Opioid use kills tens of thousands of Americans each year, devastates families and entire communities, and cripples the healthcare system. Exposure to opioids causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug-seeking and drug-taking that can remain a lifelong struggle. The persistence of these neuroadaptations is mediated in part by epigenetic remodeling of gene expression programs in discrete brain regions. Although the majority of work examining how epigenetic modifications contribute to addiction has focused on psychostimulants like cocaine, research into opioid-induced changes to the epigenetic landscape is beginning to emerge. This review summarizes our knowledge of opioid-induced epigenetic modifications and their consequential changes to gene expression. Current evidence points towards opioids promoting higher levels of permissive histone acetylation and lower levels of repressive histone methylation, as well as alterations to DNA methylation patterns and non-coding RNA expression, throughout the brain's reward circuitry. Additionally, studies manipulating epigenetic enzymes in specific brain regions are beginning to build causal links between these epigenetic modifications and changes in addiction-related behavior. Moving forward, studies must leverage advanced nextgeneration sequencing approaches and chromatin purification techniques combined with bioinformatics analyses to identify novel gene networks regulated by particular epigenetic modifications. Improved translational relevance will also require increased focus on volitional drug-intake models and standardization of exposure paradigms. Such work will significantly advance our understanding of how opioids cause persistent changes to brain function, and provide a platform on which to develop interventions for treating opioid addiction.

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The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

Olfactory processing is thought to be actively modulated by the top-down input from cortical regions, but the behavioural function of these signals remains unclear. Here we find that cortical feedback from the anterior olfactory nucleus pars medialis (mAON) bidirectionally modulates olfactory sensitivity and olfaction-dependent behaviours. To identify a limbic input that tunes this mAON switch, we further demonstrate that optogenetic stimulation of ventral hippocampal inputs to the mAON is sufficient to alter olfaction-dependent behaviours.

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT receptor ligands may have important implications when considering the 5-HT receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT 2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT 2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT 2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT 2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking. These dynamic clusters also show a nearly complete overlap of individual D1 neurons and extensive overlap among D2 neurons. Modulating D1 and D2 neural activities revealed analogous effects on feeding versus drinking behaviors. In aggregate, these data show that a highly overlapping set of D1 and D2 neurons in NAc detect food and water reward and elicit concordant responses to hunger and thirst. These studies establish a general role of this mesolimbic pathway in mediating instinctive behaviors by controlling motivation-associated variables rather than conferring behavioral specificity.