Jared W. Young - US grants

DESCRIPTION (provided by applicant): A positive link between cognitive performance and global functioning/quality of life has been established in numerous neuropsychiatric disorders including schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, and Alzheimer's disease. Of the several cognitive domains impaired in these disorders, vigilance dysfunction may constitute a core deficit, since inability to attend to relevant stimuli has a subsequently deleterious effect on higher-order integrative cognitive domains. In humans, vigilance is most often assessed with the continuous performance test (CPT), which requires that the subject attend to relevant stimuli while ignoring irrelevant stimuli. Although this task is a "gold standard" task of vigilance in humans and is very sensitive to cognitive dysfunction, there are no direct animal analogues of the CPT. The successful treatment of cognitive deficits in neuropsychiatric disorders first requires the 'translational gap'between preclinical and clinical cognitive testing to be filled, in part by the development of more predictive behavioral models. The rodent continuous performance test (rCPT) is a newly developed paradigm in mice that may narrow this gap. The rCPT assesses vigilance in mice using signal detection theory measures, similar to the human CPT. This R21 application is designed to test the predictive and construct validity of rCPT for human vigilance. Specific Aim 1 will determine whether the rCPT in mice fulfills the specific criteria that have been established for validating a vigilance task, based on the taxonomy of factors that affect vigilance performance in the human CPT. Specific Aim 2 will then use dose-response studies to assess the pharmacological predictive validity of the rCPT by determining whether psychostimulants such as nicotine, amphetamine, and methylphenidate will improve performance and whether ketamine will impair vigilance performance, consistent with human CPT studies. Aim 2 will also test a specific hypothesis regarding the predicted involvement of parietal cortex in performance on the rCPT. Specific Aim 3 will investigate the utility of the rCPT in drug discovery research. Acute and sub-chronic treatment studies will examine whether the 17 nicotinic acetylcholine receptor (nAChR) is necessary for nicotine-induced enhancement of vigilance by comparing the effects of nicotine on mutant mice with 100%, 50%, and 0% 17 nAChR expression in the rCPT. Thus the overall goal of this application is to establish this novel rCPT model as a practical and valid preclinical tool for assessing vigilance. Such a tool will allow a more complete assessment of the validity of animal models of neuropsychiatric disorders, studies which will form part of a R01 application. Furthermore, the rCPT will aid in psychiatric drug development by determining whether a putative cognitive enhancer will translate from preclinical to clinical vigilance testing. PUBLIC HEALTH RELEVANCE: Improving cognitive deficiencies in neuropsychiatric patients is vitally important, yet there has been limited progress in developing effective treatments. There remains a translational gap between preclinical and clinical testing, limiting the progression of compounds that succeed in humans. This project will validate the novel rodent continuous performance test of vigilance, providing a means by which positive results for compounds observed in rodents will likely succeed in man.

DESCRIPTION (provided by applicant): Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics, as well as premonitory urges, obsessions, compulsions and attention deficits. Current medications for TS reduce tic severity in some patients, but are ineffective against the most impairing TS symptoms and are associated with significant adverse effects. Thus, new medications that effectively target TS symptoms, but are less prone to produce deleterious side effects are critically needed. The etiology of TS remains unknown, but new evidence from genetic and neuropathological studies has led to plausible hypotheses for the etiology of some forms of this disorder. The discovery of novel medications for TS, and the assessment of new hypotheses for its causes, has been limited by the paucity of animal models for TS. Existing animal models are based primarily on decades-old measures of "tic-like" or stereotyped behaviors in rats that may have little neurobiological relevance to the most functionally impairing TS symptoms. Most of these antiquated models are limited in their ability to predict efficacy for compounds other than dopamine D2-receptor antagonists, which have only limited efficacy in treating TS. Novel TS models are needed that are sensitive to neurobiological substrates of the most impairing cognitive and sensorimotor deficits in this disorder. The goal of the present application is to develop and apply a novel predictive animal model for TS based on visuospatial priming (VSP) deficits in TS patients. The VSP paradigm is a quantitative psychophysiological measure of response inhibition and facilitation in which TS patients exhibit excessive facilitation and deficient inhibition, relative to healthy controls. VSP deficits in TS patients correlate significantly with the therapeutic outcome of habit reversal therapy, an effective controlled treatment for TS. This suggests that an animal model of VSP deficits may be a valuable and predictive model for novel TS therapeutics. A rat operant model of VSP is being developed that reproduces the patterns of normal VSP exhibited by humans. Rats are trained to respond to a target stimulus, but to inhibit responding to a simultaneously presented distracter stimulus. This discrimination task is then extended to model a full human VSP task, with prime and probe trials and measurements of reaction times to detect levels of facilitatory and inhibitory priming. Normal VSP performance will then be challenged pharmacologically, using drugs that are conceptually linked to neurochemical abnormalities in TS patients. The predictive validity of this novel model will first be assessed using "known" anti-tic medications to normalize VSP deficits, and a potential new medication for TS will then be tested that is believed to function via a novel therapeutic mechanism. Future studies will investigate the neural mechanisms regulating VSP in rats, and will use this measure to test novel genetic and neurodevelopmental hypotheses of TS etiology. If successful, the present application may provide a critical tool to bridge a significant gap in TS research, and ultimately advance our understanding and treatment of this disorder. PUBLIC HEALTH RELEVANCE: The goal of the present application is to develop and apply a novel predictive animal model for Tourette Syndrome (TS) that is based on visuospatial priming (VSP) deficits in TS patients. VSP deficits in TS patients correlate strongly, and highly significantly, with the therapeutic outcome of habit reversal therapy (HRT), an emerging and clinically controlled treatment form for TS. This suggests that a model of VSP deficits in rats may be valuable in predicting therapeutic success in TS, and ultimately help bridge the translational gap from preclinical studies to novel therapeutics for TS.

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a lifelong severe mental illness affecting up to 2% of the population. BD is unique in that patients switch between extreme states of mania (euphoria, impulsivity, etc.) to depression (sedation, despair, etc.). Poor treatment options contribute to a high rate of suicide. The lack of options is partly due to our limited knowledge of circuitry causing switches between mood states in BD. Identifying this circuitry requires model animals that share biological changes seen in BD patients. Currently, no model animals related to the causes of this switch exist. Elevating dopamine (DA) activity can induce manic episodes. The DA transporter (DAT) serves to reduce synaptic DA. DAT polymorphisms associated with BD reduce the functional expression of DAT (50%) and limit DA clearance. In BD, DAT levels are reduced irrespective of state. Reduced DAT may therefore also be important for depressed moods. Beyond nature, the environment can trigger switches, e.g., mania episodes occur most often as days grow longer while depressive episodes occur in shorter days. Similarly, normal rats housed in high and low activity-inducing photoperiods (summer- and winter-like) switch into modest mania- and depressive-like behaviors respectively. Immunocytochemistry revealed some of the neural chemistry underlying these switches. During long-activity photoperiods, DA was elevated while somatostatin (SST) was reduced in the brain region that receives light input (the hypothalamus). The opposite was true for short-activity photoperiods. The overall hypothesis tested here is that reduced DAT expression in mice confers susceptibility to extreme behavioral switches resulting from altered photoperiods. Specific Aim 1 will test if mice with 50% DAT expression exhibit mania-like behaviors when housed in long activity-inducing photoperiods and depression-like behaviors in short activity-inducing photoperiods. These behaviors will be measured using ethologically relevant tests for 'mood' and by tests of attention, risk-taking, exploration, and sensorimotor gating that are used in both mice and humans. Specific Aim 2 will map the brain circuitry hypothesized to underlie these extreme changes in behavior. The working model is that 50% DAT expression causes changes in the neurochemical environment enabling higher DA and SST expression during changing photoperiods. Hence, the hypotheses are that: A) long-activity photoperiods will elevate hypothalamic DA, elevating DA D2 receptor expression and DA in the striatum, and thereby lead to mania-like behaviors; and B) short-activity photoperiods will elevate levels of hypothalamic SST and corticotropin releasing factor, elevating hippocampal acetylcholine levels, and thereby producing depression-like behaviors. These studies will help elucidate the circuitry underlying switching between the extreme poles of BD. This research should facilitate the identification of novel treatments targeted at this neural circuitry. Furthermore, because the animal cognitive and behavioral tasks used have human analogs, any treatments developed for this circuit will have an increased chance of working in the clinic, helping patients with BD.

DESCRIPTION (provided by applicant): For those with severe mental illness, cognitive deficits are the core impediment to their independent living. Treatments to improve cognition are urgently needed, but no new pharmacotherapies have been approved in over a decade. Psychotherapeutic interventions remain helpful but exhibit only moderate effect sizes. Because these interventions predominantly aid learning through positive reinforcement strategies, augmenting such learning with pharmacotherapies should synergistically enhance the effectiveness of those interventions. Striatal dopamine D1 receptors contribute to positive reinforcement learning but directly targeting these receptors produce undesirable side-effects. Activating the a7 nicotinic acetylcholine receptor (nAChR) indirectly activates striatal dopamine D1 receptors, providing a link between the a7 nAChR and positive reinforcement learning. This project will identify dopaminergic and nAChR pro-learning treatments and determine whether their effects are mediated by striatal dopamine D1 receptors. Reward- and punishment- related learning will be measured using the probabilistic learning (PL) task. The PL task rewards and punishes responding to both target and non-target stimuli. Selecting the target stimulus is normally rewarded (80%) but occasionally punished (20%). For the non-target stimulus, the reward/punishment schedule is reversed. Thus importantly, the PL task measures the speed at which the animal acquires contingencies during uncertainty and modulates its behavior as a function of reward history. Selecting the same side after a reward (win-stay) is beneficial only after a target response, while shifting after a loss is beneficial only after a non-target response reflecting good reward- and punishment-associative learning respectively. The indirect dopamine agonist levodopa improves PL via enhancing reward-associative learning in both healthy humans and Parkinson's patients. Similarly, we demonstrated an amphetamine- (another indirect dopamine agonist) and nicotine- (a general nAChR agonist) induced improvement of PL in mice via enhancing reward-associative learning. Specific Aim 1 will identify pro-learning doses of amphetamine, nicotine, and the selective a7 nAChR agonist PNU 282987, utilizing amphetamine as a positive control. Specific Aim 2 will determine the mechanism(s) underlying pro-learning effects of amphetamine, nicotine, and PNU via combined studies with pharmacological inactivation of: 1) a7 nAChRs (methyllycaconitine); 2) dopamine D1-like (SCH 23390); and 3), D2-like receptors (haloperidol); plus 4) Genetic null-mutation of the a7 nAChR, and 5) Adeno- Associated Viral (AAV)-induced suppression of striatal dopamine D1 receptors. Thus, using complementary techniques, we will confirm that a7 nAChR activation improves learning via enhancing reward-associative learning, a mechanism that is a7 nAChR-dependent and that occurs as a result of indirect activation of striatal dopamine D1 receptors. Pro-learning treatments identified here could be tested in healthy humans, potentially augmenting psychotherapeutic interventions and improving the lives of patients with mental illness.

? DESCRIPTION (provided by applicant): There has been a fundamental failure to translate preclinically-supported compounds into clinically-approved treatments. This failure generally reflects the profound differences between phenomenon assessed in the laboratory and those targeted in the clinic. Behavioral similarity is not enough to suggest translation. For novel treatments to emerge, they will require animal models with cross-species consistency. Hence, there is a critical need for: i) neurophysiological biomarkers of behaviors relevant to domains affected in psychiatric patients that; ii) can be conducted across species; and iii) that are alterd by drug treatment. Such biomarkers would prove stronger evidence that effective preclinical pharmacological manipulations could be effective clinical treatments. We developed the 5-choice continuous performance test (5C-CPT) to quantify cognitive control and response inhibition for use in rodents and humans. We also developed a probabilistic learning (PL) task for mechanistic understanding of reward learning across species. New endeavors here include the progressive ratio breakpoint procedure (PRBP), a task first developed to quantify motivation from physical effort and a rodent cognitive effort task (CET) both of which have recently been reverse-translated for human testing. In addition, action selection/preference-based decision making can be measured across species using the risky gains task (RGT), which quantifies responding to positive vs. negative feedback on a trial-by-trial basis. The UH2 component of this application (Specific Aim 1) will use electrophysiological biomarkers to test the following hypothesis across species: 5C-CPT 1A) Non-target (nogo) stimuli response levels (response inhibition) will inversely correlate with larger frontal event-related potential (ERP) components (e.g. P3a) and 1B) Parietal beta activity will correlate with the sensitivity index measure of cognitive control. PL 2A) the Reward Positivity ERP component, which scales with the degree of positive prediction error, will vary in strength according to probability ratio (80/20>70/30>60/40) and 2B) the strength of the Reward Positivity will correlate with the % correct within each ratio block. PRBP 3) Physical effort will be linked to frontal alpha power; CET 4) Hard cognitive effort choices will be linked to ACC activation as measured by frontal midline theta power. RGT 5A) A stronger mid-frontal theta oscillatory component (Feedback-Related Negativity) will correlate with shifting choices after punishment feedback while 5B) Parietal delta power (e.g. P3) locked to the imperative cue will correlate with the likelihood of staying at the same choice after reward Tasks fulfilling these hypotheses in both mice and humans will then move onto the UH3 component (Specific Aim 2) which will test whether elevating frontal dopamine levels via tolcapone treatment will influence behavior and neurophysiological markers during these tasks. For example, we would hypothesize that tolcapone would induce stronger frontal late ERPs and reduced response inhibition in the 5C-CPT, or increased ACC activation and hard-choice preference in the CET.

ABSTRACT People with HIV-1 infection smoke at higher rates (40%) than the general population (16%), with non-HIV smokers showing a greater ability to quit. Given the movement of HIV infection from a `fatal' to `chronic' disease, increased smoking rates may negatively impact long-term health outcomes. Understanding why rates are so high remains critical to aiding quit attempts. Given that HIV infection results in inflammation, and nicotine (the primary psychoactive ingredient of tobacco) reduces inflammation, people with HIV may smoke as a means to medicate symptoms. Nicotine exerts numerous effects including improvement in cognitive domains that are deficient in people with HIV. Alternatively, those with HIV may continue to smoke because they experience greater withdrawal effects than the general population. This project will investigate these potential mechanisms. Aim 1 will determine the impact of current smoking on cognitive functioning and use a positron emission tomography (PET) marker to determine neuroinflammation in HIV positive and healthy participants (n=21/gp). Reverse-translated tasks and the NIH Toolkit will characterize the potential positive benefits of smoking satiety in HIV positive participants. Further, current microglia-based neuroinflammatory markers will be determined and compared to cognitive performance. While informative, this cross-sectional analysis will not be able to determine directionality of effects. Hence, Aim 2 will determine directionality of chronic nicotine & withdrawal effects on cognition and neuroinflammation in mice that express the HIV-associated gp120 protein and their wildtype (WT) littermates. In Expt. 1, the effects of chronic nicotine on cognition will be examined using rodent-based tasks from Aim 1. In addition, similar neuroinflammatory markers will be investigated at each stage of treatment (baseline-, acute-, chronic-, and withdrawal-induced effects). In Expt. 2, this work will be repeated in the gp120-mouse model of HIV to determine nicotine's potential interactive effects with this HIV- relevant protein. Finally, Expt. 3 will include antiretroviral treatment (ART; an integrase inhibitor) to determine potential three-way interactions of nicotine, gp120 protein, and ART on cognition and neuroinflammation. Hence, the potential for synergistic enhancement (during nicotine treatment) and deficits (during nicotine withdrawal) on each factor will be determined. Finally, potential changes in dopamine and nicotinic receptor expression will be examined. Hence, these studies will establish the cognitive profile of deficits related to HIV and comorbid cigarette/nicotine use, as well as their link to neuroinflammation. More importantly, using cross- species relevant testing, the `chicken or the egg' conundrum will be answered as to whether those with HIV smoke more and have greater difficulty quitting because of a specific remediation of such deficits with nicotine and/or greater deleterious effects during withdrawal respectively. Neuropathology studies will also help identify potential targets for treatment development and smoking cessation aids to improve the lives of HIV sufferers.  

? DESCRIPTION (provided by applicant): There is a tremendous need for improved treatments for schizophrenia (SCZ), especially for its 'negative' symptoms and cognitive deficits. Oxytocin is a reproductive hormone that is also a powerful regulator of brain processes that are very relevant to SCZ. Preliminary research in animals and humans indicate that the oxytocin system may be an auspicious target for developing new SCZ treatments. However, in order for that to occur, a much greater understanding of oxytocin's potential anti-SCZ effects is urgently needed to address inconsistencies and gaps in the existing body of data. Animal studies are an important tool for obtaining information about potential new treatments, but there has been surprisingly little animal research into oxytocin's anti-SCZ potential. The overall aim of this project is to address this critical gap in knowledge. Since it is unclear which specific features f SCZ may be benefited by oxytocin, several experiments have been thoughtfully designed to evaluate its effects in a battery of state-of-the-art animal tests developed to represent the distinct clinical features of SCZ's cognitive and negative symptoms. Other experiments are designed to uncover the biological mechanisms and brain circuits that underlie oxytocin's anti-SCZ effects, something that has not previously been well studied. By testing the effects of long-term oxytocin treatment via the intranasal route, the standard route in human studies, these experiments will provide an understanding of oxytocin's effects that is more relevant to the chronic nature of clinical treatment than the preponderance of previous animal studies on this topic, which have typically examined one-time, peripheral or central oxytocin administration. As it is highly involved in reproductive function, oxytocin's brain effects are likely to differ in maes and females, but animal experiments investigating its SCZ-relevant effects have almost exclusively included only male subjects. By incorporating both female and male animals in experiments, this project will provide much needed information about possible sex differences in oxytocin's anti-SCZ effects. Another important feature of this project is that it will advance the characterization of a promising rat model of relevance to SCZ and facilitate the ultimate assessment of the validity of the tests used to model features of SCZ. This project will greatly expand the current body of scientific knowledge regarding oxytocin's anti-SCZ properties, including important information regarding potential dose-, sex-, and time-dependent aspects of its clinical effects, potential adverse effects, as well as individual characteristics that may hel identify likely responders to oxytocin treatment. These findings will guide future studies in animals and in patients with SCZ, while the findings regarding oxytocin's neurobiological mechanisms will likely guide the design of novel drugs that are based on oxytocin, but that possess improved efficacy and/or safety.

Cannabis is used by more than half of all people with bipolar disorder (BD), which may increase with continued legalization across the United States. Some but not all of the deleterious cognitive effects of cannabis are likely exaggerated in people with BD, given that the brain's endocannabinoid (ECB) system affects the function of dopaminergic (DA) circuitry, which is thought to be dysregulated in BD. For example, administration of the cannabinoid1 (CB1) receptor agonist delta-9-tetrahydrocannabidiol (THC) - the primary active ingredient in cannabis - increases DA release in the striatum. This effect is especially problematic in BD individuals who have reduced expression of the dopamine transporter (DAT), the mechanism driving homeostatic regulation of DA levels. On the other hand, cannabidiol (CBD) is the other major ingredient of cannabis and does not increase DA levels, so cannabis containing high CBD may not be as deleterious. A better understanding of the consequences of chronic cannabis use on critical cognitive functions and ECB/DA neurochemistry in BD could further the development of treatments for BD and substance use disorders. The proposed use of cross- species measures and parallel studies in both humans and rodents enables a more nuanced understanding of both the neurobiology and clinical applicability of the ECB system in BD. Aim 1 will determine the effects of chronic cannabis use on cognitive functions relevant to BD, in chronic cannabis users and non-users compared to healthy comparison (HC) participants. A battery of cognitive and behavioral tests that measure domains such as arousal, inhibitory control, feedback-based decision making, reward preference, and temporal perception will be administered. Aim 2 will identify the effects of acute exposure to controlled doses of THC and CBD on cognition and determine the resulting levels of endogenous cannabinoids such as anandamide (AEA) and the DA metabolite homovanillic acid (HVA) via lumbar puncture. Infrequent cannabis-using BD and HC participants will be randomized to receive one of 3 preparations of placebo, THC, or THC/CBD and will be tested on the cognitive-behavioral battery. Aim 3 will determine the interactive effects of reduced DAT function (a validated mouse model for BD) and THC/CBD treatment (acute, chronic, and withdrawal states) on cognition, neuropathology, plus ECB, DA receptor, and AEA expression in mice. The rodent behavioral tests have direct translational applicability to the human tests described above. It is hypothesized that BD participants and mice with reduced DAT expression will show interactive and additive effects of chronic cannabis use both on cognition and on ECB and HVA levels, due to complex interactions between the ECB and DA systems. Acute THC exposure may decrease arousal and improve temporal perception in BD and KD mice but impair inhibition and decision making, whereas CBD will not exert as deleterious effects. In addition to shedding new light on the neurobiology of BD and cannabis use disorder, these studies may inform how pharmacological manipulation of the ECB system can become a novel approach for treating BD.

Project Summary The mission of NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. This application proposes to enhance training, mentorship, racial and ethnic inclusion, gender diversity and expansion of professional development for trainees and early stage investigators to the annual International Behavioral Neuroscience Society (IBNS). This proposal seeks to: 1) Provide financial support for trainees and early stage investigators to attend the annual IBNS meeting. Such funding will provide opportunities to showcase their research, as well as formalized network and mentee-mentorship opportunities with leading scientists in the field that extend throughout the trainees? careers; 2) Continue support of workshops that focus on training, enhancing, and promoting diversity and inclusion within IBNS, with outreach that goes beyond the annual meeting; 3) Ensure that the junior women and trainees from underrepresented groups supported by these funds obtain training in targeting NIMH scientific priorities consistent with the IBNS mission. Given that psychiatric disorders are categorized by their behavioral abnormalities, it is imperative to determine neural mechanisms underlying such behaviors, and critically, cross-species biomarkers of behavior. The IBNS since its creation in 1992, has been at the forefront of investigating behavior and underlying neural circuitry using the innovative neuroscientific tools integrated with sophisticated behavioral tools in order to: 1) Identify mechanisms of complex behaviors; 2) Determine potential neural biomarkers of such behaviors; 3) How these mechanisms are affected in disease states; 4) Target such mechanisms for preventions and cures; and 5) Improve behavioral neuroscience approaches for rigor and reproducibility and identify sex differences relevant to human behaviors. Given its international nature, IBNS has also been at the forefront at recruiting diverse viewpoints across science. With an additional goal for training the next generation of neuroscientists looking to understand and cure diseases, IBNS provides 20-26 Travel Awards annually, creating a safe space for diverse trainees. With this application, we wish to promote additional diversity of our travel awardees, as well as fund educational workshops to aid trainees from undergraduate, graduate, post doctoral (within 5 years), and early stage investigators (within 2 years of faculty appointment. This application therefore requests funding to increase the opportunities for trainees to attend our 2021 annual meetings.

PROJECT SUMMARY Understanding how co-morbidities in persons with HIV (PWH) such as substance use affect risk-taking, decision- making, and other cognitive behaviors is important given implications for everyday functioning and transmission risk. The high prevalence of cannabis use in PWH, medicinally and recreationally, may indicate disease severity, impart therapeutic benefits, or adverse consequences. In fact, cannabis is recommended to those with HIV to alleviate nausea, improve appetite, relieve pain, and lift mood. To-date, the consequences of cannabis use in PWH remain unclear as do potential interactions with HIV treatments. In healthy participants, heavy cannabis use is associated with cognitive deficits e.g., risky decision-making, response disinhibition and inattention, but pro-cognitive effects in PWH may exist at mild use levels due to its anti-inflammatory and anti-excitotoxic properties. Furthermore, little has been done to determine the effects of cannabis use on the endocannabinoid (EC) system in general or in PWH. This area of study is especially germane to cognition since the virus affects brain regions rich in ECs. CNS relevance is of particular importance given that the EC system exerts regulatory effects over the dopaminergic system, critical for these cognitive processes. This application will utilize a cross- species approach to delineate the effects EC system activation has on HIV-relevant cognitive and motivational domains. Animal studies enable mechanistic insights on chronic and withdrawal effects in this system. Both behavioral and mechanistic overlap will occur between the human and animal studies. Specific Aim 1 will determine the effects of the two primary cannabis constituents (?9-tetrahydrocannabinol [THC], cannabidiol [CBD]) vs. placebo on risky decision-making, response inhibition, reward learning, temporal perception, and motivation, plus EC and homovanillic acid (HVA; a surrogate for dopamine activity) levels in HIV+ and HIV- subjects. Participants with infrequent cannabis use will undergo baseline cognitive testing and biomarker assays with antiretrovirals (ART) use quantified. They will be randomized to a 5-day course of either THC, CBD, or placebo and return for follow-up testing and re-assaying of ECs and HVA levels. Specific Aim 2 will conduct parallel experiments in a rodent model of HIV on acute, chronic, and withdrawal effects of 2 doses of THC vs. 2 doses of CBD, plus combined THC/CBD/ART (dolutegravir) on the same cognitive and motivational tests, plus EC and HVA levels to provide directionality and potential interaction of drug effects. Each experiment will train and test HIV-1 transgenic and wildtype littermate rats on cross-species versions of tasks used in Aim 1. Rats will be tested at baseline, immediately after acute, then chronic treatment, then during withdrawal. The brains of rats will be harvested and assessed for EC and dopamine receptor levels to determine potential mechanisms of the beneficial/negative effects of cannabinoid treatments on symptoms related to HIV. Disentangling the cognitive and biological effects of THC and CBD and their relation with ART is a much-needed advance in the HIV field and will inform development of therapeutics and policy advice for co-morbid substance use.