Biology subjects

Javitch, J. A.

Publications and source records attributed to Javitch, J. A..

At least 19 recordsLinked to original sources

bioRxiv2026

CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers

The metabotropic glutamate receptor 7 (mGlu7) is an emerging therapeutic target for central nervous system disorders, but progress has been limited by a lack of selective pharmacological tools. CVN636 was recently reported as a potent and selective allosteric agonist of this receptor, capable of receptor activation in the absence of glutamate, with demonstrated efficacy in a rodent model of alcohol use disorder. Here, using complementary bioluminescence resonance energy transfer-based assays that measure both downstream signaling and G protein recruitment, we show that CVN636 does not activate the receptor on its own. Instead, CVN636 acts as a positive allosteric modulator that enhances the potency and efficacy of orthosteric agonist responses, including those of glutamate, in an agonist-dependent manner. Blockade of orthosteric agonist binding with a competitive antagonist abolished CVN636 activity, consistent with this mechanism. Furthermore, using an assay that distinguishes signaling from defined receptor dimers, we find that CVN636 activity is selective for mGlu7/7 homodimers and does not extend to any mGlu7-containing heterodimer tested. Thus, in our assay system CVN636 is an mGlu7/7 homodimer-selective positive allosteric modulator of this receptor, suggesting that its in vivo actions likely stem from action at these homomers.

pharmacology and toxicology↗

bioRxiv2026

Transformer-based framework uncovers state-dependent modular organization and conformational landscapes of the β-arrestin 1 C-terminal tail

{beta}-arrestins ({beta}arr) regulate signaling and trafficking of G protein-coupled receptors (GPCRs) across diverse physiological and pathological processes. However, mechanistic understanding of how ligand-activated GPCRs engage and activate {beta}arr remains limited, with the conformation of the entire {beta}arr tail in the active state still unknown. Here, by comparatively analyzing temperature replica-exchange molecular dynamics simulation data of {beta}arr1 in basal and active states, we investigated the conformational landscape of the {beta}arr1 tail to elucidate its role in activation. To overcome limitation of conventional analyses in characterizing the vast conformational space sampled by the 62-residue tail, we developed a transformer-based autoencoder (TAE) framework that integrates attention-derived residue relationships and latent-space clustering to identify the tails modular organization and conformational substates, providing an interpretable description of how local residue interactions couple to large-scale conformational rearrangements. Using the conformationally constrained basal state as a control, we validated the framework by showing that it recovers interpretable conformational features. In the active state, the framework revealed a reorganized modular architecture, recovered key interactions identified through manual analysis, and uncovered segment-specific dynamics inaccessible to conventional approaches. Our findings show that, in the active state, the {beta}arr1 tail preferentially engages the back side of the main body and forms substates in which the middle segment occupies the central crest crevice, suggesting that the released tail can self-engage functionally critical surfaces and influence the balance between tail-only and core-engaged receptor complexes. Together, this work establishes a TAE framework for analyzing large-scale conformational ensembles and advances our understanding of {beta}arr1 activation.

biophysics↗

bioRxiv2026

Transmembrane Domain Dominance Drives Emergent Signaling and Allosteric Inversion in mGlu1/5 Heterodimers

Class C GPCRs function as obligate dimers in which only one G protein can engage the complex at a time, but how each protomer contributes to heterodimer coupling has remained unresolved. Using CODA-RET, a BRET-based assay reporting direct Gq recruitment to defined, full-length receptor pairs, we show that signaling at the mGlu/ heterodimer flows predominantly through the mGlu protomer; domain-swapped chimeras localize this dominance to the transmembrane domain. The dominance generates emergent signaling: cis-acting mGlu PAMs and NAMs undergo allosteric inversion when coupling is restricted to mGlu. By contrast, the mGlu-selective NAM MTEP is silent at the heterodimer, mirroring mGlus minimal role in driving Gq. Because the mGlu PAM tested acts only in cis, a trans-acting mGlu PAM would theoretically be selective for mGlu/ homomers. These findings open a pharmacological design space in which protomer target and cis-versus-trans mode of action tune selectivity across mGlu/, mGlu/, and mGlu/ dimers.

neuroscience↗

bioRxiv2026

Direct tensile force activates Adgrl3 in a tethered agonist-dependent manner

Adhesion G protein-coupled receptors are proposed to function as mechanosensors, yet whether controlled mechanical force can directly activate receptor signaling in living cells remains unclear. Using optical tweezers, we demonstrate that direct tensile force applied to the N-terminus of the adhesion GPCR Adgrl3 is sufficient to induce G protein recruitment in living cells. Activation is direction-specific, requires a functional tethered agonist, and aligns with coexisting force-driven GAIN-domain conformational changes and dissociation.

cell biology↗

bioRxiv2026

Local GPCR density tips the balance of μ-opioid receptor trafficking

The extent to which local GPCR surface density governs engagement of downstream signaling and trafficking pathways remains unclear. Using single-particle tracking of the -opioid receptor (MOR), we show that receptor density differentially regulates G protein signaling and GRK2/3-{beta}-arrestin-dependent receptor trafficking. At low surface density, MORs activate G proteins but fail to enter clathrin-coated structures despite the presence of endogenous GRK2/3 and {beta}-arrestin. Increasing MOR density, co-expressing other class A GPCRs, or elevating GRK2 or {beta}-arrestin abundance rescues agonist-induced MOR trafficking. In contrast, the class B GPCR V2R blocks MOR trafficking at both low and high MOR densities. These results support a model in which increasing class A GPCR density, despite worsening effector-to-receptor stoichiometry, promotes trafficking by forming an affinity matrix that enables reversible GRK2/3 and {beta}-arrestin interactions to be productively used by neighboring receptors in a density-dependent manner, whereas class B GPCRs sequester {beta}-arrestin and block trafficking.

biophysics↗

bioRxiv2025

Novel, small molecules targeting the 5-HT4R receptor protect against stress-induced maladapative behavior with efficacy across age

BACKGROUNDStress is a risk factor for developing psychiatric disorders, including major depressive disorder (MDD). Compounds targeting the serotonin type 4 receptor (5-HT4R) hold promise as novel rapid-acting treatments of mood disorders. However, a lack of selectivity and numerous side effects have been limiting factors for their clinical use. Here, we developed and characterized novel-composition 5-HT4R compounds in mouse models of stress. METHODSThree 5-HT4R-targeting compounds were designed and synthesized based on PF-04995274, a high-affinity 5-HT4R ligand reported to be a partial agonist. G-protein assays were utilized to characterize molecular activity. Saline, PF-04995274, or a novel compound were administered before or after stress in male and female mice. Drug effects were assayed using behavioral paradigms. Patch clamp electrophysiology was used to determine the effect of drug on glutamatergic activity in hippocampal Cornu Ammonis 3 (CA3). RESULTSProphylactic administration of DL5, DL7, or DL8 was effective at reducing stress-induced maladaptive behaviors in male and female mice; DL7 and DL8 were effective when administered after stress. When administered following learned helplessness (LH), DL7 reduced behavioral despair and increased c-Fos in the dentate gyrus (DG) and CA3. All novel compounds attenuated large-amplitude AMPA receptor-mediated bursts in ventral CA3 (vCA3). In aged male mice, prophylactic DL7 reduced behavioral despair. CONCLUSIONSThese results characterize novel 5-HT4R-targeting compounds for stress-induced psychiatric disease with the potential to address unmet needs in adult and aged patients with stress-induced psychiatric illness. Future work will characterize their mechanism of action with the goal of clinical development.

neuroscience↗

bioRxiv2025

Habenular μ-opioid receptor knockout and chronic systemic receptor blockade promote negative affect and heighten nociceptive sensitivity

The -opioid receptor (MOR), a subtype of opioid G protein-coupled receptor, is expressed in multiple brain circuits and is particularly enriched in the habenula, a small epithalamic structure implicated in aversive states. MOR dysfunction has been linked to several psychiatric and nociceptive disorders. Identifying the key brain regions mediating the behavioral consequences of disrupted MOR signaling can shed light on the role of the opioid system in mood and pain regulation. In this study, we administered methocinnamox (MCAM), a long-acting, pseudo-irreversible MOR antagonist, acutely or chronically to adult C57BL/6J mice. A comprehensive behavioral battery was used to assess affective, social, and pain behavior. A single MCAM administration (10 mg/kg, s.c.) did not alter baseline behavior, but blocked opioid-induced analgesia, suggesting that basal {micro}-opioid tone does not contribute to these behaviors. In contrast, chronic MCAM administration (10 mg/kg, s.c., 3x/week for 4 weeks) led to increased anxiety-like behavior and decreased sociability, as well as enhanced mechanical allodynia and thermal hyperalgesia. Remarkably, selective knockout of habenular MORs in adult Oprm1fl/fl mice reproduced key features of the chronic MCAM phenotype, including anxiety-like behavior and mechanical hyperalgesia. Together, these findings reveal that sustained inhibition of MOR signaling disrupts affective and nociceptive processing and highlight the habenula as a node mediating key behavioral deficits of disrupted opioid signaling.

neuroscience↗

bioRxiv2025

Altered striatal dopamine regulation in ADGRL3 knockout mice

Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

neuroscience↗

bioRxiv2025

CD33 and Clusterin Interact Biophysically and Genetically to Modulate Alzheimer Risk

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimers disease (AD). The full-length CD33M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and A{beta}). This interaction induces CD33M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33M{Delta}4bp).

neuroscience↗

bioRxiv2025

Conformational dynamics of the active state of β-arrestin 1

{beta}-arrestins ({beta}arr) regulate the signaling and trafficking of G protein-coupled receptors (GPCRs) in numerous physiological processes and have been implicated in various diseases. Structural and kinetic insights into how ligand-mediated GPCR activation drives {beta}arr coupling and activation remain limited, with the binding mechanism of the phosphorylated GPCR C-terminal tails, such as that of the vasopressin receptor-2 (V2Rpp), and the conformation of the entire {beta}arr tail in the active state still unknown. Here, we simulated both the basal and V2Rpp-bound states of {beta}arr1 with temperature replica-exchange molecular dynamics (TREMD) simulations to probe the activation mechanism of {beta}arr1. Compared to conventional MD, our TREMD simulations, employing an unprecedented 200-replica setup, significantly broadened conformational sampling while preserving the basal state. Our analysis showed that, without the bound Fab30 antibody fragment, the main body of V2Rpp-bound {beta}arr1 tended to transition toward the basal conformation; however, binding of V2Rpp in the N-domain groove allosterically oriented the finger loop to point upward for core engagement with a GPCR. Furthermore, V2Rpp dissociation events suggest that its binding involves a sliding movement along the N-domain groove, during which its phosphorylated residues p3 and p4 transiently occupy the S5 site to facilitate repositioning of p5 into the S5 site, thereby triggering a zippering process of p1 to p3. The dynamic 62-residue {beta}arr1 tail explored a vast conformational space, forming transient secondary structures, and could favorably anchor on the main bodys back side and within the central crest crevice. These findings elucidate key mechanistic steps underlying {beta}arr1 activation.

biophysics↗

bioRxiv2023

The in vitro functional profiles of fentanyl and nitazene analogs at the μ-opioid receptor - high efficacy is dangerous regardless of signaling bias

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as the -opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G protein biased MOR agonists are safer pain medications, while other evidence indicates that low intrinsic efficacy at MOR better explains reduced opioid side effects. Here, we characterized the in vitro functional profiles of various NSOs at MOR using adenylate cyclase inhibition and {beta}-arrestin2 recruitment assays, in conjunction with the application of the receptor depletion approach. By fitting the concentration-response data to the operational model of agonism, we deduced the intrinsic efficacy and affinity for each opioid in the Gi protein signaling and {beta}-arrestin2 recruitment pathways. Compared to the reference agonist DAMGO, we found that several fentanyl analogs were more efficacious at inhibiting cAMP production, whereas all fentanyl analogs were less efficacious at recruiting {beta}-arrestin2. In contrast, the non-fentanyl 2-benzylbenzimidazole (i.e., nitazene) analogs were highly efficacious and potent in both the cAMP and {beta}-arrestin2 assays. Our findings suggest that the high intrinsic efficacy of the NSOs in Gi protein signaling is a common property that may underlie their high risk of intoxication and overdose, highlighting the limitation of using in vitro functional bias to predict the adverse effects of opioids. Instead, our results show that, regardless of bias, opioids with sufficiently high intrinsic efficacy can be lethal, especially given the extremely high potency of many of these compounds that are now pervading the illicit drug market.

pharmacology and toxicology↗

bioRxiv2023

Dopaminergic D2 receptor modulation of striatal cholinergic interneurons governs sequence learning

Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs. In vivo electrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task. Significance statementThe role of striatal projection neurons in encoding action sequences has been extensively studied, and cholinergic interneurons play a central role in striatal physiology, but we do not yet understand how cholinergic interneurons contribute to action sequencing. Using a combination of mouse genetics, behavior, and in vivo electrophysiology this work shows that genetic deletion of D2 receptors from striatal cholinergic interneurons disrupts the learning, performance, and encoding of action sequences, without changing general locomotion or motor skill learning. Virally replacing D2 receptors specifically in dorsal striatal cholinergic interneurons is sufficient to rescue the sequence behavior. Our observations may be useful in understanding and treating movement disorders in which dopamine and acetylcholine are imbalanced.

neuroscience↗

bioRxiv2022

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a receptor in distal CA1 neurons to direct their axons to proximal subiculum, and as a repulsive ligand in proximal subiculum to direct proximal CA1 axons to distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to G12/13 in heterologous cells, which is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2s tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor. By contrast, neither tethered agonist activity nor autoproteolysis was necessary for Lphn2s role as a repulsive ligand. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

developmental biology↗

bioRxiv2022

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

cell biology↗

bioRxiv2021

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, there is an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in rat models of opioid use, and no cardiac pro-arrhythmic potential, in contrast to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine and fentanyl intake after a single dose, persistent reduction of morphine intake and reinforcing efficacy after a short treatment regimen, and suppression of morphine and fentanyl drug seeking in relapse models. Oxa-noribogaine also induces a lasting elevation of neurotrophin proteins in the ventral tegmental area and medial prefrontal cortex, consistent with targeted neuroplasticity induction and alteration of addiction-like states. As such, oxa-iboga compounds represent candidates for a novel type of pharmacotherapy for treatment of opioid use disorder.

pharmacology and toxicology↗

bioRxiv2021

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratoms natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal {beta}-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and {beta}-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both {beta}-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.

pharmacology and toxicology↗

bioRxiv2021

Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine

Depression and anxiety are two of the most common mental health disorders, often sharing symptoms and administrations. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. Therefore, to better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through the mu-opioid receptor (MOR) instead of directly targeting monoaminergic systems, would be more effective in this model. We injected C57BL/6J (C57) pups with either FLX (10 mg/kg, i.p) or vehicle from postnatal (PN) day 2 to 11, a period in which mouse brain development parallels that of the third trimester of a human pregnancy. Prior work established that adult 129SvEv (129) mice exposed to FLX in this time period (PN-FLX) showed increased avoidant and decreased hedonic behaviors, which correspond to anxiety- and depressive-like symptoms in humans, respectively. We performed baseline testing in adulthood in C57 PN-FLX animals and confirmed a similar avoidant phenotype to that reported in 129 PN-FLX mice. We then treated these animals with chronic FLX (18 mg/kg in the drinking water) and evaluated effects on two tasks that measure avoidant behavior - the open field and novelty suppressed feeding (NSF) tasks. This administration failed to improve, and even exacerbated, avoidance symptoms in PN-FLX mice. The same animals then underwent chronic administration with TIA (30 mg/kg, 2x/day, i.p.) as an alternative treatment strategy. TIA administration decreased avoidance behavior as measured in the open field and NSF. Overall, this demonstrates that TIA may be a promising alternative treatment to typical antidepressants, especially in patients whose serotonergic system has been altered.

neuroscience↗

bioRxiv2020

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and points to a role of the pause in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

neuroscience↗