Mu opioid receptor expression by nucleus accumbens inhibitory interneurons promotes affiliative social behavior.

Mu opioid receptors in the nucleus accumbens regulate motivated behavior, including pursuit of natural rewards like social interaction as well as exogenous opioids. We used a suite of genetic and viral strategies to conditionally delete mu opioid receptor expression from all major neuron types in the nucleus accumbens. We pinpoint inhibitory interneurons as an essential site of mu opioid receptor expression for typical social behavior, independent from exogenous opioid sensitivity.

Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for Mouse Studies.

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket.

A master regulator of opioid reward in the ventral prefrontal cortex.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone.

Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement.

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs.

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice.

Opioid use disorder (OUD) is a chronic relapsing disorder that is a major burden for the lives of affected individuals, and society as a whole. Opioid withdrawal is characterized by strong physical symptoms, along with signs of negative affect. Negative affect due to opioid withdrawal is a major obstacle to recovery and relapse prevention.

Chronic Morphine Leaves a Durable Fingerprint on Whole-Brain Functional Connectivity.

Background: Opioid use disorder is a chronic relapsing disorder. The brain adapts to opioids that are taken for pain treatment or recreational use so that abstinence becomes a true challenge for individuals with opioid use disorder. Studying brain dysfunction at this stage is difficult, and human neuroimaging has provided highly heterogeneous information.

Manipulating ΔFOSB in D1-Type Medium Spiny Neurons of the Nucleus Accumbens Reshapes Whole-Brain Functional Connectivity.

Background: The transcription factor ΔFOSB, acting in the nucleus accumbens, has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain, which are required for its regulation of complex behavior, remain unknown.

Methods: We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene and thereby decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the nucleus accumbens and tested whether these modifications affect the organization of functional connectivity (FC) in the brain.

Mu Opioid Receptor-Positive Neurons in the Dorsal Raphe Nucleus Are Impaired by Morphine Abstinence.

Background: Chronic opioid exposure leads to hedonic deficits and enhanced vulnerability to addiction, which are observed and even strengthen after a period of abstinence, but the underlying circuit mechanisms are poorly understood. In this study, using both molecular and behavioral approaches, we tested the hypothesis that neurons expressing mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) are involved in addiction vulnerability associated with morphine abstinence.

Methods: MOR-Cre mice were exposed to chronic morphine and then went through spontaneous withdrawal for 4 weeks, a well-established mouse model of morphine abstinence.

Mu Opioid Receptor-Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors.

Background: Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses.

Advances in the characterization of negative affect caused by acute and protracted opioid withdrawal using animal models.

Opioid use disorder (OUD) is a chronic brain disease which originates from long-term neuroadaptations that develop after repeated opioid consumption and withdrawal episodes. These neuroadaptations lead among other things to the development of a negative affect, which includes loss of motivation for natural rewards, higher anxiety, social deficits, heightened stress reactivity, an inability to identify and describe emotions, physical and/or emotional pain, malaise, dysphoria, sleep disorders and chronic irritability. The urge for relief from this negative affect is one of major causes of relapse, and thus represents a critical challenge for treatment and relapse prevention.

Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation.

GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 () as the first active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties.

Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Knock-in Rats.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells.

Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor.

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [H]RTI-33, derived from a synthetic agonist RTI-13951-33. [H]RTI-33 has a specific activity of 83.

Visualization of real-time receptor endocytosis in dopamine neurons enabled by NTSR1-Venus knock-in mice.

Dopamine (DA) neurons are primarily concentrated in substantia nigra (SN) and ventral tegmental area (VTA). A subset of these neurons expresses the neurotensin receptor NTSR1 and its putative ligand neurotensin (Nts). NTSR1, a G protein-coupled receptor (GPCR), which classically activates Gαq/calcium signaling, is a potential route for modulating DA activity.

Habenular Neurons Expressing Mu Opioid Receptors Promote Negative Affect in a Projection-Specific Manner.

Background: The mu opioid receptor (MOR) is central to hedonic balance and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states.

The mu opioid receptor and the orphan receptor GPR151 contribute to social reward in the habenula.

The mu opioid receptor (MOR) and the orphan GPR151 receptor are inhibitory G protein coupled receptors that are enriched in the habenula, a small brain region involved in aversion processing, addiction and mood disorders. While MOR expression in the brain is widespread, GPR151 expression is restricted to the habenula. In a previous report, we created conditional ChrnB4-Cre × Oprm1 (so-called B4MOR) mice, where MORs are deleted specifically in Chrnb4-positive neurons restricted to the habenula, and shown a role for these receptors in naloxone aversion.

Zn inhibits spatial memory and hippocampal place cell representation through high-affinity binding to the NMDA receptor GluN2A subunit.

A subset of glutamatergic neurons in the forebrain uses labile Zn as a co-transmitter alongside glutamate. Synaptic Zn plays a key role in learning and memory processes, but its mechanisms of action remain poorly understood. Here, we used a knock-in (KI) mouse line carrying a point mutation at the GluN2A Zn binding site that selectively eliminates zinc inhibition of NMDA receptors.

The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse.

The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD).

Supraspinal melatonin MT receptor agonism alleviates pain via a neural circuit that recruits mu opioid receptors.

Melatonin, through its G protein-coupled receptor (GPCR) (MTNR1B gene) MT , is implicated in analgesia, but the relationship between MT receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured [SNI]), the selective melatonin MT agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924.

Translational Structural and Functional Signatures of Chronic Alcohol Effects in Mice.

Background: Alcohol acts as an addictive substance that may lead to alcohol use disorder. In humans, magnetic resonance imaging showed diverse structural and functional brain alterations associated with this complex pathology. Single magnetic resonance imaging modalities are used mostly but are insufficient to portray and understand the broad neuroadaptations to alcohol.

Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine.

Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. Thus, our studies aim to understand the neural circuits underlying tianeptine's antidepressant effects.