Aaron Ettenberg - US grants

Antipsychotic drugs (neuroleptics) used to treat human psychiatric patients have long been known to suppress rewarded behaviours in laboratory animals. Controversy exists, however, over whether these behavioural disruptions result from reductions in pleasure/reward ("limbic system" effects), or from an interruption of the brain's control of movement ("extrapyramidal" effects). In previous work, Dr. Ettenberg has developed laboratory tests which clearly distinguish between the reward-attenuating and performance- debilitating actions of these drugs. His results suggest that neuroleptics can attenuate the rewarding properties of a number of positive reinforcers, such as the taste of sugar. Dr. Ettenberg will conduct experiments to extend these results, testing the generality with which neuroleptics attenuate the rewarding effects of several different positive reinforcing rewards, and also, to identify those critical brain regions responsible for the drugs' actions. This work will provide scientifically relevant information about the mood-altering or pleasure-diminishing consequences of antipsychotic drugs, and also help in the identification of brain mechanisms responsible for positive affective states.

Studies of food, water and brain-stimulation rewards have provided evidence that central dopaminergic (DA) substrates represent an important link in the neurobiology of positive reinforcement. Since abused drugs are presumed to act via a central activation of the brain's natural reward mechanism(s) it has been suggested that these DA pathways also mediate the reinforcing properties of self-administered drugs. Controversy exists, however, over whether or not such DA systems underlie the reward produced by all positive reinforcers or whether various independent systems exist in parallel within the CNS. The proposed research was devised to test the hypothesis that central DA neurons mediate the reinforcing properties of two major classes of abused drugs - the psychomotor stimulants (amphetamine, cocaine), and the opiate agonists (morphine and heroin). the effects of peripheral and central DA receptor antagonists on drug reward shall be examined in two novel behavioral paradigms: a Partial Reinforcement Extinction Test and an Incentive Motivation test. Both tests have the important advantage of assessing reward changes in animals that are no longer drugged at the time of testing. The proposed research should a) provide information relevant to our understanding of human stimulant and opiate drug abuse; and b) help elucidate the role of central DA neurons in the neural basis of drug reward.

The primary long-term goal of this ongoing project is to elucidate the nature of the underlying neural mechanisms responsible for the reinforcing and motivational properties of drugs of abuse. Previous work in this field has concentrated on cocaine's reinforcing actions, which motivate animals to self-administer the drug, or the aversive state that accompanies withdrawal from chronic use and presumably motivates animals to reinstate its drug-seeking behavior after a period of drug abstinence. Studies from the current project have identified the presence of both positive and negative actions of cocaine even from the earliest exposure to the drug. A thorough investigation of the nature of these dual and opposing actions of cocaine would seem necessary for a complete understanding of the factors that result in the initiation and maintenance of cocaine self-administration. In that context, experiments are proposed to address two specific aims each of which builds upon and extends the findings obtained during the first twenty one years of the project. Specific Aim 1 is to elucidate the role of central serotonergic systems in the anxiogenic/aversive properties of cocaine;and Specific Aim 2 is to assess the contributions of the structures comprising the "extended amygdala" in the opponent process actions of cocaine. The primary behavioral method to be employed in this research is a novel model of drug-seeking in which animals traverse a straight alley once a day to obtain a single IV injection of a drug reinforcer (e.g., cocaine). In this model, the time required to cross the runway and enter the goal box (i.e. Run Time) provides a reliable index of the undrugged subject's motivation to seek the drug reinforcer. Since animals are tested on but a single trial/day, the resulting behavioral data are always collected prior to drug delivery and hence are devoid of any confounding performance-altering properties of the drug reinforcer itself. The runway method is also uniquely sensitive to concurrent positive and negative properties of goal-box events. Ss exhibit an oscillating approach-avoidance conflict (i.e., retreat behaviors) about entering the goal box for drugs, like cocaine, having mixed positive + negative features. Experiments are planned to challenge runway IV selfadministration of cocaine with centrally applied selective antagonists of neurotransmitter function, and to assess the impact of lidocaine-induced reversible lesions of selective brain structures on the runway behavior of cocaine-reinforced animals. Together, these studies are intended to help elucidate the neural mechanisms subserving the mixed positive and negative properties of cocaine that ultimately interact to produce the acquisition and maintenance of the drug's self-administration and abuse.

This project provides funds for expanding and improving undergraduate biopsychology teaching laboratory curriculum. Two upgraded versions of current courses (Laboratories in Neuroanatomy and Animal Learning) and two new ones (Laboratories in Hormones and Behavior and Human Psychophysiology) are being offered to approximately 200 biopsychology majors. A laboratory complement is provided to lecture course material and emphasizes the dynamic, i.e., ever-changing, nature of scientific discovery. Other goals of the laboratory curriculum are as follows: (1) to provide undergraduates with hands on experience in state-of-the-art neuroscience research methodologies through small group instruction in the laboratory, preparing them for careers in the health sciences; (2) to teach undergraduates the scientific method, by having them design and conduct independent experiments to test specific, self-generated scientific hypotheses; (3) to improve scientific literacy (including critical thinking) and communication, by requiring students to read the original scientific literature and present their own data in written and/or oral form; (4) to enhance our students' computer usage skills. Achievement of these goals enables graduates: (1) to be cognizant of their own physiology; (2) to evaluate critically the enormous amount of information (scientific or otherwise) presented by the media; (3) to compete successfully in the markeplace for jobs or additional postgraduate education; (4) to succeed in the increasingly technology-driven workplace of current and future society.

9720633 Olster The energetic costs of reproduction for a female mammal are enormous. Thus, it is not surprising that in many animals, reproduction is influenced by factors related to energy balance, such as food intake, body weight, energy expenditure, and metabolism. Animals that are undernourished or obese often suffer from reproductive abnormalities. The experiments described by Dr. Olster will use the genetically obese Zucker rat to explore the interaction between obesity and abnormal reproductive function. Females of this strain overeat, expend less energy than normal and are obese. These animals exhibit many other abnormalities, including overproduction of insulin and corticosterone (hormones related to the use and storage of nutrients obtained from the diet), insulin resistance, and higher than normal concentrations of neuropeptide Y, a hypothalamic neurochemical that stimulates food intake. Finally, obese Zucker females are infertile. Previous research from this laboratory has demonstrated that these animals have delayed puberty, do not ovulate regularly, and show minimal mating behavior with males. When normal (i.e., lean) rats are experimentally given extra neuropeptide Y, they exhibit a syndrome that is very similar to the abnormal metabolic and reproductive physiology of obese Zucker rats, namely overeating, obesity, oversecretion of insulin and corticosterone, insulin resistance, aberrant reproductive cyclicity and impaired sexual behaviors. The experiments in this proposal are designed to explore the roles of neuropeptide Y, insulin and corticosterone in reproductive dysfunction in obese Zucker rats, with an emphasis on sexual behaviors. These substances will be experimentally manipulated in an effort to improve the reproductive capacity of obese Zucker rats and/or induce reproductive abnormalities in lean females. The knowledge gained from these studies will provide new, exciting information about the signals (of brain, endocrine and/or metabolic origin) that convey i nformation regarding energy balance to the systems regulating reproduction. This cross-talk is of critical importance in allowing animals to reproduce only when it is energetically appropriate to do so.

Project Summary/Abstract The primary long-term goal of this project is to elucidate the nature of the underlying neural mechanisms responsible for the reinforcing and motivational properties of stimulant and opiate drugs of abuse. Behavioral, pharmacological, physiological and neurochemical methodologies will be combined to address two specific aims each of which builds upon and extends the findings obtained during the first nineteen years of the project. Specific Aim 1 is to continue ongoing investigations into the neurobiology of cocaine[unreadable]s mixed rewarding and anxiogenic properties with the goal of better understanding the brain loci and neurochemical bases of the drug[unreadable]s dual and opposing actions. Specific Aim 2 is to distinguish underlying motivational processes that serve to initiate drug-seeking behavior from those reinforcing processes that are activated as a consequence of drug self-administration. The primary behavioral method to be employed in the proposed research is a novel model of drug-seeking in which animals traverse a straight alley once a day to obtain a single IV injection of a drug reinforcer (e.g., cocaine, nicotine, heroin[unreadable]). In this model, the time required to cross the runway and enter the goal box (i.e. Run Time) provides a valid and reliable index of the undrugged subject[unreadable]s motivation to seek the drug reinforcer. Since animals are tested on but a single trial/day, the resulting behavioral data are always collected prior to drug delivery and hence are devoid of any confounding performance-altering properties of the drug reinforcer itself. The runway method is also uniquely sensitive to concurrent positive and negative properties of goal-box events. Ss exhibit an oscillating approach-avoidance conflict (i.e., retreat behaviors) about entering the goal box for drugs having mixed positive+negative features (e.g., cocaine). These behavioral measures of drug-seeking motivation will be combined with physiological measures of arousal (radio-telemetric assessments of heart rate and respiration), and neurochemical indices of drug-induced changes in brain function (c-Fos, in vivo microdialysis). Experiments are planned to employ intracranial and IV self-administration of reinforcing drugs, to challenge such self-administration with systemic and centrally applied selective agonists and/or antagonists of neurotransmitter function (e.g., DA, 5-HT, CRF), and to assess the impact of lidocaine-induced reversible lesions of selective brain structures on the reinforcing and motivating properties of self-administered drugs. Together, these studies are intended to provide important new information on the complex neurobiological and neurobehavioral factors responsible for the self-administration of cocaine and other drugs of abuse, and to further test the hypothesis that different/dissociable neural systems are responsible for the motivational antecedents of drug abuse (drug seeking) and the reinforcing consequences of actually attaining the drug (drug administration).

DESCRIPTION (provided by applicant): Cocaine has been shown to have profound positive and negative actions that adhere closely to the classic opponent process theory of motivated behavior. That theory postulates that dual and opposing systems work in tandem to maintain emotional homeostasis. Indeed, cocaine administration in both humans and animals has been shown to produce an initial euphoric/rewarding action followed in time by an aversive crash that is characterized by states of anhedonia and anxiety. The underlying hypothesis guiding the proposed research is that a thorough understanding of the factors that underlie the initiation, maintenance and reinstatement of cocaine abuse must include an understanding of how these dual and opposing properties of the drug interact to motivate drug-seeking behavior. In this context, three specific aims are proposed: Specific Aim 1 involves studies intended to assess the relative roles of positive and negative drug-cue associations, and the drug's own direct positive and negative actions, in the reinstatement of cocaine-seeking behavior in both addicted and non-addicted animals following varying periods of drug abstinence. Specific Aim 2 will test the hypothesis that individual differences in the positive and negative responses to cocaine and cocaine-paired cues predict an animal's risk for drug self-administration. Specific Aim 3 describes research intended to extend previous results showing that functional lesions of structures within the extended amygdala can prevent the expression of cocaine's negative/anxiogenic properties. Studies will examine the roles of NE, 5-HT and CRF systems within these structures to identify the substrates responsible for cocaine's negative properties, and immunocytochemical studies are planned to link cocaine's dual behavioral effects to patterns of neuronal activation in select brain regions associated with reward and aversion. Each of these aims logically builds upon and extends previous findings from the Principal Investigator's laboratory and each is based upon the view that a) cocaine- seeking behavior (in both addicted and non-addicted animals) ultimately depends upon the balance between the inherent positive and negative properties of the drug, or stimuli associated with the drug, b) that this balance determines the vulnerability for the acquisition and relapse of cocaine-seeking behavior, and c) that the dual actions of cocaine are mediated by separate and identifiable neuronal systems. Two behavioral methods will be employed: a runway model of cocaine self-administration that is uniquely sensitive to cocaine's mixed positive and negative actions in the same animal on the same trial (animal's exhibit approach-avoidance conflict about entering a goal-box associated with cocaine administration) and a modified conditioned place test that permits for the dissociation of the positive and negative properties of the drug (animals come to prefer distinct locations paired with the immediate effects of cocaine while avoiding places associated with the effects present 15-min post IV injection). When used in tandem, these two tests provide a unique and powerful behavioral toolkit for dissociating whether an experimental manipulation alters the positive and/or the negative properties of IV cocaine. The proposed research will therefore employ behavioral, pharmacological and immunocytochemical methodologies to elucidate the behavioral and neurobiological mechanisms underlying the dual opponent properties of cocaine that ultimately interact to motivate rats to seek cocaine and to reinstate cocaine-seeking after a period of drug abstinence.