Stephen J. Kohut - US grants

? DESCRIPTION (provided by applicant): Neuroimaging methodologies have become increasingly important tools in neuroscience research, providing a means for understanding the neural substrates related to drug action. This K01 Award will provide support and protected time for Dr. Stephen Kohut to obtain additional experience and mentoring that will complement and expand his existing expertise in preclinical IV drug self-administration and medication testing by acquiring new skills in pharmacologic magnetic resonance imaging (phMRI). During the proposed award period the PI will first complete an intensive training program to develop the core skills and knowledge necessary to design, conduct, and analyze phMRI studies. Training will occur at the McLean Imaging Center and Massachusetts General Hospital and will involve coursework and seminars, and discussions and meetings with a world-renowned mentoring team that will facilitate completion of an innovative research project. A major strength of the research project is that it will optimize the PI's training experience through a systematic series f experiments evaluating neuronal function during the phases of drug addiction typically modeled in the laboratory including IV self-administration (i.e., drug-taking) and reinstatement (i.e., relapse) and the effects of novel treatment approaches (pharmacological and/or behavioral) in non-human primates (NHP). Another major strength of the research plan, which will have a major impact on the field, is that it involves the use of awake, behaving NHP to study the functional consequences of nicotine self-administration and reinstatement and how they are altered during treatment. Functional brain activity in multiple brain regions will be directly relaed to ongoing real time behavior that can be measured within and across behavioral sessions. Focused research training in phMRI will occur at 3 Tesla (3T) through the Research Plan, but the PI will also receive training on a state-of-the-art, ultra-high field 9.4T magnet, large enough to accommodate NHP. The combination of training at clinical field strength (3T) coupled with training at ultra-high field strength (9.4T) will equip the Candidate with the knowledge and skills necessary to become an R01-funded independent investigator at the forefront of truly translational addiction research relating behavior and brain function. Overall, this training experience will allow the Candidate to develop a novel investigative approach for examining how novel treatments influence the various neuronal effects of nicotine and other drugs of abuse during periods of drug-taking and relapse, and will establish the PI as an independent scientist who is qualified to conduct highly translational addiction research that will address the need for highly trained investigators who can explore the neural correlates of drug abuse and addiction.

Cannabis is the most widely self-administered psychoactive substance among adolescents in the U.S., and its use shows no signs of abatement. Studies in humans suggest that heavy cannabis use during this critical period of development can alter brain structure and function and impair cognitive and behavioral processes. However, the extent to which neural changes and neuropsychological deficits produced by cannabis use during adolescence persist into adulthood remains poorly understood, hampering the assessment of long-term health risks. Consequently, there continues to be a pressing need for carefully controlled research on the potential long-term impact of adolescent cannabis exposure on brain development, cognitive competency and addiction. The present research addresses this need with longitudinal studies in nonhuman primates to examine the long-term impact of chronic exposure to the cannabinoid ?9-THC during adolescence. In this research, groups of adolescent male and female squirrel monkeys will be treated daily with a low active dose or a high active dose of ?9-THC or with vehicle. Daily treatment will continue throughout adolescence for 6 months, during which time observational and activity data will be collected to assess behavioral status and the any tolerance to the effects of drug treatment. Neuroimaging data will be collected before, during, and after daily treatment to evaluate changes in neural structure or function that may be associated with chronic exposure to ?9-THC. After the chronic regimens are discontinued, subjects will remain drug-free for 6 weeks to allow for the elimination of the lipophilic cannabinoid. Next, using touchscreen-based tasks, subjects will be studied to determine whether prior exposure to ?9-THC may have persisting effects on motivation or different types of cognitive function. First, using a behavioral economic demand analysis, motivation will be assessed by comparing the reinforcing strength of sweetened condensed milk, a highly palatable reinforcer, in the different treatment groups. Subsequently, two tasks (stimulus discrimination/reversal and delayed matching to position) will be used to compare learning, response inhibition, and spatial short-term memory across treatment groups. Neuroimaging information will be collected prior to and following the above testing. Finally, the acquisition of ?9-THC self-administration will be studied to determine whether adolescent exposure to ?9- THC may have enhanced its reinforcing effects. Lastly, the study will conclude with a final neuroimaging scan. Overall, these longitudinal studies will provide information regarding the persistence of neural abnormalities that may be produced by ?9-THC exposure during adolescence, their association with cognitive impairments or changes in sensitivity to abuse-related effects of ?9-THC, and whether such sequelae and associations can be related to the chronic dosage ?9-THC or differ in males and females.

Abstract The abuse of substituted cathinones, the main psychoactive components of ?bath salts? and other illicit preparations, has emerged as a persistent public health concern over the past decade. Substituted cathinones, like other phenethylamines including methamphetamine (MA) or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), produce their psychoactive effects through monoaminergic actions resulting from their ability to either block the reuptake or increase the release of neuronal dopamine (DA) and/or serotonin (5-HT). New cathinones are continually being introduced into the underground drug market and differ in one or more structural features, but the balance of neurochemical activity at DA and/or 5-HT transporters is thought to be a key feature that mediates the expression of their MA- or MDMA-like effects (i.e., stimulant or entactogen). However, little is known about how substituted cathinones alter neural activity and whether, like their abuse-related behavioral effects, regional patterns of activation may be related to the balance of their monoaminergic actions. This application, in response to PAR 18-510, is designed to address this issue and proposes cutting-edge, integrated behavioral pharmacology and neuroimaging studies in nonhuman primates to examine the abuse-related behavioral and neural effects of substituted cathinones that vary in selectivity for DA and 5-HT release. First, as drug history is known to play an important role in individual vulnerability to different types of drug abuse and relapse, substituted cathinones will be compared in different groups of both male and female subjects that discriminate or self- administer either MA (DA-selective) or MDMA (5-HT-selective). Next, using well-validated and translationally- relevant animal behavioral models, the subjective, reinforcing, and relapse-inducing (reinstatement) effects of selected cathinones will be compared to those of MA and MDMA. Finally, awake fMRI studies, conducted at ultra-high field strength (9.4T), will be employed in the same subjects to identify key features in the patterns of regional brain activity (neural signature) produced by substituted cathinones that may be related to their MA-like or MDMA-like abuse-related effects. Overall, our planned studies will yield key insights to improve our understanding of the roles of drug history and sex in the abuse-related behavioral effects and neural signatures of different types of synthetic cathinones and, more generally, abused drugs with DA- and/or 5-HT-mediated actions. Such information is essential for accelerating the development of novel treatment strategies for the management of addiction to cathinones and other monoaminergic drugs.