Lisa R. Gerak - US grants

DESCRIPTION (provided by applicant): Benzodiazepine dependence can limit the clinical use of this important class of drugs and contribute to their abuse. Emerging evidence suggests that the chronic effects of neuroactive steroids are different from those of benzodiazepines; such differences can be exploited to improve our understanding of GABAA receptor function, particularly during chronic treatment, and might offer clinical advantages. Like benzodiazepines, neuroactive steroids are positive GABAA modulators, and when administered acutely, they produce effects that are qualitatively similar to those of benzodiazepines. However, studies supported by this grant have demonstrated fundamental differences between neuroactive steroids and benzodiazepines during chronic treatment. In rats receiving the benzodiazepine flunitrazepam chronically, sensitivity to flunitrazepam decreases (i.e., tolerance develops), whereas when rats receive the neuroactive steroid pregnanolone chronically, sensitivity to flunitrazepam increases. Although this exciting observation could be exceptionally beneficial clinically, the generality of this finding has not been investigated. Moreover, the extent to which these unexpected changes in sensitivity predict the potency of these drugs to reverse withdrawal is not known. Aim 1 will examine potency changes during chronic treatment to understand the range of conditions under which these differences occur. The ability of neuroactive steroids to modulate benzodiazepine tolerance, dependence and withdrawal will be evaluated in Aim 2 to determine whether treatment with neuroactive steroids, either instead of or in addition to, benzodiazepine treatment reduces tolerance and prevents the emergence of withdrawal. Together, these two specific aims will explore changes in GABAA receptor function that occur during chronic treatment and determine whether neuroactive steroids could provide unique strategies for preventing or reversing benzodiazepine withdrawal. Because such strategies might be equally useful in treating ethanol withdrawal, the final specific aim will compare ethanol to neuroactive steroids. Aim 3 will build upon another key finding of these studies which indicates that the discriminative stimulus effects of neuroactive steroids are not identical to those of ethanol, despite their overlapping mechanisms of action; this Aim will examine differences between ethanol and neuroactive steroids under a broader range of conditions.

[unreadable] DESCRIPTION (provided by applicant): Benzodiazepines are extremely important in the treatment of disorders, such as anxiety, insomnia and ethanol withdrawal. Unfortunately, these drugs have abuse and dependence liability. Other drugs are being investigated to provide therapeutic effects similar to benzodiazepines with reduced abuse or dependence liability; one possible replacement is neuroactive steroids, which have effects that are qualitatively the same as benzodiazepines under many conditions. Recent studies from this laboratory indicate that effects of neuroactive steroids in benzodiazepine-dependent monkeys could lead to new insights into how GABAA receptor function changes with benzodiazepine dependence and could provide better strategies for treating benzodiazepine withdrawal. Studies in this application are designed to explore further the behavioral effects of neuroactive steroids, discover the nature of differences between the effects of neuroactive steroids and those of benzodiazepines, investigate changes in GABAA receptor function with benzodiazepine dependence, and determine whether these differences can be exploited for clinical benefit. Studies under Aim 1 assess the ability of neuroactive steroids to reverse (Aim 1A) or prevent (Aim 1B) the discriminative, physiological, and directly observable signs of benzodiazepine withdrawal in rhesus monkeys. The unexpected effectiveness and relative potency of neuroactive steroids in acutely withdrawn benzodiazepine-dependent monkeys suggest that not all aspects of GABAA receptor function are similarly changed by benzodiazepine dependence. Aim 2A tests the hypothesis that affinity of negative and neutral modulators does not change as a consequence of benzodiazepine dependence. Aim 2B tests the hypothesis that efficacy demands at GABAA receptors will increase as a consequence of benzodiazepine dependence. Finally, because neuroactive steroids appear to have multiple mechanisms of action, the selectivity of drug discrimination is exploited to identify receptors that contribute to their behavioral effects in monkeys. Studies under Aim 3A establish stimulus control with the neuroactive steroid pregnanolone and characterize pharmacological selectivity. Drugs acting at benzodiazepine sites will be studied in combination with neuroactive steroids under Aim 3b in order to determine the role of GABAA receptors in the discriminative stimulus effects of pregnanolone. Taken together, these studies will systematically compare neuroactive steroids to benzodiazepine-site ligands between normal and benzodiazepine-dependent monkeys. These studies will improve our understanding of how GABAA receptor function changes with benzodiazepine dependence, will improve our understanding of the pharmacology of neuroactive steroids, and may lead to improved treatments for benzodiazepine withdrawal, anxiety, insomnia, and perhaps even ethanol withdrawal. Benzodiazepine withdrawal can make discontinuation of treatment difficult and is the predominant limitation to the use of these otherwise safe drugs. This grant investigates other drugs (e.g., neuroactive steroids) with particular attention to the possible advantage of these compounds in treating benzodiazepine dependence. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Abuse of prescription opioids had reached epidemic levels and is responsible for increasing emergency department visits and overdose deaths. Most prescription opioid deaths involve at least one other drug, often a benzodiazepine (BZD). Up to 70% of opioid abusers also use BZDs, reportedly to enhance opioid-induced feelings of euphoria. Coabuse of opioids and BZDs increases the risk of physical dependence and overdose, and studies in humans suggest that BZD enhancement of abuse-related effects of opioids occurs in dependent, and not in nondependent, individuals. Despite its prevalence and many anecdotal reports of the problem, few studies have systematically examined coabuse of opioids and BZDs, and little is known about the reinforcing effects of mixtures and how they compare to those of either drug alone in nondependent, dependent or withdrawn subjects. Because of this paucity of data, it is not clear how to best treat coabusers. Proposed studies address this major gap in our knowledge about opioid/BZD mixtures by establishing a model of coabuse in monkeys. A choice procedure will be used because it appears to be more sensitive to the reinforcing effects of drug mixtures than single-response, self-administration procedures, and it provides a measure of preference that is relatively independent of response rate, an important feature when studying dependence and withdrawal. Aim 1 establishes choice (self administration) between opioid/BZD mixtures (heroin/midazolam) and heroin alone and compares preference for the mixture in monkeys who are physically dependent on a combination of an opioid (morphine) and a BZD (lorazepam) to those who are not dependent. This Aim tests the hypothesis that heroin/midazolam mixtures are preferred over the same doses of heroin alone in codependent, but not in nondependent, monkeys. Aim 2 examines preference for opioid/BZD mixtures in withdrawn monkeys and compares choice of the mixture to the emergence of other signs of withdrawal. This Aim tests the hypothesis that withdrawal from combined treatment with an opioid and a BZD increases the reinforcing effects of opioid/BZD mixtures, which covary with the emergence of other withdrawal signs. Despite overwhelming epidemiological evidence in drug abusers indicating preference for an opioid/BZD mixture, studies in nonhumans have not replicated these effects perhaps because the procedures are not sensitive to the reinforcing effects of mixtures or the physiological condition of subjects (i.e., nondependent) do not model the typical condition of coabusers. Because systematic studies on drug mixtures are neither safe nor ethical in humans, proposed studies use nonhuman primates and procedures that are well established in this laboratory to model the pharmacological conditions (i.e., opioid/BZD codependence) that are common in coabusers, thereby determining how codependence on and withdrawal from opioids and BZDs impact choice of opioid/BZD mixtures and providing a platform that will be used to investigate other factors that might contribute to coabuse and to assess current and new therapeutic approaches for this important public health problem.

Abstract The opioid epidemic remains a serious national crisis, with deaths from opioid overdose skyrocketing over the last 10 years. This escalation is driven by abuse of prescription opioids and heroin, indicating that improved treatment would reduce the incidence of abuse and the risk of overdose. A multi-modal approach that includes behavioral and pharmacological interventions is most effective in treating abuse, and several pharmacotherapies, including buprenorphine, are available. Even with these treatment options, opioid abuse is not decreasing, perhaps because it is a complex problem and multiple factors must be addressed during treatment. For example, most patients are physically dependent and polydrug abusers. After proper initiation of treatment, buprenorphine can suppress withdrawal signs and decrease abuse of opioids; however, its ability to alter abuse of drugs from other pharmacological classes, such as cocaine, is limited. To better treat these complicated issues, buprenorphine could be combined with a second medication, and one drug that is receiving considerable attention is the serotonin2C (5-HT2C) receptor agonist lorcaserin. Drugs of abuse can increase extracellular dopamine; by decreasing dopamine neurotransmission, which can be accomplished indirectly using lorcaserin, abuse of a variety of drugs, including those for which there are no approved pharmacotherapies (e.g. cocaine), might be reduced. In fact, lorcaserin has been shown to decrease ongoing self-administration of cocaine, nicotine, ethanol, and opioids and to attenuate reinstatement of extinguished responding that was previously maintained by cocaine or heroin. Because lorcaserin would not be expected to suppress opioid withdrawal, it would not be adequate as a stand-alone treatment for most opioid abusers; however, a combination of buprenorphine and lorcaserin might be a novel, safe and highly effective approach for treating opioid use disorder. Proposed studies use nonhuman primates and procedures that are well established in this laboratory to provide proof of concept for using buprenorphine/lorcaserin mixtures to treat opioid abuse. In Aim 1, a self- administration procedure is used to model ongoing abuse, and in Aim 2, reinstatement of extinguished responding is used to model relapse to drug use. In both Aims, mixtures of buprenorphine and lorcaserin are expected to attenuate the effects of heroin and cocaine at dose combinations that do not alter responding for food, and these results would support the continued development of this drug combination for treating drug abuse. Importantly, these potential treatment drugs have already been approved for use in humans, and if proposed studies demonstrate therapeutic potential for this combination in monkeys, buprenorphine/lorcaserin mixtures could be evaluated in humans very soon. Meanwhile, because long-term treatment would be needed in drug abusers, future studies in monkeys would examine the chronic effects of these mixtures, including tolerance and physical dependence. These studies could lead to a novel treatment option to address the ongoing and very complicated opioid epidemic.