This application for a FIRST Award outlines a series of studies designed to explore the neuroanatomical and neuropharmacological substrates mediating the early stages in the development of opiate dependence. Opiate addiction is commonly associated with a neuroadaptive state of dependence that may play an important role in the maintenance of addiction. While the neural mechanisms mediating opiate dependence and withdrawal have traditionally been studied under conditions of chronic opiate treatment, empirical evidence indicates that even a single exposure to an opiate agonist can lead to withdrawal symptoms upon treatment with an opiate antagonist several hours later. This phenomenon of """"""""acute dependence"""""""" suggests that neuroadaptive responses to opiates may begin with a single dosing of the drug, and that the motivational significance of drug abstinence could begin to play a role early in the addiction process. The proposed studies using rats will characterize an animal model of the progressive development of dependence beginning with initial exposure to morphine, and will begin to elucidate the neural mechanisms mediating this acute dependence-like phenomenon. Withdrawal-like signs elicited by the opiate antagonist naloxone following single or repeated intermittent treatment with low doses of morphine will be examined using the following well-established measures of opiate withdrawal: suppression of operant responding, conditioned place aversion, and ratings of somatic withdrawal signs. By varying systematically the dose of morphine and the interval between successive morphine exposures, initial studies will determine the minimum conditions necessary for the initiation and progressive development of this dependence-like state (Specific Aims 1 and 2). Local intracerebral microinjections of the hydrophilic antagonist methylnaloxonium will be used to explore the neuroanatomical substrates which mediate precipitated withdrawal-like effects following acute morphine exposure (Specific Aim 3). Finally, the role of NMDA receptor activation in the initial development of neuroadaptation to morphine will be examined using the non-competitive NMDA antagonist MK801 (Specific Aim 4). These experiments will permit a validation of the acute dependence model as a reliable index of the early stages in the development of opiate dependence, and establish the basic framework and necessary tools for subsequent elucidation of the cellular and molecular mechanisms which mediate the initial neuroadaptive response to opiates. An understanding of these neural mechanisms should provide information critical for the prevention and treatment of opiate addiction and drug addiction in general.
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| Schulteis, Gery; Chiang, David; Archer, Clay (2009) Relative potency of the opioid antagonists naloxone and 6-alpha-naloxol to precipitate withdrawal from acute morphine dependence varies with time post-antagonist. Pharmacol Biochem Behav 92:157-63 |
| Amitai, Nurith; Liu, Jian; Schulteis, Gery (2006) Discrete cues paired with naloxone-precipitated withdrawal from acute morphine dependence elicit conditioned withdrawal responses. Behav Pharmacol 17:213-22 |
