Dopamine System Research Articles

Decreased Ventral Tegmental Area CB1R Signaling Reduces Sign Tracking and Shifts Cue-Outcome Dynamics in Rat Nucleus Accumbens.

Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels. We use cell type-specific optogenetics, intra-VTA pharmacology, and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign tracking. We trained male and female rats in a Pavlovian lever autoshaping (PLA) task to determine their tracking groups before testing the effect of VTA → NAc dopamine inhibition. We found that this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRABDA (AAV9-hSyn-DA2m), we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping in female rats. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases in NAc shell, but not core, dopamine levels during reward delivery [unconditioned stimulus (US)]. Our results suggest that CB1R signaling in the VTA influences the balance between the conditioned stimulus-evoked and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats.SIGNIFICANCE STATEMENT Substance use disorder (SUD) is a chronically relapsing psychological disorder that affects a subset of individuals who engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences before drug experience that predict SUD and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug-motivated behaviors.

Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Activation of a hypothalamus-habenula circuit by mechanical stimulation inhibits cocaine addiction-like behaviors

BackgroundMechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry.ResultsMechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit.ConclusionThese findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.

The Pesticide Chlordecone Promotes Parkinsonism-like Neurodegeneration with Tau Lesions in Midbrain Cultures and C. elegans Worms.

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson's disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomotor deficits secondary to alterations in food perception. L-DOPA, a molecule used for PD treatment, corrected these deficits. Cholinergic and serotoninergic neuronal cells were also affected by CLD in C. elegans, although to a lesser extent than DA neurons. Noticeably, CLD also promoted the phosphorylation of the aggregation-prone protein tau (but not of α-synuclein) both in midbrain cell cultures and in a transgenic C. elegans strain expressing a human form of tau in neurons. In summary, our data suggest that CLD is more likely to promote atypical forms of Parkinsonism characterized by tau pathology than classical synucleinopathy-associated PD.

Learning new words via feedback-Association between feedback-locked ERPs and recall performance-An exploratory study.

Feedback learning is thought to involve the dopamine system and its projection sites in the basal ganglia and anterior cingulate cortex (ACC), regions associated with procedural learning. Under certain conditions, such as when feedback is delayed, feedback-locked activation is pronounced in the medial temporal lobe (MTL), which is associated with declarative learning. In event-related potential research, the feedback-related negativity (FRN) has been linked to immediate feedback processing, while the N170, possibly reflecting MTL activity, has been related to delayed feedback processing. In the current study, we performed an exploratory investigation on the relation between N170 and FRN amplitude and memory performance in a test for declarative memory (free recall), also exploring the role of feedback delay. To this end, we adapted a paradigm in which participants learned associations between non-objects and non-words with either immediate or delayed feedback, and added a subsequent free recall test. We indeed found that N170, but not FRN amplitudes, depended on later free recall performance, with smaller amplitudes for later remembered non-words. In an additional analysis with memory performance as dependent variable, the N170, but not the FRN amplitude predicted free recall, modulated by feedback timing and valence. This finding shows that the N170 reflects an important process during feedback processing, possibly related to expectations and their violation, but is distinct from the process reflected by the FRN.

Obsessive-compulsive disorder: Etiology, neuropathology, and cognitive dysfunction.

This review provides an overview of obsessive-compulsive disorder (OCD) symptoms, including the four partially distinct subtypes of the disorder, current diagnostic criteria, and common comorbidities. Critically, it focuses on the etiology of OCD, including its underlying neuropathology, and examines cognitive dysfunction in OCD. This review study was conducted by library method. We show how dysfunction in cortico-striato-thalamo-cortical (CSTC) circuits may underpin symptoms; and shed light on the putative neurochemistry within these loops such as the role of serotonin, dopamine, and glutamate systems. We also show how OCD is characterized by cognitive dysfunction including problems in cognitive flexibility, visuospatial memory, response inhibition, and goal-directed behavior, linked to aberrant activity within CSTC circuits. In brief, research questions we shed light on include (1) what are the symptoms in OCD; (2) what is the etiology of the disorder and do existing models explain OCD; and (3) what are key cognitive deficits in OCD and do these improve with treatment?

Striatal serotonin transporter gain-of-function in L-DOPA-treated, hemi-parkinsonian rats

L-DOPA is the standard treatment for Parkinson’s disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex interaction between the remaining dopamine (DA) system and the semi-homologous serotonin (5-HT) system. Since serotonin transporters (SERT) have some affinity for DA uptake, they may serve as a functional compensatory mechanism when DA transporters (DAT) are scant. DAT and SERT’s functional contributions in the dyskinetic brain have not been well delineated. The current investigation sought to determine how DA depletion and L-DOPA treatment affect DAT and SERT transcriptional processes, translational processes, and functional DA uptake in the 6-hydroxydopamine-lesioned hemi-parkinsonian rat. Rats were counterbalanced for motor impairment into equally lesioned treatment groups then given daily L-DOPA (0 or 6 mg/kg) for 2 weeks. At the end of treatment, the substantia nigra was processed for tyrosine hydroxylase (TH) and DAT gene expression and dorsal raphe was processed for SERT gene expression. The striatum was processed for synaptosomal DAT and SERT protein expression and ex vivo DA uptake. Nigrostriatal DA loss severely reduced DAT mRNA and protein expression in the striatum with minimal changes in SERT. L-DOPA treatment, while not significantly affecting DAT or SERT alone, did increase striatal SERT:DAT protein ratios. Using ex vivo microdialysis, L-DOPA treatment increased DA uptake via SERT when DAT was depleted. Overall, these results suggest that DA loss and L-DOPA treatment uniquely alter DAT and SERT, revealing implications for monoamine transporters as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction.

Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment.

Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson's disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients with 22q11.2DS, was generated. The behavior of this mouse model was extensively studied and several abnormalities related to the symptoms of 22q11.2DS were found. However, the histological features of their brains have been little addressed. Here we describe the cytoarchitectures of the brains of Del(3.0Mb)/+ mice. First, we investigated the overall histology of the embryonic and adult cerebral cortices, but they were indistinguishable from the wild type. However, the morphologies of individual neurons were slightly but significantly changed from the wild type counterparts in a region-specific manner. The dendritic branches and/or dendritic spine densities of neurons in the medial prefrontal cortex, nucleus accumbens, and primary somatosensory cortex were reduced. We also observed reduced axon innervation of dopaminergic neurons into the prefrontal cortex. Given these affected neurons function together as the dopamine system to control animal behaviors, the impairment we observed may explain a part of the abnormal behaviors of Del(3.0Mb)/+ mice and the psychiatric symptoms of 22q11.2DS.

Providing or receiving alloparental care promote partner preference and alter central oxytocin and dopamine systems in adult mandarin voles

Juveniles of cooperative breeding species usually remain in the natal area and provide care to younger siblings, a behavior considered one form of alloparenting in the natural condition. Previous studies have demonstrated the effects of providing or receiving alloparental care on adult behaviors, including anxiety-like behavior, social interaction, and parental behavior, but little is known about the influences on species-typical bonding behaviors, such as pair-bond formation. In this study, we explored this concept using socially monogamous mandarin voles (Lasiopodomys mandarinus). As the oxytocin (OT) and dopamine systems are involved in alloparental and pair-bonding behaviors, we also examined the levels of central OT and tyrosine hydroxylase (TH), as well as OT receptor (OTR) and dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and amygdala to investigate the underlying mechanisms. Our results show that mandarin voles providing alloparental care to younger siblings displayed facilitation of partner preference formation, lower levels of OT expression in the paraventricular nucleus of the hypothalamus (PVN) and lateral hypothalamus (LH), and increased OTR and D2R mRNA expression in the NAcc compared to controls. Individuals receiving alloparental care also demonstrated facilitation of partner preference formation in adult voles. Additionally, alloparental care enhanced OT expression in the PVN, anterior medial preoptic nucleus (MPOAa), medial amygdala (MeA), and TH expression in the ventral tegmental area (VTA) and zona incerta (ZI). Furthermore, males displayed decreased D1R mRNA expression in the NAcc, whereas females showed slightly increased D2R expression in the amygdala. These results demonstrate that providing or received alloparental care can promote partner preference formation in monogamous species and that these changes are associated with altered OT and dopamine levels and their receptors in specific brain regions.

Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study.

Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003-0.005) and higher LEDD over time (P range <0.001-0.01) were significantly associated with increased risk for CI. Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

Anticipation of Appetitive Operant Action Induces Sustained Dopamine Release in the Nucleus Accumbens.

The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. These implications are commonly investigated in either pavlovian or operant reinforcement paradigms, where only the latter requires instrumental action. To parse contributions of reward- and action-related information to dopamine signals, we directly compared the two paradigms: male rats underwent either pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. Task conditions were identical with the exception of the operant-lever response requirement. Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire 5 s cue presentation (preceding the required action). This dopamine ramp was unaffected by probabilistic reward delivery, occurred exclusively before operant actions, and was not related to task performance or task acquisition as it persisted throughout the 2 week daily behavioral training. Instead, the ramp flexibly increased in duration with longer cue presentation, seemingly modulating the initial cue-onset-triggered dopamine release, that is, the reward prediction error (RPE) signal, as both signal amplitude and sustainment diminished when reward timing was made more predictable. Thus, our findings suggest that RPE and action components of dopamine release can be differentiated temporally into phasic and ramping/sustained signals, respectively, where the latter depends on the former and presumably reflects the anticipation or incentivization of appetitive action, conceptually akin to motivation.SIGNIFICANCE STATEMENT It is unclear whether the components of dopamine signals that are related to reward-associated information and reward-driven approach behavior can be separated. Most studies investigating the dopamine system use either pavlovian or operant conditioning, which both involve the delivery of reward and necessitate appetitive approach behavior. Thus, used exclusively, neither paradigm can disentangle the contributions of these components to dopamine release. However, by combining both paradigms in the same study, we find that anticipation of a reward-driven operant action induces a modulation of reward-prediction-associated dopamine release, producing so-called dopamine ramps. Therefore, our findings provide new insight into dopamine ramps and suggest that dopamine signals integrate reward and appetitive action in a temporally distinguishable, yet dependent, manner.

From Prediction to Action: Dissociable Roles of Ventral Tegmental Area and Substantia Nigra Dopamine Neurons in Instrumental Reinforcement.

Reward seeking requires the coordination of motor programs to achieve goals. Midbrain dopamine neurons are critical for reinforcement, and their activation is sufficient for learning about cues, actions, and outcomes. Here we examine in detail the mechanisms underlying the ability of ventral tegmental area (VTA) and substantia nigra (SNc) dopamine neurons to support instrumental learning. By exploiting numerous behavioral tasks in combination with time-limited optogenetic manipulations in male and female rats, we reveal that VTA and SNc dopamine neurons generate reinforcement through separable psychological processes. VTA dopamine neurons imbue actions and their associated cues with motivational value that allows flexible and persistent pursuit, whereas SNc dopamine neurons support time-limited, precise, action-specific learning that is nonscalable and inflexible. This architecture is reminiscent of actor-critic reinforcement learning models with VTA and SNc instructing the critic and actor, respectively. Our findings indicate that heterogeneous dopamine systems support unique forms of instrumental learning that ultimately result in disparate reward-seeking strategies.SIGNIFICANCE STATEMENT Dopamine neurons in the midbrain are essential for learning, motivation, and movement. Here we describe in detail the ability of VTA and SNc dopamine neurons to generate instrumental reinforcement, a process where an agent learns about actions they can emit to earn reward. While rats will avidly work and learn to respond for activation of VTA and SNc dopamine neurons, we find that only VTA dopamine neurons imbue actions and their associated cues with motivational value that spur continued pursuit of reward. Our data support a hypothesis that VTA and SNc dopamine neurons engage distinct psychological processes that have consequences for our understanding of these neurons in health and disease.

Ventral striatum dopamine release encodes unique properties of visual stimuli in mice.

The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that plays a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system's ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.

Preclinical evidence for the use of the atypical antipsychotic, brexpiprazole, for opioid use disorder

Opioid addiction is characterized by adaptations in the mesolimbic dopamine system that occur during chronic opioid use. Alterations in dopaminergic transmission contribute to pathological drug-seeking behavior and other symptoms associated with opioid withdrawal following drug discontinuation, making drug abstinence challenging and contributing to high rates of relapse among those suffering from substance use disorder. Recently, the use of dopamine partial agonists has been proposed as a potential strategy to restore dopaminergic signalling during drug withdrawal, while avoiding the adverse side effects associated with stronger modulators of dopaminergic transmission. We investigated the effects of the atypical antipsychotic brexpiprazole, which is a partial agonist at dopamine D2 and D3 receptors, in a mouse model of opioid dependence. The development of opioid dependence in mice is characterized by locomotor sensitization, analgesic tolerance, opioid-induced hyperalgesia, and drug-seeking behavior. We set up four paradigms to model the effects of brexpiprazole on each of these adaptations that occur during chronic opioid use in male and female C57BL/6J mice. Concomitant treatment of brexpiprazole during chronic morphine administration attenuated the development of locomotor sensitization. Brexpiprazole treatment abolished morphine place preference and blocked reinstatement of this behavior following extinction. Brexpiprazole treatment did not alter morphine analgesia, nor did it impact the development of morphine tolerance. However, brexpiprazole treatment did prevent the expression of opioid-induced hyperalgesia in a tail-withdrawal assay, while failing to improve somatic withdrawal symptoms. Altogether, these results provide preclinical evidence for the efficacy of brexpiprazole as a modulator of dopamine-dependent behaviors during opioid use and withdrawal.

Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease.

Antipsychotics increase the risk of death in elderly patients with Alzheimer's disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.

Blockade of the Dopamine D3 Receptor Attenuates Opioids-Induced Addictive Behaviours Associated with Inhibiting the Mesolimbic Dopamine System.

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.