurons projecting to mNAc were confined to the lateral aspect of the DRN, and the principal source of dynorphinergic (Pdyn) afferents in the mNAc was from local neurons. Excision of Pdyn from the mNAc blocked stress-potentiation of cocaine CPP. Prior studies suggested that stress-induced dynorphin release within the mNAc activates KOR to potentiate cocaine preference by a reduction in 5-HT tone. Consistent with this hypothesis, a transient pharmacological blockade of mNAc 5-HT1B receptors potentiated subsequent cocaine CPP. 5-HT1B is known to be expressed on 5-HT terminals in NAc, and 5-HT1B transcript was also detected in Pdyn+, Adora2a+ and ChAT+ (markers for direct pathway, indirect pathway, and cholinergic interneurons, respectively). Following stress exposure, 5-HT1B transcript was selectively elevated in Pdyn+ cells of the mNAc. These findings suggest that Dyn/KOR regulates serotonin activation of 5HT1B receptors within the mNAc and dynamically controls stress response, affect, and drug reward.

Sign tracking predicts cue-induced but not drug-primed reinstatement to methamphetamine seeking in rats: Effects of oxytocin treatment

Background: The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues (‘sign trackers’ (STs); ‘goal trackers’ (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant methamphetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs. Methods: Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests. Results: Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction. Conclusions: This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.

The role of the mTOR pathway in models of drug-induced reward and the behavioural constituents of addiction

Background: Exposure to drugs of abuse induces neuroadaptations in critical nodes of the so-called reward systems that are thought to mediate the transition from controlled drug use to the compulsive drug-seeking that characterizes addictive disorders. These neural adaptations are likely to require protein synthesis, which is regulated, among others, by the mechanistic target of the rapamycin kinase (mTOR) signalling cascade. Methods: We have performed a narrative review of the literature available in PubMed about the involvement of the mTOR pathway in drug-reward and addiction-related phenomena. Aims: The aim of this study was to review the underlying architecture of this complex intracellular network and to discuss the alterations of its components that are evident after exposure to drugs of abuse. The aim was also to delineate the effects that manipulations of the mTOR network have on models of drug reward and on paradigms that recapitulate some of the psychological components of addiction. Results: There is evidence for the involvement of the mTOR pathway in the acute and rewarding effects of drugs of abuse, especially psychostimulants. However, the data regarding opiates are scarce. There is a need to use sophisticated animal models of addiction to ascertain the real role of the mTOR pathway in this pathology and not just in drug-mediated reward. The involvement of this pathway in behavioural addictions and impulsivity should also be studied in detail in the future. Conclusions: Although there is a plethora of data about the modulation of mTOR by drugs of abuse, the involvement of this signalling pathway in addictive disorders requires further research.