Kevin S. Murnane - US grants

DESCRIPTION (provided by applicant): Abuse of cocaine is a widespread and severely deleterious public health problem. Although it is well established that there is substantial variability in an individual's response to cocaine exposure, we do not yet understand the mechanisms that mediate individual differences in the etiology of cocaine abuse and addiction. In particular, we do not understand why some individuals are resistant to the effects of cocaine and will consume cocaine at low rates whereas other individuals are relatively vulnerable to the effects of cocaine and will consume cocaine at high rates. In the present proposal, we will evaluate several novel biomarkers that may predict the vulnerability of an individual to abuse cocaine or to relapse following abstinence. We will evaluate these processes using drug self-administration (SA) and reinstatement of previously drug-maintained behavior in nonhuman primates, as these are well established animal models of cocaine abuse and relapse. Moreover, we propose to determine, in a highly systematic manner, whether the availability of specific brain proteins, the acute brain activational effects of cocaine, or the integrity of functional bran networks predicts cocaine abuse and relapse. We believe that these studies will have important public health implications because these techniques can be translated into use in human subjects, and they will allow physicians to individually tailor treatment plans based on the current status of the cocaine-dependent patient. PUBLIC HEALTH RELEVANCE: Abuse of cocaine is a widespread and severely deleterious public health problem, yet we do not understand the processes that govern an individual's propensity to abuse cocaine or to relapse once abstinence has been achieved. A better understanding of these processes would further the development of effective treatments for this disorder. In the proposed studies, we will use multimodal neuroimaging and a nonhuman primate model of cocaine abuse and relapse to determine novel vulnerability factors that predispose individuals to cocaine abuse and relapse.

ABSTRACT Epilepsy is a family of chronic neurologic disorders characterized by periodic, unpredictable seizures. Current pharmacotherapy for epilepsy relies on ion channel inhibitors, GABAergics, and compounds of unknown mechanism. Following first-line or dual treatment with these drugs, more than 30% of patients continue to experience seizures. A critical barrier in the epilepsy field is the poor brain penetrance of many promising therapeutics. Indeed, there are a number of large or lipophobic compounds that do not readily enter the brain when given systemically, but which are well known in animal studies to show great promise for controlling seizures when they are administered through direct cannulation of the brain. In the proposed studies, we intend to focus on the development of a new technology that will use endogenous biological mechanisms to actively transport these compounds into the brain. We will focus our efforts on neuropeptide Y (NPY) and oxytocin (OT) because 1) these compounds do not readily enter the brain through passive diffusion, 2) there is evidence that these compounds control seizure activity, 3) we have generated exciting preliminary data supporting the use of our technology to transport these compounds into the brain, and 4) these compounds are excellent prototypes with which to conduct proof-of-concept feasibility studies. The long-term goal of this research program is to develop a safe and effective approach to the delivery of neuropeptide treatments for epilepsy and other neurological disorders to the central nervous system. The completion of these studies will provide a solid foundation for further studies to develop even more advanced formulations. These formulations would further refine our approach to increase the brain penetrance, sustain the release, or compartmentalize to the brain novel neuropeptide therapeutics. As such, this proposal will form the foundation of a new research program which we hope will support a new wave of therapeutics for epilepsy.

? DESCRIPTION (provided by applicant): The National Institute on Drug Abuse recognizes that the abuse of synthetic cathinones (SC) is a serious public health issue. SC use can cause panic, psychosis, neurological complications, cardiac and renal toxicity, and fatal overdose. SC is ?-ketone analogs of amphetamines, and have similar subjective effects (e.g., stimulant and hallucinogenic effects) as their respective amphetamine counterparts. However, humans report conspicuous differences in psychological effects between amphetamines and SC, highlighting that SC is a unique drug class with unique pharmacological properties and neurobiological effects, much of which are presently unknown. With the recent DEA scheduling of many widely abused SC, e.g. mephedrone, methylenedioxypyrovalerone (MDPV), and methylone, second-generation SC have emerged, most of which contain a pyrrolidine moiety in place of the secondary amine of first-generation SC. MDPV was the first of the pyrrolidine SC to gain popularity among stimulant users, however, due to MDPV's scheduling with other first-generation SC, illicit chemists have synthesized and distributed many other pyrrolidine SC. Pyrrolidine SC appear to have an unusually high propensity to induce panic and psychosis, which suggests they may be acting through receptor systems in addition to monoamine transporters. However, systematic studies testing the fear-inducing effects of pyrrolidine SC are lacking, and systematic pharmacological assessments of pyrrolidine SC at receptors that could contribute to psychiatric events are warranted. Also, to date, no approved medications exist for acute SC overdose, but our preliminary data demonstrate a promising, new pharmacological intervention, 5-HT2A receptor antagonism, to mitigate psychostimulant-induced psychosis, hyperthermia, convulsions, and fatal overdose. Our proposed studies will compare new and widely available, second-generation pyrrolidine SC to mephedrone and will determine: 1) how the pyrrolidine substitution affects affinity and function at serotonin 5-HT2 and adrenergic ?1 receptor subtypes expressed in HEK293 cells; 2) whether the pyrrolidine substitution contributes to fear, anxiety, and psychosis in mice; and 3) the efficacy of 5-HT2 and ?1 selective ligands to block clinically critical components of acute SC overdose in mice. The experiments in Aims 1 and 2 will address the goal of this public funding announcement to provide information regarding the pharmacology and unique effects of SC. The results from Aim 3 will guide discovery of novel fast-acting treatments for acute SC overdose.

PROJECT SUMMARY Dysfunction of voltage-gated sodium channels (VGSCs) is responsible for several forms of catastrophic childhood encephalopathies. Over 1000 loss-of-function mutations in the VGSC SCN1A have been identified during the last two decades and are the main cause of Dravet syndrome (DS), characterized by recurrent early- life febrile seizures (FSs), severe afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. Mutations in the VGSC SCN8A were more recently identified in 2012, and already over 200 gain-of-function SCN8A mutations have been reported in patients with a range of clinical features including catastrophic treatment-resistant childhood epilepsy, autism, intellectual disability and developmental delay. Unfortunately, most anti-epileptic drugs (AEDs) fail to adequately treat the broad range of severe seizures and behavioral phenotypes in patients with SCN1A- and SCN8A-derived epilepsy. Thus, despite recent progress in pharmacological treatments for DS, there remains a need to develop more effective, longer lasting treatments with fewer side effects. Neuropeptides are well known in animal studies to show great promise for controlling seizures and ameliorating behavioral abnormalities; however, they do not readily cross the blood brain barrier and are rapidly metabolized when given systemically. Thus, poor brain penetrance is a critical barrier to the clinical application of these promising therapeutics. To overcome this challenge, we developed and validated an approach based on the encapsulation of neuropeptides in nanoparticles conjugated to rabies virus glycoprotein (RVG). Using this approach, we have found that intranasal delivery of nanoparticle-encapsulated oxytocin (NP- OT) greatly increases brain penetrance and the capacity of OT to confer robust and sustained increases in resistance to seizures in mouse models of SCN1A and SCN8A dysfunction. We have also extended our strategy to encapsulate neuropeptide Y (NP-NPY), and similarly observed a robust improvement in its ability to confer seizure resistance. In the proposed study, we will establish the ability of NP-OT and NP-NPY to ameliorate spontaneous seizures and behavioral abnormalities in Scn1a and Scn8a mouse mutants (Aim 1). While the role of OT in social behavior is well-studied, less is known about the mechanisms by which it modulates seizure susceptibility. Thus, we will also identify the cellular and neural circuit mechanisms that contribute to the ability of OT to increase seizure resistance in the Scn1a and Scn8a mutants (Aim 2). Our long-term goal is to develop safe and effective approaches for the brain delivery of neuropeptides for the treatment of epilepsy and other neurological disorders.