Dopamine In Accumbens Research Articles

Accumbal Dopamine Responses Are Distinct between Female Rats with Active and Passive Coping Strategies.

There is a gap in existing knowledge of stress-triggered neurochemical and behavioral adaptations in females. This study was designed to explore the short-term consequences of a single social defeat (SD) on accumbal dopamine (DA) dynamics and related behaviors in female Wistar rats. During the SD procedure, rats demonstrated different stress-handling strategies, which were defined as active and passive coping. The "active" subjects expressed a significantly higher level of activity directed toward handling stress experience, while the "passive" ones showed an escalated freezing pattern. Remarkably, these opposite behavioral manifestations were negatively correlated. Twenty-four hours following the SD exposure, decreased immobility latency in the Porsolt test and cognitive augmentation in the new object recognition evaluation were evident, along with an increase in electrically evoked mesolimbic DA release in passive coping rats. Rats exhibiting an active pattern of responses showed insignificant changes in immobility and cognitive performance as well as in evoked mesolimbic DA response. Furthermore, the dynamics of the decline and recovery of DA efflux under the depletion protocol were significantly altered in the passive but not active female rats. Taken together, these data suggest that female rats with a passive coping strategy are more susceptible to developing behavioral and neurochemical alterations within 24 h after stress exposure. This observation may represent both maladaptive and protective responses of an organism on a short timescale.

The Influence of Strain and Sex on High Fat Diet-Associated Alterations of Dopamine Neurochemistry in Mice.

Objective: The objective of this study was to determine the influence of sex and strain on striatal and nucleus accumbens dopamine neurochemistry and dopamine-related behavior due to a high-saturated-fat diet (HFD). Methods: Male and female C57B6/J (B6J) and Balb/cJ (Balb/c) mice were randomly assigned to a control-fat diet (CFD) containing 10% kcal fat/g or a mineral-matched HFD containing 60% kcal fat/g for 12 weeks. Results: Intraperitoneal glucose tolerance testing (IPGTT) and elevated plus maze experiments (EPM) confirmed that an HFD produced marked blunting of glucose clearance and increased anxiety-like behavior, respectively, in male and female B6J mice. Electrically evoked dopamine release in the striatum and reuptake in the nucleus accumbens (NAc), as measured by ex vivo fast scan cyclic voltammetry, was reduced for HFD-fed B6J females. Impairment in glucose metabolism explained HFD-induced changes in dopamine neurochemistry for B6J males and, to a lesser extent, Balb/c males. The relative expressions of protein markers associated with the activation of microglia, ionized calcium binding adaptor molecule (Iba1) and cluster of differentiation molecule 11b (CD11b) in the striatum were increased due to an HFD for B6J males but were unchanged or decreased amongst HFD-fed Balb/c mice. Conclusions: Our findings demonstrate that strain and sex influence the insulin- and microglia-dependent mechanisms of alterations to dopamine neurochemistry and associated behavior due to an HFD.

Individual differences in decision-making shape how mesolimbic dopamine regulates choice confidence and change-of-mind.

Nucleus accumbens dopamine signaling is an important neural substrate for decision-making. Dominant theories generally discretize and homogenize decision-making, when it is in fact a continuous process, with evaluation and re-evaluation components that extend beyond simple outcome prediction into consideration of past and future value. Extensive work has examined mesolimbic dopamine in the context of reward prediction error, but major gaps persist in our understanding of how dopamine regulates volitional and self-guided decision-making. Moreover, there is little consideration of individual differences in value processing that may shape how dopamine regulates decision-making. Here, using an economic foraging task in mice, we found that dopamine dynamics in the nucleus accumbens core reflected decision confidence during evaluation of decisions, as well as both past and future value during re-evaluation and change-of-mind. Optogenetic manipulations of mesolimbic dopamine release selectively altered evaluation and re-evaluation of decisions in mice whose dopamine dynamics and behavior reflected future value.

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning.

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison among a wide set of cognitive models based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation contributes to instrumental task performance in mice and is reflected in mesolimbic dopamine signaling.

Dietary protein restriction diminishes sucrose reward and reduces sucrose-evoked mesolimbic dopamine signaling in mice

A growing literature suggests manipulating dietary protein status decreases sweet consumption in rodents and in humans. Underlying neurocircuit mechanisms have not yet been determined, but previous work points towards hedonic rather than homeostatic pathways. Here we hypothesized that a history of protein restriction reduces sucrose seeking by altering mesolimbic dopamine signaling in mice. We tested this hypothesis using established behavioral tests of palatability and conditioned reward, including the palatability contrast and conditioned place preference (CPP) tests. We used modern optical sensors for measuring real-time nucleus accumbens (NAc) dopamine dynamics during voluntary sucrose consumption, via fiber photometry, in male C57/Bl6J mice maintained on low-protein high-carbohydrate (LPHC) or control (CON) diet for ∼5 weeks. Our results showed that a history of protein restriction decreased the consumption of a sucrose ‘dessert’ in sated mice by ∼50% compared to controls [T-test, p < 0.05]. The dopamine release in NAc during sucrose consumption was reduced, also by ∼50%, in LPHC-fed mice compared to CON [T-test, p < 0.01]. Furthermore, LPHC-feeding blocked the sucrose-conditioned place preference we observed in CON-fed mice [paired T-test, p < 0.05], indicating reduced sucrose reward. This was accompanied by a 33% decrease in neuronal activation of the NAc core, as measured by c-Fos immunolabeling from brains collected directly after the CPP test [T-test, p < 0.05]. Together, these findings advance our mechanistic understanding of how dietary protein restriction decreases the consumption of sweets—by inhibiting the incentive salience of a sucrose reward, together with reduced sucrose-evoked dopamine release in NAc.

Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice

Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect—via ventral pallidium (VP)—pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.

Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology.

Synaptogyrin-3 Prevents Cocaine Addiction and Dopamine Deficits.

Synaptogyrin-3, a functionally obscure synaptic vesicle protein, interacts with vesicular monoamine and dopamine transporters, bringing together dopamine release and reuptake sites. Synaptogyrin-3 was reduced by chronic cocaine exposure in both humans and rats, and synaptogyrin-3 levels inversely correlated with motivation to take cocaine in rats. Synaptogyrin-3 overexpression in dopamine neurons reduced cocaine self-administration, decreased anxiety-like behavior, and enhanced cognitive flexibility. Overexpression also enhanced nucleus accumbens dopamine signaling and prevented cocaine-induced deficits, suggesting a putative therapeutic role for synaptogyrin-3 in cocaine use disorder.

Hypoactivity and neurochemical alterations in the basal ganglia of female Sprague-Dawley rats after repeated exposure to atrazine.

The herbicide atrazine (ATR) has been one of the most widely used herbicides worldwide. However, due to its indiscriminate use, it has been considered an environmental contaminant. Several studies have classified ATR as an endocrine disruptor, and it has been found to have neurotoxic effects on behavior, along with alterations in the dopaminergic, GABAergic, and glutamatergic systems in the basal ganglia of male rodents. These findings suggest that these neurotransmitter systems are targets of this herbicide. However, there are no studies evaluating the neurotoxicity of ATR in female rodents. Our study aimed to assess the effects of repeated IP injections of 100mg ATR/kg or a vehicle every other day for 2weeks (six injections) on the locomotor activity, content of monoamines, GABA, glutamate, and glutamine in the striatum, nucleus accumbens, ventral midbrain, and prefrontal cortex, and tyrosine hydroxylase (TH) protein levels in striatum and nucleus accumbens of female rats. Repeated 100mg ATR/kg injections immediately decreased all the locomotor activity parameters evaluated, and such hypoactivity persisted for at least 48h after the last ATR administration. The ATR administration increased dopamine and DOPAC content in the nucleus accumbens and the dopamine and DOPAC and serotonin and 5-HIAA content in the ventral midbrain. In contrast, the TH protein levels in the striatum and nucleus accumbens were similar between groups. Meanwhile, GABA, glutamine, and glutamate levels remained unaltered in all brain regions evaluated. The observed behavioral alterations could be associated with the monoamine changes presented by the rats. These data reveal that the nucleus accumbens and ventral midbrain are susceptible to repeated ATR exposure in female rats.

Effects of heat stress on the feeding preference of yellow-feathered broilers and its possible mechanism

Heat stress is the most critical factor affecting animal feeding in summer. This experiment was conducted to investigate the effects of heat stress on the feeding preference of yellow-feathered broilers and its possible mechanism. As a result, the preference of yellow-feathered broilers for Tenebrio molitor was significantly decreased, and the fear response and serum corticosterone of broilers were significantly increased when the ambient temperatures are 35 °C (P < 0.05). In the central nervous system, consistent with the change in feeding preference, decreased dopamine in the nucleus accumbens (NAc) and increased mRNA levels of MAO-B in the ventral tegmental area (VTA) and NAc were found in yellow-feathered broilers (P < 0.05). In addition, we found significantly increased mRNA levels of corticotropin-releasing hormone receptor 1, corticotropin-releasing hormone receptor 2 and glucocorticoid receptor in the VTA and NAc of female broilers (P < 0.05). However, no similar change was found in male broilers. On the other hand, the serum levels of insulin and glucagon-like peptide-1 were increased only in male broilers (P < 0.05). Accordingly, the mRNA levels of insulin receptor and glucagon-like peptide-1 receptor in the VTA and the phosphorylation of mTOR and PI3K were increased only in male broilers (P < 0.05). In summary, the preference of yellow-feathered broilers for Tenebrio molitor feed decreased under heat stress conditions, and hedonic feeding behavior was significantly inhibited. However, the mechanism by which heat stress affects hedonic feeding behavior may contain gender differences. The insulin signaling pathway may participate in the regulation of heat stress on the male broiler reward system, while stress hormone-related receptors in the midbrain may play an important role in the effect of heat stress on the reward system of female broilers.

Antidepressant effect of new coumarin derivatives

BACKGROUND: The incidence of bipolar disorder is increasing worldwide. The search for new compounds with antidepressant activity and milder adverse drug reactions is an urgent task of modern psychopharmacology. AIM: This study aimed to analyze the effect of new neuroactive coumarin derivatives on the level of depressive behavior and monoamine metabolism in the brain structures of rats. MATERIALS AND METHODS: The antidepressant effects of LVM-091, LVM-099, LVM-S144, and IEM-2886 were evaluated in rats subjected to the Porsolt forced swimming test and the metabolism of monoamines in brain structures (LVM-099) using high-performance liquid chromatography. RESULTS: LVM-091, LVM-099, LVM-S144, and IEM-2886, synthesized from coumarin, decreased the immobilization time of the experimental rats in the Porsolt forced swimming test, indicating the antidepressant effect of these substances. The administration of LVM-099 at a dose of 10 mg/kg increased the level of homovanillic acid and the homovanillic acid-to-dopamine ratio in the nucleus accumbens. LVM-099 also increased 5-hydroxyindoleacetic acid levels and the 5-hydroxyindoleacetic acid-to-serotonin ratio in the nucleus accumbens. In the amygdala, the levels of norepinephrine, dopamine, serotonin, and their metabolites did not change after LVM-099 administration. CONCLUSIONS: New coumarin derivatives exert antidepressant effects and increase the metabolism of dopamine and serotonin in rat nucleus accumbens, which can be used in the development of new highly effective antidepressants.

Haploinsufficiency of the Parkinson's disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling.

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Effects of psychedelic, DOI, on nucleus accumbens dopamine signaling to predictable rewards and cues in rats.

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic 5-HT2A/2C agonist, DOI, effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute DOI administration in rats during well learned Pavlovian tasks in which sequential cues predict rewards. We find that DOI (0.0-1.2 mg/kg, i.p.) increases dopamine signals, photometrically measured using GRABDA optical sensor, to rewards and proximal reward cues, but not to the distal cues that predict these events. We determine that the elevated dopamine produced by DOI to reward cues occurs independently of DOI-induced changes in reward value. The increased dopamine associated with predictable reward cues and rewards supports DOI-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations.

Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit.

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm 2 I sppa ) of 2-minute LIFU to the prelimbic region (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm 2 to the PLC significantly reduced dopamine release by ∼ 50% for up to 2 hours. However, double the intensity (26 W/cm 2 ) resulted in less inhibition (∼30%), and half the intensity (6.5 W/cm 2 ) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling of temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm 2 , suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.

Dietary protein restriction diminishes sucrose reward and reduces sucrose-evoked mesolimbic dopamine signaling.

A growing literature suggests manipulating dietary protein status decreases sweet consumption in rodents and in humans. Underlying neurocircuit mechanisms have not yet been determined, but previous work points towards hedonic rather than homeostatic pathways. Here we hypothesized that a history of protein restriction reduces sucrose seeking by altering mesolimbic dopamine signaling. We tested this hypothesis using established behavioral tests of palatability and motivation, including the 'palatability contrast' and conditioned place preference (CPP) tests. We used modern optical sensors for measuring real-time nucleus accumbens (NAc) dopamine dynamics during sucrose consumption, via fiber photometry, in male C57/Bl6J mice maintained on low-protein high-carbohydrate (LPHC) or control (CON) diet for ∼5 weeks. A history of protein restriction decreased the consumption of a sucrose 'dessert' in sated mice by ∼50% compared to controls [T-test, p< 0.05]. The dopamine release in NAc during sucrose consumption was reduced, also by ∼50%, in LPHC-fed mice compared to CON [T-test, p< 0.01]. Furthermore, LPHC-feeding blocked the sucrose-conditioned place preference we observed in CON-fed mice [paired T-test, p< 0.05], indicating reduced motivation. This was accompanied by a 33% decrease in neuronal activation of the NAc core, as measured by c-Fos immunolabeling from brains collected directly after the CPP test. Despite ongoing efforts to promote healthier dietary habits, adherence to recommendations aimed at reducing the intake of added sugars and processed sweets remains challenging. This study highlights chronic dietary protein restriction as a nutritional intervention that suppresses the motivation for sucrose intake, via blunted sucrose-evoke dopamine release in NAc.

Dopamine neurons drive spatiotemporally heterogeneous striatal dopamine signals during learning

Environmental cues, through Pavlovian learning, become conditioned stimuli that invigorate and guide animals toward rewards. Dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) are crucial for this process, via engagement of a reciprocally connected network with their striatal targets. Critically, it remains unknown how dopamine neuron activity itself engages dopamine signals throughout the striatum, across learning. Here, we investigated how optogenetic Pavlovian cue conditioning of VTA or SNc dopamine neurons directs cue-evoked behavior and shapes subregion-specific striatal dopamine dynamics. We used a fluorescent biosensor to monitor dopamine in the nucleus accumbens (NAc) core and shell, dorsomedial striatum (DMS), and dorsolateral striatum (DLS). We demonstrate spatially heterogeneous, learning-dependent dopamine changes across striatal regions. Although VTA stimulation-evoked robust dopamine release in NAc core, shell, and DMS, predictive cues preferentially recruited dopamine release in NAc core, starting early in training, and DMS, late in training. Negative prediction error signals, reflecting a violation in the expectation of dopamine neuron activation, only emerged in the NAc core and DMS. Despite the development of vigorous movement late in training, conditioned dopamine signals did not emerge in the DLS, even during Pavlovian conditioning with SNc dopamine neuron activation, which elicited robust DLS dopamine release. Together, our studies show a broad dissociation in the fundamental prediction and reward-related information generated by VTA and SNc dopamine neuron populations and signaled by dopamine across the striatum. Further, they offer new insight into how larger-scale adaptations across the striatal network emerge during learning to coordinate behavior.

Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice

BackgroundPast research has illuminated pivotal roles of dopamine D3 receptors (D3R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear. MethodsWe employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1 receptor (D1R)–expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D3R in cocaine and opioid actions. ResultsOur results revealed D3R expression in ∼25% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While dopamine D2 receptors (D2R) were expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D3R from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, deletion of D3R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. ConclusionsWe dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D3R are critically involved in the actions of opioids but not cocaine.

Ventral Tegmental Area Amylin Receptor Activation Differentially Modulates Mesolimbic Dopamine Signaling in Response to Fat versus Sugar.

Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.

Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (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 drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types.

The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine releasein reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.