Brett C. Ginsburg - US grants

DESCRIPTION No pharmacological therapy exists for cocaine addiction. Further, understanding of the mechanism of cocaine-reinforced behavior could aid in the development of an affective therapy for human cocaine addicts. Cocaine acts pharmacologically to inhibit presynaptic reuptake of monoamines including dopamine and serotonin. Specific dopamine or serotonin monoamine reuptake inhibitors can attenuate cocaine self- administration in animal models of drug abuse. This project will explore the relative contributions of dopamine and serotonin reuptake inhibition to cocaine-reinforced in non-human primates. In conjunction, microdialysis experiments performed while animals self-administer in non-human primates. In conjunction, microdialysis experiments performed while animals self-administer cocaine following treatments with each of the above drugs will provide a unique approach to understanding the behavioral effects of drug interactions and concurrent neurochemical changes. By addressing the neurochemical mechanisms that underlie cocaine-reinforced behavior in a non-human primate model, this project will afford greater understanding of the relationship of specific neurotransmitter systems to cocaine abuse.

cocaine; drug abuse; chemical structure function; Saimiri; animal colony; amines;

[unreadable] DESCRIPTION (provided by applicant): Central cannabinoid receptors (CB1) have gained interest as a therapeutic target. Agonist activated CB1 receptors propagate their signals downstream via coupling with G-proteins. Normally, this coupling occurs at a high efficiency, resulting in a high receptor reserve. Both aging and ethanol exposure reduce the efficiency of cannabinoid receptor coupling with G-proteins, and thus receptor reserve. Similarly, inbred C57BL/6J mice have higher cannabinoid receptor reserve than inbred DBA/2J mice, suggesting strain- dependent responses to cannabinoids. However, the impact of differences in cannabinoid receptor reserve on behavioral responses to cannabinoids remains unclear. The present proposal is designed to examine the effects of the CB1 agonist delta-9-tetrahydrocannabinol (THC) and the CB1 inverse agonist/partial agonist rimonabant (SR141716A) on fixed-ratio responding in rats and mice. Proposed experiments will characterize changes in the behavioral response to these drugs (alone and in combination) due to aging, ethanol exposure, or genotype. Young rats, ethanol-naive rats, and C57BL/6J mice have more efficient cannabinoid systems, resulting in higher receptor reserve. The potency of THC is expected to be enhanced in subjects with higher cannabinoid receptor reserve. Further, in subjects with a higher receptor reserve, rimonabant alone is expected to reduce response rate due to its intrinsic activity at CB1 receptors, and will be unable to completely antagonize THC effects due to this activity. Conversely, in older rats, ethanol- exposed rats, and DBA/2J mice, presumed to have a lower receptor reserve, rimonabant is expected to have no activity when administered alone and should completely antagonize THC effects. In addition to fostering the development of the applicant into an independent researcher, the present proposal will characterize the behavioral pharmacology of cannabinoids under conditions known to alter cannabinoid system efficiency. These studies will provide valuable information linking cellular and behavioral effects of cannabinoids. LAY SUMMARY: Cannabis is thought to produce euphoric and therapeutic effects through the cannabinoid receptors in the brain. Drugs that act at these receptors are important because they are involved in cannabis abuse and may be valuable medications. This project will help us understand how aging, exposure to ethanol, and perhaps genetic disposition change the behavioral response to these drugs. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Drugs that alter behaviors maintained by ethanol to a greater extent than behaviors maintained by an alternative reinforcer are considered selective. Such selective drugs are thought to target neurobiological systems involved in ethanol reinforcement and may prdict clinical efficacy in alcoholics. However, such selective effects may instead depend more on the schedule of reinforcement than on any direct, pharmacological effect of the drug on ethanol reinforcement per se. Acamprosate, naltrexone, and ondansetron selectively reduce several measures of ethanol reinforcement in animal studies and provide long-term benefits to alcoholics. By testing the acute effects of each drug on ethanol and food maintained behaviors under several different schedules of reinforcement, the generality of selective effects on ethanol self-administration will be assessed. Effects of each drug (expressed in ED50) on responding for either food or ethanol will be assessed in terms of response rate, reinforcerment rate, and context (independent or concurrent access). These experiments will aid our interpretation of reports of selective drug treatment effects on ethanol self- administration. Results will provide information about whether selective effects of treatments on ethanol self-administration are predictive of clinical efficacy. Further, results will address whether such selective effects are due to the pharmacology of the treatments or are due to other determinants of drug effects on behavior such as baseline response rate, reinforcement rate, or context of ethanol availability. (Relevance) By testing how different drugs alter the way animals work for alcohol, scientists can better understand how alcohol works in the brain and develop better treatments for alcoholism. Yet, the degree to which the circumstances chosen for such experiments impact these results is still poorly understood. This project will use several particularly sensitive procedures to study the effects of three promising treatments for alcoholism that also seems to decrease the amount of alcohol animals work for and drink under different conditions. This project will clarify important factors involved in studies of alcohol effects and potential medications for alcoholics. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Only by understanding behavioral and neurobiological mechanisms that underlie relapse can we reduce the high prevalence of relapse to drug addiction. To study these mechanisms, the reinstatement model of relapse has been developed, where animals learn to self-administer a drug, and then responding for the drug is suppressed by extinction: responses no longer provide access to the drug. Once responding is suppressed, exposure to the drug, drug-associated stimuli, or stimuli signaling drug availability result in a resumption of responding for the drug, despite its continuing absence. These same conditions promote relapse in recovering addicts. Also, inactivating brain regions that are active during self-reported craving reduce reinstatement behavior. However, in humans, abstinence is rarely forced;addicts choose to reduce or stop drug use, replacing maladaptive drug use with other, adaptive behaviors. Additionally, in the animal model, increasing the period of forced abstinence increases subsequent reinstatement;yet in humans longer periods of abstinence reduce the likelihood of relapse. Thus there could be a fundamental difference in the behavioral and neurobiological mechanisms that underlie drug self-administration behavior that has been suppressed by extinction verses behavior suppressed by reinforcing an alternative behavior. In this proposal, (1) conditions are established that result in ethanol-predominant or ethanol-suppressed choices under a concurrent fixed-ratio schedule of food and ethanol reinforcement. Then, reinstatement of extinction-suppressed or choice-suppressed responding is compared following several treatments known to reinstate extinction-suppressed responding and precipitate relapse. (2) The impact of reversible inactivation of several brain regions on reinstatement responding under extinction-suppressed and choice-suppressed responding is compared. (3) The impact of the length of the period of response suppression on reinstatement responding in each procedure is determined. Finally, (4) stimulus generalization curves are established following 30 or 60 days of ethanol self-administration or suppressed ethanol-self-administration under both procedures. This method provides information about the stimulus control of a behavior and could help us understand conditions that increase vulnerability to relapse or promote recovery. These studies will begin to build an integrative relationship between studies on the determinates of choice and reinstatement behaviors. PUBLIC HEALTH RELEVANCE This project enhances a commonly used animal model of relapse behavior by suppressing drug taking by reinforcing an alternative behavior rather than removing drug altogether. This is more similar to the decisions required of recovering addicts. The influence of brain regions and abstinence period will be tested.

DESCRIPTION (provided by applicant): Attending to alcohol-associated stimuli (alcohol cues) is assessed in humans using attentional bias procedures and (a) can interfere with other activities in heavy drinkers, (b) is related to the pattern and severity of problematic drinking, nd (c) is greater among current drinkers versus those in recovery. This evidence suggests that therapies that decrease attentional bias to alcohol cues might prevent cue-induced relapse. Conversely, it is also possible that effective therapies decrease attentional bias by facilitating abstinence. Better understanding the mechanisms responsible for changes in attentional bias could elucidate the relationship between attentional bias and relapse. Such research would be facilitated by a preclinical model of attentional bias. Here we develop an animal model of the human attentional bias procedure, where attending to alcohol cues interferes with the identification of a target. In this project, rats are trained to attend to stimuli that signal whee and when to respond for food (food stimuli). Stimulus presentation is brief, and incorrect or omitted responses are penalized by withholding food reward. Once rats learn this serial reaction time (SRT) task, we pair a tone (alcohol cue) with alcohol delivery in separate sessions. Ultimately, rats will attend to the alcohol cue, but not another (control cue) during an SRT session, which will be evident from a relative increase in latency to correct responses and in incorrect or omitted responses during alcohol versus control cue presentation. We first determine how increasing the attentional demand of the SRT task influences the effect of alcohol cue presentation by decreasing the duration of the food stimuli presentations (Aim 1). This allows parameter optimization for subsequent studies. We then examine how increasing the number of alcohol + alcohol-cue pairing sessions affects interference with SRT performance by alcohol cue presentation (Aim 2). This would be consistent with human literature demonstrating greater attentional bias among heavier versus occasional drinkers. Finally, we determine how extinction (where the alcohol cue is presented without alcohol) affects interference with SRT performance by alcohol cue presentation (Aim 3). We compare these results to those from rats with a matched period of suspended exposure (where neither alcohol or the cue are present). This will address whether treatments that decrease attentional bias to alcohol cues might provide protection against relapse by reducing attention to alcohol cues encountered in familiar environments and then precipitate relapse. Treatments that do not target attending to alcohol cues but instead only impose abstinence may not provide this additional protection. These experiments establish a novel, innovative, and translational preclinical model of the clinical attentional bias procedure. This will facilitate future studies relating clinical observations of attentional bias to preclinical observations of conditioned approach or instrumental responding. These studies will also facilitate future investigation of neurobiological mechanisms of attentional bias to alcohol cues and could identify more effective therapies to prevent relapse.

Abstract Recovery involves replacing drinking with more adaptive behavior. Once the more adaptive behavior becomes habitual, recovery is more resistant to relapse produced by stimuli previously occasioning drinking. However, until this transition occurs, the new adaptive behavior is easily displaced. This transition requires cognitive flexibility in order to attend to the stimuli and contingencies associated with the new behavior. Unfortunately, heavy drinking reduces cognitive flexibility, especially in females. This reduced cognitive flexibility appears to result from reduced cholinergic activity at ?4?2 and ?7 nicotinic receptors, particularly those in the hippocampus and anterior cingulate innervated by cholinergic neurons originating in the medial septum. Restoring cholinergic function may restore cognitive flexibility during the new learning involved in transitioning from habitual drinking to more adaptive habits; and thus, speed this transition. Speeding this transition minimizes the most fragile period of recovery, the early stages before new habits have developed. However, increasing cholinergic function above an optimal level impairs new learning. Thus, enhancing cholinergic function may only speed recovery when chronic drinking has reduced cognitive flexibility, perhaps more so in females. We explore these possibilities using a rat model of recovery we developed. Like in the real world, in this model high and low levels of drinking are controlled not by changing ethanol availability, but rather by changing the contingencies governing the availability of alternatives, in this case food. In the presence of one stimulus, food is costly and drinking predominates. In the presence of another, food is easily available and little drinking occurs, simulating recovery. After several consecutive recovery sessions in which rats only encounter low cost food conditions, presenting the high-cost food stimulus no longer controls responding for ethanol. Instead rats persist at responding for food, indicating this response has become habitual and control by the high-cost food stimulus has weakened. We propose examining whether chronic intermittent ethanol exposure slows the development of recovery, and whether this effect is greater in females. Further, we compare effects of nicotine to those of epibatidine and PNU-282987, which preferentially activate ?4?2 and ?7 receptors, respectively. Finally, we examine effects of delivering nicotine into the hippocampus and cingulate and compare these to those following administration into the thalamus (not expected to influence cognitive flexibility). This project explores an innovative target for relapse prevention: medications intended to speed new habit formation, such as might occur during behavioral therapy. This strategy may reduce relapse during the early, critical period of recovery, thus improving therapeutic outcomes.