Abstract ID 87801Poster Board 499Opioid use disorder is prevalent, and current medications often cause undesirable side effects (e.g., sleep disturbances). Despite technological advances in neuroscience, pre-clinical substance use research often lacks translational appeal. Reverse translating models with high postdictive and ecological validity is warranted to improve treatment outcomes. As a result, our lab designed an economic choice assay with high postdictive validity to evaluate non-opioid candidate medications to treat opioid use disorder. Recently, the literature has focused on the orexin system as a possible therapeutic target for substance use disorders. Pre-clinical rodent studies suggest that high doses of both single and dual orexin receptor antagonists may attenuate opioid self-administration, decrease opioid-seeking during reinstatement, reduce opioid demand, and increase demand elasticity. The present study’s primary aim is to elucidate the effects of orexin antagonists on economic choice between remifentanil and food in squirrel monkeys. Namely, we hypothesized that suvorexant and SB-334867 would dose-dependently attenuate drug choice. To this end, squirrel monkeys (n = 7) received daily intravenous pre-treatments of orexin antagonists before completing an economic choice assay. Indifference values (the point at which subjects displayed an equal probability of selecting drug or milk) served as our primary outcome of interest, such that shifts in the IV during the 5-day treatment period compared to a contemporaneous baseline denoted changes in drug preference. Effective treatments shift responding away from drug toward the non-drug alternative. Because suvorexant treats insomnia, we also examined sleep using actigraphy monitors. Suvorexant significantly increased sleep but had a negligible effect on choice; studies with SB-334867 are currently underway.This research was supported by the Intramural Research Program of the NIH, NIDA.

Background Non-human primates play a critical role in neuroscience research. Though they are social animals, laboratory study requirements can sometimes require single housing and thereby prevent social housing. New Method To eliminate single housing and promote well-being within our squirrel monkey colony, we used positive reinforcement training in combination with magnetic/mechanical clasps and custom jackets to permit pair housing of catheterized squirrel monkeys used in behavioral studies. Results Adult Saimiri boliviensis boliviensis monkeys (n = 7) readily progressed through a six-stage training procedure for cooperative handling and transport from the home cage to the experimental testing rooms.Comparison with existing methods and conclusions: Given the evidence of isolation induced stress and neurobiological consequences in multiple species, and consistent with an increased regulatory emphasis on social housing of non-human primates, the methods presented herein provide a method for handling squirrel monkeys in behavioral studies that is compatible with social housing.

We recently reported an economic choice task in which squirrel monkeys chose between differing amounts of remifentanil, a fast-acting opioid, or a food reward to develop a preclinical screen for evaluating potential pharmacotherapies for opioid dependence. Herein, two known opioid addiction treatments were evaluated using this task, as well as a potential new agent, cariprazine, a dopamine D2/D3 receptor partial agonist currently used to treat bipolar disorder and schizophrenia. Preclinical rodent studies suggest this class of compounds may reduce opioid self-administration. Squirrel monkeys were pretreated daily with clinically relevant doses of each compound during the five days of treatment evaluation using the economic choice task. Shifts in drug preference were measured as changes in subjects’ indifference values, where the probability of drug and milk choice are equivalent. Buprenorphine produced a significant shift in indifference value between baseline and treatment weeks, indicating a decrease in drug preference. Subjects treated with methadone and cariprazine did not show any significant shift in drug preference. Differences between the buprenorphine and methadone results likely reflect a lack of opioid dependence in the subjects. The cariprazine results suggest that it does not alter opioid reward in non-dependent primates over a five day period.

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner. ChRERα consists of the prototypical excitatory opsin channelrhodopsin-2 (ChR2) and the ligand-binding domain (LBD) of the human estrogen receptor α (ERα). ChRERα showed conserved ChR2 functionality and high affinity for [ 18 F]16α-fluoroestradiol (FES), an FDA-approved PET radiopharmaceutical. Experiments in rats demonstrated that adeno-associated virus (AAV)–mediated expression of ChRERα enables neural circuit manipulation in vivo and that ChRERα expression could be monitored using FES-PET imaging. In vivo experiments in nonhuman primates (NHPs) confirmed that ChRERα expression could be monitored at the site of AAV injection in the primary motor cortex and in long-range neuronal terminals for up to 80 weeks. The anatomical connectivity map of the primary motor cortex identified by FES-PET imaging of ChRERα expression overlapped with a functional connectivity map identified using resting state fMRI in a separate cohort of NHPs. Overall, our results demonstrate that ChRERα expression can be mapped longitudinally in the mammalian brain using FES-PET imaging and can be used for neural circuit modulation in vivo.

A growing preclinical and clinical body of work on the effects of chronic drug use and drug addiction has extended the scope of inquiry from the putative reward-related subcortical mechanisms to higher-order executive functions as regulated by the prefrontal cortex. Here we review the neuroimaging evidence in humans and non-human primates to demonstrate the involvement of the prefrontal cortex in emotional, cognitive, and behavioral alterations in drug addiction, with particular attention to the impaired response inhibition and salience attribution (iRISA) framework. In support of iRISA, functional and structural neuroimaging studies document a role for the prefrontal cortex in assigning excessive salience to drug over non-drug-related processes with concomitant lapses in self-control, and deficits in reward-related decision-making and insight into illness. Importantly, converging insights from human and non-human primate studies suggest a causal relationship between drug addiction and prefrontal insult, indicating that chronic drug use causes the prefrontal cortex damage that underlies iRISA while changes with abstinence and recovery with treatment suggest plasticity of these same brain regions and functions. We further dissect the overlapping and distinct characteristics of drug classes, potential biomarkers that inform vulnerability and resilience, and advancements in cutting-edge psychological and neuromodulatory treatment strategies, providing a comprehensive landscape of the human and non-human primate drug addiction literature as it relates to the prefrontal cortex.

Insight into psychiatric disease and development of therapeutics relies on behavioral tasks that study similar cognitive constructs in multiple species. The reversal learning task is one popular paradigm that probes flexible behavior, aberrations of which are thought to be important in a number of disease states. Despite widespread use, there is a need for a high-throughput primate model that can bridge the genetic, anatomic, and behavioral gap between rodents and humans. Here, we trained squirrel monkeys, a promising preclinical model, on an image-guided deterministic reversal learning task. We found that squirrel monkeys exhibited two key hallmarks of behavior found in other species: integration of reward history over many trials and a side-specific bias. We adapted a reinforcement learning model and demonstrated that it could simulate monkey-like behavior, capture training-related trajectories, and provide insight into the strategies animals employed. These results validate squirrel monkeys as a model in which to study behavioral flexibility.

BACKGROUND: An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed. METHODS: We addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) selfadministration. A magnetic resonance imaging-only time point was also obtained following 2 years of forced abstinence. RESULTS: We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence. CONCLUSIONS: Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments.

Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power.

Most of our daily decisions are governed by one of two systems: an impulsive system driving instantaneous decisions and a deliberative system driving thoughtful ones. The impulsive system reacts to immediately available concrete rewards. In contrast, the deliberative system reacts to more delayed rewards and/or punishments, which imposes consideration of longer-term choice consequences. Contingency management for addiction treatment is hypothesized to engage deliberative processes. Ultimately, in both decision-making situations, an action is needed to enact the decision. Whether those actions differ in implementation is an open question whose answer could inform as to whether distinct neural systems are engaged. To explore whether there is evidence of separate mechanisms between deliberated and immediate choices, we trained monkeys to perform a decision-making task where they made a choice on a touch screen between two visual cues predicting different amounts of reward. In immediate choice (IC) trials, the cues appeared at the final response locations where subjects could immediately touch the chosen cue. In deliberated choice (DC) trials, compound cues appeared orthogonally to the response locations. After a delay, allowing for decision formation, an identifying cue component was displaced to the randomly assigned response locations, permitting subjects to reach for the chosen cue. Both trial types showed an effect of cue value on cue selection time. However, only IC trials showed an effect of the competing cue on response vigor (measured by movement duration) and a reach trajectory that deviated in the direction of the competing cue, suggesting a decision reexamination process. Reward modulation of response vigor implicates dopaminergic mechanisms. In DC trials, reach trajectories revealed a commitment to the chosen choice target, and reach vigor was not modulated by the value of the competing cue. Our results suggest that choice–action dynamics are shaped by competing offers only during instantaneous, impulsive choice. After a deliberated decision, choice–action dynamics are unaffected by the alternative offer cue, demonstrating a commitment to the choice. The potential relevance to contingency management is discussed.

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Transgenic neuromodulation tools have transformed the field of neuroscience over the past two decades by enabling targeted manipulation of neuronal populations and circuits with unprecedented specificity. Chemogenetic and optogenetic neuromodulation systems are among the most widely used and allow targeted control of neuronal activity through the administration of a selective compound or light, respectively. Innovative genetic targeting strategies are utilized to transduce specific cells to express transgenic receptors and opsins capable of manipulating neuronal activity. These allow mapping of neuroanatomical projection sites and link cellular manipulations with brain circuit functions and behavior. As these tools continue to expand knowledge of the nervous system in preclinical models, developing translational applications for human therapies is becoming increasingly possible. However, new strategies for implementing and monitoring transgenic tools are needed for safe and effective use in translational research and potential clinical applications. A major challenge for such applications is the need to track the location and function of chemogenetic receptors and opsins in vivo, and new developments in positron emission tomography (PET) imaging techniques offer promising solutions. The goal of this review is to summarize current research combining transgenic tools with PET for in vivo mapping and manipulation of brain circuits and to propose future directions for translational applications.

Back to table of contents Previous article Next article EditorialsFull AccessNeuromelanin MRI: Dark Substance Shines a Light on Dopamine Dysfunction and Cocaine UseCharles W. Bradberry, Ph.D.Charles W. Bradberry, Ph.D.Published Online:1 Nov 2020https://doi.org/10.1176/appi.ajp.2020.20091305AboutSectionsView articleView PDFView EPUB Start CME ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleLike celestial navigation, multimodal imaging approaches help guide us closer to the truth through the power of triangulation. Unlike the certainty of location that converging sight lines to stars can provide, however, neural events and states are often only shadows of ideas, especially in the highly interconnected realm of systems neuroscience. It is the confluence of multiple approaches in support of an idea that can provide needed confidence as we try to discern the ever-elusive inner workings of the human brain. This month's issue features an elegant demonstration of just such a triangulation. A unique MR imaging approach for quantifying neuromelanin, in concert with positron emission tomography (PET) imaging observations, both of which were validated by good analytical chemistry, led Cassidy et al. (1) to assert a unifying proposal of altered nigrostriatal dopamine function associated with cocaine use.There are two contiguous regions in the brainstem from which dopamine neurons send diverging innervations throughout the forebrain: the substantia nigra and the ventral tegmental area. The former contributes more projections to dorsal and motor-associated striatum, while the ventral tegmental area is more likely to innervate reward-related ventral striatum. Substantia nigra, or "black substance," is so named because of the presence of neuromelanin, formed through a series of reactions and aggregations that begin with the oxidation of cytosolic dopamine, promoted in part by the presence of ferric iron (Fe+3). The reactive dopamine-ortho-quinone produced can bind to aggregated and β-structured proteins in the cytosol, and subsequent oxidative polymerization then initiates formation of melanin-protein complexes, which polymerize to pheomelanin moieties that can bind high amounts of metals such as iron, as well as lipids and proteins. Macroautophagy of pheomelanin and fusion with lysosomes and autophagic vacuoles produce the enduring neuromelanin organelles that accumulate over the lifetime of a nigral dopaminergic neuron. It is only on the death of the neuron that the neuromelanin is removed, resulting in the bleaching of the substantia nigra that occurs in Parkinson's disease noted by Tretiakoff a century after Parkinson's initial description (2). Quantitative analysis of postmortem neuromelanin by Zecca and colleagues (3) revealed a monotonic increase in neuromelanin with age in non-Parkinson's subjects, and elegant work by Sulzer and colleagues demonstrated a mass action effect of cytosolic dopamine on neuromelanin formation. Thus, neuromelanin content reflects an integration of cytosolic dopamine concentration over the life of the neuron (2).The sequestration of iron by neuromelanin renders it paramagnetic, and therefore it has a unique MR signature relative to nonmelanotic tissue. In a prescient observation, Zecca and colleagues opined that "the development of neuromelanin in vivo imaging techniques may offer diagnostic and disease staging measurements matching the available tools used to monitor striatal dopamine depletion." That in vivo method, neuromelanin-sensitive MRI (NM-MRI), was developed soon thereafter (4). It was made possible by the interaction between neuromelanin and iron—other tissues equally rich in iron but with less neuromelanin do not produce MR signal hyperintensities. Those hyperintensities obtained with specific NM-MRI acquisition parameters are quantified as a contrast-to-noise ratio (CNR) in comparison with nearby melanin-lacking tissue. (See the excellent review by Sulzer and colleagues [2] for more on neuromelanin formation, its diagnostic use, and the physics of its detection with MR imaging.)While it had been demonstrated that NM-MRI CNR could distinguish populations with Parkinson's disease from control subjects, it was only recently that sufficient resolution was demonstrated to support investigation of individual differences in the absence of neurodegeneration (5). That earlier study by Cassidy et al. was a tour-de-force validation of a voxelwise NM-MRI approach capable of resolving nigral subregions by imaging postmortem sections followed by dissection along a grid with chemical analysis, demonstrating that regionally varying tissue levels of neuromelanin correlated with the NM-MRI CNR. That approach was then combined with a multimodal data set of molecular PET and fMRI, demonstrating that the in vivo NM-MRI CNR was related to both amphetamine-induced dopamine release in the dorsal striatum and resting blood flow within the substantia nigra. Specifically, the NM-MRI CNR in substantia nigra correlated positively with raclopride displacement in the dorsal striatum from the D2 receptor by endogenous dopamine released by amphetamine, which acts on presynaptic vesicular and cytosolic pools in dopamine neurons (6). This suggests that individual differences in the size of these releasable dopamine pools correlates positively with NM accumulation. In their earlier study, Cassidy et al. also measured resting cerebral blood flow in the substantia nigra (with arterial spin labeling) as a measure of basal neural activity, and this also correlated with the NM-MRI CNR in nigra only, not an anatomically contiguous reference region, or whole brain gray matter. Thus, the correlations with both a PET measure of the presynaptic amphetamine-releasable pool of dopamine and a measure of resting neural activity in the substantia nigra indicate that NM-MRI CNR reflects individual differences in presynaptic dopaminergic function. The icing on the cake was applied in the demonstration that symptom severity, known to relate to dopaminergic function in the associative striatum (7), was also significantly correlated with NM-MRI in a population of patients diagnosed with schizophrenia and a prodromal population considered at high risk of schizophrenia.Having validated the utility of an MR approach for probing dopamine function in clinical non-neurodegenerative populations, Cassidy et al. have now used their approach to probe dopaminergic differences between control and cocaine-using populations. Given dopaminergic mediation of cocaine reward and its dysfunction linked to addiction, there is an abundance of literature within which to frame predictions. Preclinical studies of sensitized increases in stimulant-elevated extracellular dopamine in rodents were the basis for assuming that the same should occur in humans. However, in a landmark study, Volkow and colleagues (8) demonstrated (using PET and raclopride displacement) that exactly the opposite is observed—a blunted presynaptic response. This has been confirmed in other human imaging studies (9), and nonhuman primate studies have also confirmed a divergence from the observations in rodents (10–12).Thus, given the evidence of reduced dopaminergic function in human and nonhuman primates following chronic cocaine use, and that NM-MRI CNR correlates with the ability of a psychostimulant to increase extracellular dopamine, the prediction by Cassidy et al. was that a cocaine-using population should have a reduced NM-MRI CNR. In order to use NM-MRI, it was critical that cocaine use is not associated with dopamine neurotoxicity or risk for Parkinson's disease, which would directly affect melanin levels through loss of dopamine neurons. Also, correcting for age was necessary, given the known relationship between age and neuromelanin accumulation (3). The results obtained were clear and unambiguous: cocaine use is associated not with reduced NM, but instead with elevated NM.The discrepancy between predicted results based on PET and postmortem measures of presynaptic dopamine function provided a glimpse into altered dopamine function in cocaine use disorder. The combination of blunted dopamine release in the striatum with elevated NM in the substantia nigra suggested that dopamine is distributed differently intracellularly in cocaine users compared with control subjects, but how? If synthesis were reduced, one would expect both decreased release and decreased NM, but what was observed instead were opposite effects. What was needed was a mechanism that explained a redistribution of dopamine such that the releasable pool was diminished while the cytosolic pool was enhanced. Triangulation of other imaging approaches in humans and nonhuman primates provided the answer.Using PET imaging, Narendran et al. (13) had observed that, consistent with postmortem results, cocaine users had reduced measures of VMAT2, the vesicular monoamine transporter that can be labeled with 11C-(+)-dihydrotetrabenazine ([11C]DTBZ). This would be consistent with the measures of reduced dopamine release, because VMAT2 is required for uptake of dopamine into vesicles from the cytosol, where it is synthesized—less uptake into vesicles would leave less available for release. That observation was significant, because reduced release was also linked to an increased risk of relapse among cocaine users attempting to quit (9). But was this a consequence of cocaine use, or a predisposing risk factor? A convergence between clinical and preclinical studies provided the answer. Longitudinal PET imaging with [11C]DTBZ in rhesus macaques before and after 16 months of cocaine self-administration indicated a 25% reduction in VMAT2. It was important that the preclinical model for cocaine use was a primate, because these reductions in VMAT2 are not seen in rodents. Most importantly, by virtue of the experimental control that animal studies can provide, Narendran et al. established causality by cocaine in reducing VMAT2.The confluence of these results from other imaging modalities and animal models enabled Cassidy et al. to provide a parsimonious and compelling mechanism for their unanticipated results. Cocaine, through a yet-to-be-determined process, causes a reduction in vesicles in dopamine neurons, with a resulting redistribution of dopamine to the cytosol, where, in the cell body, increased NM results. Exploratory analyses with functional MRI during a monetary incentive delay task did not reveal any relationship between the blood-oxygen-level-dependent (BOLD) activation in ventral striatum and the NM-MRI measures in the substantia nigra shown to be altered by cocaine use. This could be due to less neuromelanin in the more medial and dorsal regions of the ventral tegmental area and substantia nigra that project to the ventral striatum, which is most engaged by the monetary incentive delay task, rendering NM-MRI less useful for interrogating dopamine function in the ventral striatum. Also unclear is the extent to which alterations in dopamine signaling contribute to BOLD findings (14).The advantages of the approach so successfully developed and applied by Cassidy et al. are many. PET imaging, the most widely used approach for exploring aspects of dopamine function in humans, is expensive, and it cannot be used in youths because of the risks of radiation exposure. NM-MRI offers an inexpensive approach for observing an aspect of dopaminergic function which could be especially informative in longitudinal approaches or in sampling larger populations. It isn't perfect, as no technique is. However, combined with other modalities and approaches, it is helping to point the way toward intersections that will help us understand behavioral, psychiatric, and neurological disorders linked to dopaminergic dysfunction.Preclinical Pharmacology Section, NIDA Intramural Research Program, Baltimore.Send correspondence to Dr. Bradberry ([email protected]).The author reports no financial relationships with commercial interests.Supported by the NIDA Intramural Research Program.References1 Cassidy CM, Carpenter KM, Konova AB, et al.: Evidence for dopamine abnormalities in the substantia nigra in cocaine addiction revealed by neuromelanin-sensitive MRI. Am J Psychiatry 2020; 177:1038–1047Link, Google Scholar2 Sulzer D, Cassidy C, Horga G, et al.: Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson's disease. 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Psychopharmacology (Berl) 2012; 221:67–77Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited BySubstance Use Disorders and Addiction: Mechanisms, Trends, and Treatment ImplicationsNed H. Kalin, M.D.1 November 2020 | American Journal of Psychiatry, Vol. 177, No. 11 Volume 177Issue 11 November 01, 2020Pages 1019-1021 Metrics KeywordsCocaine Use DisorderSubstantia NigraNeuromelanin-Sensitive MRIDopamineSupported by the NIDA Intramural Research Program. History Accepted 4 September 2020 Published online 1 November 2020 Published in print 1 November 2020