Michael A. Bozarth - US grants

The objective of this research proposal is to identify and characterize brain systems involved in opite reinforcement. The relationship of these systems to those involved in other rewards, especially psychomotor stimulant reward, is also examined. The methodological focus of this project is on drug microinjetion techniques. The central line of study involves self-administration of morphine directly into brain tissue. Other studies determine the effects of drug microinjections on various behaviors such as brain stimulation reward and intravenous drug self-administration. Considerable evidence suggests tht opiates and psychomotor stimulants can activate the same reward system. This project should determine if additional neural systems are involved in opiate reward. One such system might be that responsible for physical dependence on opiates. Many investigators believe physical dependence to be a major factor in opiate addiction. While recent work has shown that opiates can be rewarding from an action on brain systems not involved in physical dependence, the relief of withdrawal distress may provide an additional motivation to ingest opiates. This research project will examine the ability of this negative reinforcement process to maintain behavior, and the efficacy of positive and negative reinforcement processes in the maintenance of opiate addiction will be directly compared. Other specific aims of this project include the characterization of morphine self administration into the ventral tegmental area, the continuation of anatomical mapping for other brain sites where morphine microinjections are rewarding, a determination of the effect of rewarding ventral tegmental morphine on heroin and cocaine intravenous self-administration, and the identification of opiate-induced effects that are anatomically dissociated from their rewarding actions. The successful characterization of brain systems subserving opiate reinforcement will not only contribute to a basic understanding of drug addiction but may also provide the foundation for developing potential analgesics devoid of high abuse liability.

Considerable evidence suggests that opiates and psychomotor stimulants activate the same reward system. At least part of the reinforcing effects of opiates involve the activation of the ventral tegmental dopamine system, and psychomotor stimulant reinforcement is mediated primarily through this system. This research project should determine if another neural system is also involved in opiate reward. Many investigators believe that physical dependence is a major factor in opiate addiction. While previous work has shown that opiates can be reinforcing from an action on brain systems not involved in physical dependence, the relief of withdrawal distress may provide an additional motivation to self- administer opiates. This series of experiments will examine the ability of this potential negative reinforcement process to maintain drug-taking behavior, and it will provide the basis for evaluating the efficacy of positive and negative reinforcement processes in the maintenance of opiate addiction. Intravenous opiate administration distributes drug throughout the brain, and many different effects are produced by concurrent opiate actions in different brain regions. Research using direct drug application into brain tissue has shown a neuroanatomical dissociation of some opiate effects, such as positive reinforcement, physical dependence, and thermoregulatory changes. By using intracranial microinjections, neural systems mediating positive reinforcement can be activated (viz, from ventral tegmental opiate application) without the development of physical dependence, and physical dependence can be produced (viz, from periventricular gray opiate application) without activating neural systems involved in positive reinforcement. Thus, selective activation of these two opiate-receptor fields can evoke mechanisms subserving either positive or negative reinforcement processes. A major objective of this project is to determine if animals made physically dependent on morphine infused directly into the periventricular gray area will learn to intracranially self-administer morphine into that brain region. If so, this would provide the first substantial evidence that a negative reinforcement process can maintain opiate drug-taking behavior, and it would provide an experimental preparation for further tests of the importance of such negative reinforcement mechanisms. Others studies examine the development of physical dependence during intravenous opiate self-administration, and they explore the role of physical dependence in intravenous drug reinforcement. This series of studies will evaluate the potential role of negative reinforcement processes in opiate self-administration. The successful establishment of periventricular gray morphine self-administration in physically dependent laboratory rats provides a method for assessing the importance of negative reinforcement mechanisms in drug-taking behavior. This experimental procedure would permit-for the first time-a direct comparison of the relative reinforcing strength of appetitive and aversive motivational mechanisms in the maintenance of opiate intake.