Alan I. Green - US grants

DESCRIPTION: (Applicant's Abstract) Cannabis use disorder contributes to the morbidity of schizophrenia, leading to, poorer overall functioning. The typical antipsychotic drugs are of limited value in controlling cannabis use in these "dual diagnosis" patients. This study will assess whether new antipsychotic medications, introduced into clinical practice in the past decade, are of value for this purpose. Preliminary data suggest that the atypical antipsychotic drug clozapine (CLOZ), currently used primarily for treatment resistant patients, may limit cannabis use in "dual diagnosis" patients with schizophrenia much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotic risperidone (RISP). In a recently published paper, we have hypothesized (a) that CLOZ will lessen substance use in such "dual diagnosis" patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex (PFC), and (b) that the CLOZ-induced release of DA in the PFC will decrease negative symptoms (an effect shared especially by the novel antipsychotic RISP). Moreover, we have further hypothesized, (c) that through its diverse effects on both dopaminergic and noradrenergic systems, CLOZ (but not RISP or typical antipsychotics) will help to normalize dysfunctional brain reward circuits that may underlie the comorbid substance use in patients with schizophrenia. In the proposed study, patients comorbid for both schizophrenia and a cannabis use disorder will be randomly assigned to double-blind treatment (for 12 weeks) with either CLOZ or RISP. The primary aim of this study is to launch a carefully controlled pharmacological trial of the short-term effects of CLOZ and RISP on cannabis use in this population to test the hypothesis that patients treated with CLOZ will have decreases in cannabis use as compared to patients treated with RISP. A secondary aim is to begin to investigate the process by which CLOZ produces its effects on cannabis use through study of negative symptoms. A subsidiary aim is to begin to address key auxiliary measures of the effects of CLOZ in this "dual diagnosis" population: psychiatric symptoms, quality of life, and measures of neuropsychological functions. If the results of this study confirm the preliminary data, they could suggest a new use for CLOZ, one that could have important public health implications.

[unreadable] DESCRIPTION (provided by applicant): Patients with schizophrenia (SCH) commonly develop alcohol use disorders. While typical antipsychotic drugs (e.g., haloperidol - HAL) do not control alcohol use in these patients, recent data suggest that the atypical antipsychotic clozapine (CLOZ) does. We recently presented a neurobiologic formulation suggesting: (a) that persons with SCH have a dysfunction in their dopamine (DA) mediated mesocorticolimbic reward pathways underlying alcohol use; (b) that most antipsychotic drugs (e.g., HAL) do not decrease alcohol use in this population because they do not restore the normal function of these pathways; but (c) that CLOZ, through its actions on multiple neurotransmitter systems, particularly its potent blockade of alpha 2 noradrenergic receptors, as well as its weak blockade of DA D2 receptors, has a normalizing effect on the signal detection capability of these pathways. To further elucidate the differential effects of HAL and CLOZ, we recently initiated a study in Syrian golden hamsters, an outbred animal that drinks large amounts of alcohol. Our initial data indicate that CLOZ but not HAL substantially decreases hamster alcohol drinking. In this R03 proposal, we seek to expand our investigations and prepare for submission of an R01 proposal. We will continue studies of the hamster, but will also expand to include the "P" rat, a genetically- bred strain that has been proposed as an excellent animal model for alcoholism. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring animals, as in patients with SCH and comorbid alcohol use disorder, relates to its action in DA-mediated mesolimbic circuits. The primary specific aim seeks: (1) To determine whether CLOZ will decrease alcohol drinking more than HAL does in the P rat, a rodent with known dysfunction in the DA-mediated mesolimbic system. The other aims are designed to further inform the neurobiologic basis by which CLOZ, but not HAL, limits alcohol use in the hamster and, potentially, in the P rat: (2) To explore whether loss of suppression of alcohol drinking develops during long-term treatment with CLOZ; and (3) to begin to explore (a) whether addition of a potent D2 antagonist to CLOZ will lessen the CLOZ's ability to suppress alcohol drinking, and (b) whether addition of a potent alpha 2 antagonist to HAL will allow HAL to suppress alcohol drinking. The long-term goal of our research is to create better treatments for alcoholism in patients with SCH (and possibly even in those without SCH). [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD), common in patients with schizophrenia (SCHIZ), contributes greatly to the morbidity of SCHIZ. Although typical antipsychotic medications do not control cannabis use in these patients, preliminary data from our group and others suggest that the atypical antipsychotic drug clozapine (CLOZ) may limit cannabis use in patients with SCHIZ much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotics risperidone (RISP) or olanzapine (OLAN). We are conducting a NIDA funded (DA 13196) 12-week randomized clinical trial to further assess CLOZ effects on cannabis use, clinical symptoms/quality of life in patients with schizophrenia and comorbid CUD, as compared to patients treated with RISP or OLAN. This R21 application proposes an "add-on" functional MRI (fMRI) pilot study of brain reward circuitry to this "base" study. We have previously hypothesized that CLOZ (but not RISP, OLAN or typical antipsychotics) will help normalize dysfunctional brain reward circuits that may underlie comorbid cannabis use in SCHIZ. In this "add-on" study, a sub-sample of 24 RISP treated patients from the "base" study will undergo an fMRI monetary reward probe of brain reward circuit while being treated with RISP. In the "base" study, half of these patients will be randomized to CLOZ and half will remain on RISP for the 12- week clinical trial; in the "add-on" study, all patients will have repeat fMRI reward circuit testing at 12 weeks, and a matched group of normal controls will also be tested, twice (at recruitment and at 12 weeks). The proposed study will attempt to identify a potential imaging biomarker" of the action of CLOZ (as compared to RISP) on brain reward circuits. The overarching hypothesis for this research is that patients treated with RISP will demonstrate deficiencies in response to a brain reward circuit probe compared to normal controls and that these deficiencies will be normalized in patients treated with CLOZ. We also predict that there will be a relationship between the normalization of brain reward circuit response and decrease in cannabis use by patients. We expect this research to lead to an efficient method for testing medications that putatively may decrease cannabis use in SCHIZ. This is of great importance because, despite the benefits of CLOZ, its toxicity discourages many clinicians from using it. Finding new medications, safer than CLOZ, that may be able to limit cannabis use In patients with SCHIZ is thus of considerable public health relevance.

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD), common in patients with schizophrenia (SCHIZ), contributes greatly to the morbidity of SCHIZ. Although typical antipsychotic medications do not control cannabis use in these patients, preliminary data from our group and others suggest that the atypical antipsychotic drug clozapine (CLOZ) may limit cannabis use in patients with SCHIZ much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotics risperidone (RISP) or olanzapine (OLAN). We are conducting a NIDA funded (DA 13196) 12-week randomized clinical trial to further assess CLOZ effects on cannabis use, clinical symptoms/quality of life in patients with schizophrenia and comorbid CUD, as compared to patients treated with RISP or OLAN. This R21 application proposes an "add-on" functional MRI (fMRI) pilot study of brain reward circuitry to this "base" study. We have previously hypothesized that CLOZ (but not RISP, OLAN or typical antipsychotics) will help normalize dysfunctional brain reward circuits that may underlie comorbid cannabis use in SCHIZ. In this "add-on" study, a sub-sample of 24 RISP treated patients from the "base" study will undergo an fMRI monetary reward probe of brain reward circuit while being treated with RISP. In the "base" study, half of these patients will be randomized to CLOZ and half will remain on RISP for the 12- week clinical trial; in the "add-on" study, all patients will have repeat fMRI reward circuit testing at 12 weeks, and a matched group of normal controls will also be tested, twice (at recruitment and at 12 weeks). The proposed study will attempt to identify a potential imaging biomarker" of the action of CLOZ (as compared to RISP) on brain reward circuits. The overarching hypothesis for this research is that patients treated with RISP will demonstrate deficiencies in response to a brain reward circuit probe compared to normal controls and that these deficiencies will be normalized in patients treated with CLOZ. We also predict that there will be a relationship between the normalization of brain reward circuit response and decrease in cannabis use by patients. We expect this research to lead to an efficient method for testing medications that putatively may decrease cannabis use in SCHIZ. This is of great importance because, despite the benefits of CLOZ, its toxicity discourages many clinicians from using it. Finding new medications, safer than CLOZ, that may be able to limit cannabis use In patients with SCHIZ is thus of considerable public health relevance.

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD) occurs frequently in patients with schizophrenia (SCZ) and worsens the course of this severe psychiatric disorder. Treatments available for these "dual diagnosis" patients are inadequate. Most of the antipsychotic drugs appear to be of limited value for controlling their cannabis use. The one antipsychotic medication that preliminary studies have shown to have some ability to limit cannabis use in these patients, clozapine, has substantial toxicity and is thus used by only a small percentage of patients who might benefit from it. New treatments to limit cannabis use in patients with schizophrenia are sorely needed. While the basis of cannabis use in patients with SCZ is not clear, some have suggested that use of substances may "self-medicate" negative symptoms or the side effects they experience from antipsychotic treatment. We have proposed an alternative formulation of this "self-medication hypothesis" -- that a dysregulated mesocorticolimbic "brain reward circuit" (BRC) in patients with SCZ underpins their substance use, and that cannabis use ameliorates this dysregulated circuitry. Using a monetary probe linked to fMRI (functional Magnetic Resonance Imaging), we have demonstrated that patients with SCZ and CUD do indeed have a deficit within their BRC as compared to normal subjects. This application will allow us to directly test the effects of cannabis on the BRC in patients with SCZ and CUD and thus to confirm our hypothesis regarding its effects in these patients. In addition, the application seeks to assess whether the cannabinoid agonist dronabinol, when given to patients with SCZ and CUD, will also ameliorate this BRC deficit, and, thus, whether dronabinol could be considered as a potential adjunctive treatment (given with an antipsychotic medication) to decrease their cannabis use. This "proof of concept" application is submitted in response to the RFA "Medication Development for Cannabis Use Disorders". The first aim of this study is to determine whether a BRC deficiency in patients with SCZ and CUD will be normalized when patients are given cannabis or dronabinol: (1a) to confirm our preliminary data suggesting that an fMRI scan linked to a monetary brain reward probe will be abnormal (compared to controls) in patients at baseline;(1b) to determine whether this fMRI measure will be normalized in patients when they smoke a cannabis cigarette;and (1c) to determine whether this fMRI measure will be normalized when patients are given oral dronabinol. The second aim will serve to further assess the effects of dronabinol in this population: (2a) to determine whether measures of craving, mood and negative symptoms will improve;and (2b) to determine whether measures of psychotic symptoms and cognitive deficits will increase (worsen). By probing the BRC dysregulation and testing the effects of smoked cannabis on this dysregulation, this study will help elucidate whether "self-medication" may be an important component of cannabis use in these patients. Moreover, by further elucidating the effects of dronabinol, this research can lead to development of therapeutic agents, potentially including dronabinol, that may limit cannabis use in these patients. PUBLIC HEALTH RELEVANCE: Cannabis use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This medication development study seeks to establish that cannabis is used for "self-medication" by these patients because it corrects a deficit in their brain circuitry, and further, that dronabinol, an orally administered drug approved for certain medical conditions, can also correct this deficit and therefore be of value in limiting cannabis use in these patients. Finding medications that may be able to limit cannabis use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.

DESCRIPTION (provided by applicant): Patients with schizophrenia (SCZ) have elevated rates of substance use disorders (SUD) relative to the general population, most prominently for alcohol, nicotine and cannabis. Co-occurring alcohol use disorder (AUD) in SCZ is associated with increased symptoms, violence and victimization, homelessness, institutionalization, and poorer overall outcome of SCZ. Despite the prevalence and ramifications of AUD (and other SUDs) in SCZ, effective treatments for co-occurring AUD/SUD in patients with SCZ are limited. Many theoretical models, including biological, cognitive or psychosocial, have been discussed in an attempt to explain the increased prevalence of such co-occurring disorders in SCZ and to guide treatments. There have been few attempts, however, to integrate these models into a unified theory of the basis of alcohol and other SUD in patients with SCZ - a theory that could be tested over time and one that might lead to development of new treatment strategies. If better treatments are to be developed, the creation of integrative theoretical and practical models of the basis of these co-occurring disorders is essential. We propose a conference to bring together a multi-disciplinary group of scientists and scientist-practitioners whose research is based on (or informs) biological, cognitive, and/or psychosocial models of etiology and treatment of AUD, SCZ, and of co-occurring AUD/SUD in SCZ. Visiting scientists, both expert and junior, will join with Dartmouth faculty to present their research and related literature. A series of discussions led by the conference chairs will seek to integrate these presentations, find theoretical bridges between the domains, and foster the development of testable hypotheses to empirically evaluate integrative models of AUD in SCZ. Thus, the specific aims of this conference will be: (1) To describe the prevalence and phenomenology of co- occurring AUD in SCZ;(2) to explain and integrate biological, cognitive and psychosocial etiological theories of co-occurring AUD/SUD in SCZ;(3) to describe current and potentially effective pharmacological, psychological, behavioral, social and environmental interventions for co-occurring AUD and SCZ;and (4) to propose new therapeutic approaches based on theoretical models to explain the co-occurrence of AUD/SUD in SCZ. PUBLIC HEALTH RELEVANCE: Co-occurring alcohol (and other substance) use disorder is common in patients with schizophrenia and contributes to a poor outcome for those with this severe psychiatric disorder. Current treatment approaches have only limited effectiveness for such patients. This Conference will gather experts in the field to integrate existing theories related to the basis of alcohol (and other substance use) disorder in schizophrenia, and based on this integration, will develop new treatment approaches aimed at improving outcomes for these difficult to treat patients.

DESCRIPTION (provided by applicant): Patients with schizophrenia commonly develop alcohol use disorders, which worsen the course of schizophrenia. While typical antipsychotic drugs (e.g., haloperidol -- HAL) appear to be of little value in controlling alcohol use in these patients, the atypical antipsychotic clozapine (CLOZ), although prescribed infrequently because of its toxicity, substantially decreases their alcohol use. We have proposed that a dysfunction in brain reward circuitry underlies alcohol use in this population, and that: (1) HAL does not decrease alcohol use in this population because it does not restore the normal function of the reward circuitry (in part because of its potent dopamine [DA] D2 receptor antagonism);but (2) that CLOZ, through its pharmacologic effects (including its weak DA D2 receptor antagonism, its potent norepinephrine (NE) alpha 2 receptor antagonism, and its NE reuptake inhibition), has a normalizing effect on this circuit. To further elucidate the effects of CLOZ and HAL on alcohol use, we have performed studies in alcohol preferring rodents. Preliminary data from these rodent studies, indicating that (1) CLOZ decreases their alcohol drinking more than HAL;(2) adding the potent DA D2/D3 receptor antagonist raclopride to CLOZ decreases CLOZ's effect on alcohol drinking;and (3) combining HAL with a NE 1-2 receptor antagonist or a NE reuptake inhibitor increases HAL's ability to decrease alcohol drinking, provide support for our proposal about the actions of CLOZ and HAL on alcohol drinking. In this second revision of a two year, "proof of concept" application, we seek to extend our preliminary data. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring rodents, as in patients with schizophrenia and co-occurring alcohol use disorder, relates to its actions on DA and NE systems as noted above, actions that can be mimicked through creation of agents that have CLOZ-like pharmacologic activity. This proposal seeks to more fully elucidate this hypothesis, and to provide data enabling further research related to the biologic basis of CLOZ's effect on alcohol drinking. The long-term goal of our research program is to develop better treatments (e.g., safer CLOZ-like medications) for alcohol use disorder in patients with schizophrenia. The specific aims of this proposal, involving research in hamsters, are: (1) To extend and further elucidate our preliminary data suggesting that CLOZ's ability to decrease alcohol drinking relates in part to its weak DA D2 receptor antagonism and to assess the role of its potent NE 1-2 receptor antagonism. (2) To extend and further elucidate our preliminary data suggesting that HAL's ability to decrease alcohol drinking in rodents can be amplified by combining it (in low dose, to provide a weak DA D2 receptor blockade) with a NE 1-2 receptor antagonist or a NE reuptake inhibitor. (3) To explore the effect of the combination of a DA D2 receptor antagonist, a NE 1-2 receptor antagonist and a NE reuptake inhibitor on alcohol drinking in rodents. PUBLIC HEALTH RELEVANCE: Public health significance: Alcohol use disorder is common in schizophrenia and worsens the course of this severe psychiatric disorder. While most antipsychotics do not lessen alcohol use in schizophrenia, the atypical antipsychotic clozapine does, although the mechanism by which this occurs is uncertain. While clozapine's toxicity severely restricts its use, understanding its mechanism of action, as proposed here, may lead to development of new drugs, safer than clozapine, which could limit alcohol use disorder in patients with schizophrenia.

DESCRIPTION (provided by applicant): Alcohol use disorder (AUD), which is three times more common in schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Thus, the co-occurrence of AUD and SCZ is an important public health problem. While most available antipsychotic medications do not limit alcohol use in patients with SCZ, the atypical antipsychotic clozapine (CLOZ) appears to do so. However, because CLOZ has important side effects, its clinical use is limited to only the most severely ill patients with SCZ. Thus, new medications for the treatment of SCZ and AUD, medications at least as effective as CLOZ for limiting alcohol abuse in these patients, but safer than CLOZ, need to be found. We have developed a neurobiologic formulation of the action of CLOZ in patients with SCZ and AUD, and we have tested this formulation in groups of alcohol preferring rodents to begin to search for medications able to treat patients with SCZ and AUD. This neurobiologic formulation suggests that alcohol may enhance the functioning of a dysregulated dopamine- mediated mesocorticolimbic brain reward circuitry in patients with SCZ that underpins their use of alcohol. Further, this formulation also proposes that CLOZ, through its diverse effects on both dopaminergic and noradrenergic systems, is able to decrease alcohol use because it ameliorates the dysfunctional brain reward circuit in these patients. Recent studies by our group in alcohol-preferring hamsters and rats have suggested that the effect of CLOZ can be duplicated when medications possessing dopamine D2 receptor antagonism, norepinephrine a2 receptor antagonism and norepinephrine reuptake inhibition are combined together. These studies have indicated that the atypical antipsychotic risperidone (RISP), a medication producing antagonism at the dopamine D2 receptor and the norepinephrine a2 receptor, which by itself has a minimal ability to decrease alcohol drinking in patients with SCZ or in alcohol-preferring rodents, will decrease alcohol drinking in rodents when combined with the norepinephrine reuptake inhibitor desipramine (DMI). This proposed translational proof of concept R21 clinical trial seeks to extend the results of these animal studies into patients with SCZ and AUD. Our goal in this resubmitted application is to begin to assess whether RISP in combination with DMI will limit alcohol use in these patients. Our Specific Aims are: (1) To determine whether subjects who are treated with RISP in combination with DMI have less alcohol use (fewer drinking days; fewer heavy drinking days) than do patients who are treated with RISP alone; (2) To explore symptoms (of SCZ and of depression) in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone; and (3) To explore the medication side effect burden in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone. Information developed during this translational proof of concept trial will allow us to determine whether a larger clinical trial of RISP in combination with DMI should be undertaken in patients with SCZ and AUD. PUBLIC HEALTH RELEVANCE: Alcohol use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This translational research proposal, based on studies in animals, seeks to begin to assess whether the combination of two commonly used medications, risperidone and desipramine, will limit alcohol use in patients with co-occurring schizophrenia and alcohol use disorder. Finding medications that may be able to limit alcohol use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD), which is up to ten times more common in patients with schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Since SCZ occurs in 1% of the population, the co-occurrence of CUD in 13% to 42% of people with this disorder presents society with an important public health problem. Unfortunately, most antipsychotics available for treatment of patients with SCZ do not appear to limit their cannabis use. Moreover, the one antipsychotic that preliminary data suggest may well limit cannabis use in these patients, clozapine (CLOZ), is not used for this purpose; it is reserved for patients whose psychosis is treatment resistant. The overarching idea behind this proposal, however, is that CLOZ's use is being unreasonably restricted and should be made more widely available for patients with SCZ who have a co-occurring CUD but whose psychosis is not necessarily treatment resistant. This notion is supported by our preliminary clinical and animal data on the effects of CLOZ, as well as our neurobiological model of the basis of cannabis use in patients with SCZ that provides a pharmacologic rationale for this effect of CLOZ. Even given all the arguments favoring the potential benefits of CLOZ in patients with SCZ and CUD, however, its side effect profile will likely limit its use until a fully powered study demonstrates its ability to decrease cannabis use n patients with SCZ. This proposal aims to launch such a study. If, as we hypothesize, this study confirms and extends our previous preliminary data of the effects of CLOZ in patients with SCZ and CUD, it will provide a strong impetus to expand the use of CLOZ in this population. In the proposed study, 132 patients who are comorbid for both SCZ and CUD will be randomized to a 12 week treatment course with either CLOZ or risperidone (RISP). The primary specific aim of this proposal is: (1) To test the hypothesis that patients treated with CLOZ will have decreased cannabis use as compared to patients treated with RISP. Subsidiary aims will further elucidate the effects of CLOZ in this population: (2) a) To determine whether patients treated with CLOZ will have improvements in (i) psychiatric symptoms; (ii) quality of life; and (iii) neuropsychological functions as compared to those taking RISP; and b) to explore whether patients taking CLOZ will show improved reward responsiveness as compared to those taking RISP; and (3) To explore whether those patients with the val/val genotype at the COMT Val158Met locus are more likely to decrease cannabis use during CLOZ treatment than are those without the val/val COMT genotype. Should this study indicate that CLOZ will lessen cannabis use in patients with SCZ more than RISP, it will provide evidence needed to begin to shift clinical practice toward its use in these patients. Given the increased morbidity associated with CUD in patients with SCZ, doing so could dramatically improve the clinical outcome of these individuals. Lastly, CLOZ's use in this study may also reflect its potential to serve as a prototype of the next generation of medications for treatment of SCZ and co-occurring CUD.

DESCRIPTION (provided by applicant): Cannabis use disorder (CUD) occurs frequently in patients with schizophrenia (SCZ) and worsens the course of this severe psychiatric disorder. Treatments available for these dual diagnosis patients are inadequate. New treatments to limit cannabis use in patients with schizophrenia are sorely needed. We have proposed that a dysregulated mesocorticolimbic brain reward circuit (BRC) in patients with SCZ underpins their cannabis use, and that cannabis use ameliorates this dysregulated circuitry. Studying the neural effects of a monetary probe linked to fMRI, as well as a behavioral measure of reward responsiveness, we and others have demonstrated that patients with SCZ do indeed have a deficit within their BRC and decreased reward responsiveness, as compared to normal subjects. Moreover, pilot data from our ARRA- funded grant involving resting state functional connectivity (RSC) suggest that such patients also have decreased intrinsic inter-regional synchronization within the BRC. Lastly, our pilot imaging data further indicate that both cannabis, as well as the cannabinoid agonist dronabinol, decrease the dysfunctional BRC deficit, as assessed by a monetary probe linked to fMRI and by resting state functional connectivity. In this proposal, we seek to confirm and expand upon our ARRA-funded investigation. The first aim is to assess the status of the BRC in patients with SCZ and co-occurring CUD (SCZ-CUD), as well as in those with SCZ (without CUD) and CUD (without SCZ): (1a) To confirm that (i) task-related fMRI activity linked to a monetary brain reward probe; (ii) inter-regional resting state functional connectivity; and (iii) a behavioral measure of reward responsiveness, will be decreased in patients with SCZ-CUD as compared to healthy controls; and (1b) to explore these measures in those with SCZ (without CUD) and with CUD (without SCZ). The second aim will assess the effect of cannabis and dronabinol on BRC in patients with SCZ- CUD and in those with CUD (without SCZ): (2a) To confirm whether dysfunctional (i) task-related fMRI activity linked to a monetary brain reward probe, and (ii) inter-regional resting state functional connectivity will be ameliorated; and (2b) to explore whether a behavioral measure of reward responsiveness will be improved in patients with SCZ-CUD, and (2c) to explore these measures in those with CUD (without SCZ), and to compare the results to those from (2a). The third aim will assess other effects of dronabinol in patients with SCZ-CUD -- on craving, mood, negative symptoms, psychotic symptoms and cognition. By probing BRC dysregulation and testing the effects of smoked cannabis on this dysregulation, this study will help further elucidate whether self-medication of a BRC deficit may be an important component of cannabis use in patients with SCZ. Moreover, by probing the physiological and behavioral effects of dronabinol, this research can lead to development of therapeutic agents, potentially including dronabinol, other cannabinoids or non-cannabinoid agents that may ameliorate a BRC deficiency and thus limit cannabis use in these patients.

The overarching goal of this proposal is to support and enhance our institutionally-funded Dartmouth Center for Clinical and Translational Science, called SYNERGY-an integrated home for clinical and translational science at Dartmouth. Dartmouth launched SYNERGY in 2010, a Center built on Dartmouth's richly collaborative and collegial culture, its interdisciplinary life sciences and health services research programs, and its commitment to accelerating the translation of scientific knowledge into practice and improved population health. Over the past two years, fueled by Dartmouth's resources, and by the Center status and authority given by Dartmouth's leaders, SYNERGY has taken bold steps to begin to transform the institution's landscape for clinical and translational research. We propose four overarching aims designed to continue to expand our ability to conduct decisive science on the biology of disease and to use new and existing knowledge to transform the practice of medicine and thus to improve health-locally, regionally and nationally. Over the next five years we will: (1) strengthen SYNERGY to achieve greater interdisciplinary and programmatic research synergism and efficiency and promote an institutional culture aimed at advancing clinical and translational science; (2) ensure that SYNERGY investigators can easily and efficiently access resources and services, and thus enhance their productivity; (3) expand and integrate training and career development programs to build research focus and passion among trainees from diverse disciplines who aim to build successful careers in clinical and translational research; and (4) create a Center for Translational Population Research , a technical and analytic resource that harnesses the value of population-based research across the spectrum from T l (basic research) to T4 (population research and health policy), as a resource both for Dartmouth and for the national CTSA consortium. Dartmouth is united to ensure that SYNERGY will continue to transform the landscape for clinical and translational research locally, regionally, and-as a member of the CTSA consortium-nationally, and thus to improve population health. RELEVANCE (See instructions): Dartmouth has a history of collaborative research and interdisciplinary education in the life sciences and health services research that have led to the creation of Dartmouth's Center for Clinical and Translational Science, named SYNERGY. As proposed in this application, SYNERGY will be expanded to support the efficient and rapid translation of scientific findings into clinical care and improved population health.

ABSTRACT Although substance use disorder (SUD) occurs commonly in patients with schizophrenia (SCZ) and dramatically worsens their overall clinical course, the mechanisms underlying their substance use remain unknown, and new treatments to limit their substance use are needed. Our translational research program, using fMRI imaging in patients and in animals, aims to uncover mechanisms that underlie SUDs in patients with SCZ, and to facilitate strategies toward treatment development to limit their substance use. Much of this work is based on our published theoretical neurobiologic formulation suggesting that a dysfunction in the brain reward circuit (BRC) underlies substance use in SCZ, and that substances transiently ameliorate this dysfunction. Our recent study using fMRI resting state functional connectivity in patients with SCZ and cannabis use disorder provided some support for this formulation by showing that these patients have a hypoconnected BRC, which is ameliorated by use of cannabis or ?9- tetrahydrocannabinol (THC). Unfortunately, previous substance use (which, in SCZ, often begins prior to the first episode) potentially confounds interpretation of our data on BRC function in patients with SCZ. Thus, to further elucidate the potential role of BRC dysfunction in patients with SCZ-SUD, and to facilitate development of new treatments, we have turned to the neonatal ventral hippocampal lesioned (NVHL) rat, an animal model of SCZ that displays a propensity for substance use. In this R21 proposal, we begin to bridge the gap between our clinical studies and our theoretical formulation of the basis of substance use in SCZ through study of fMRI resting state functional connectivity of the BRC in the NVHL rat. In our primary aim, we seek to establish that the adult NVHL rat displays a hypoconnected BRC prior to being exposed to any substances, to provide (unconfounded) translational support that a dysregulated BRC underpins substance use in SCZ. In our secondary aim, we will explore whether: (a) cocaine, known to be preferentially self-administered by the NVHL rat; and (b) THC, shown to modulate the connectivity in patients with SCZ and cannabis use disorder, will ameliorate the dysregulated connectivity in the NVHL rat. If we are able to confirm the aims of this R21 investigation, and thus provide further support for our formulation regarding the basis of substance use in SCZ, in subsequent studies, we can begin to utilize BRC connectivity in the NVHL rat as a translational biomarker to facilitate new treatment development (e.g., as a bioassay), and as a platform for mechanistic and behavioral investigations. Given the severity of SCZ, which is worsened by substance use, this research is of great public health importance.