Animal models of drug self-administration have been useful for identifying variables that control drug taking behavior in humans, but little emphasis has been placed on factors predisposing acquisition of drug abuse and factors related to abstinence craving and relapse. Protracted alterations in performance can be detected by sensitive behavioral tests after removal of cocaine and other drugs that do not result in an observable withdrawal syndrome. There may be subtle factors that alter performance long after drug use is stopped that contribute to the high rate of relapse. The purpose of this research is to investigate and compare behavioral and pharmacological interventions for cocaine and other drug abuse at 5 phases of the addiction process (e.g., acquisition, drug-rewarded behavior, abstinence, """"""""craving"""""""" and """"""""relapse""""""""). In the first experiment groups of rats will be trained to self-administer cocaine using an autoshaping procedure to obtain a quantitative measure of the rate of acquisition. Next, the magnitude of the cocaine-induced regard will be evaluated by using break-point on a progressive ratio schedule. Chronic access to cocaine will be restored, and behavior maintained by food, a glucose and saccharin (G+S) solution will be measured when cocaine access is terminated. Earlier work with a similar design has shown long-lasting behavioral disruptions in behavior maintained by G+S. To develop an animal model of """"""""craving"""""""", saline will be substituted for cocaine and after behavior stabilizes, stimuli associated with cocaine will be presented and the number of responses on the drug lever will be recorded. """"""""Relapse"""""""" will be explored by replacing cocaine with saline and then priming the rats with one injection of cocaine, the number of drug lever responses will be recorded. Other drugs of abuse and therapeutic substances will also be tested for their ability to reinstate responding that was previously reinforced by cocaine. Some groups of 5 rats will have behavioral interventions such as food satiation, food deprivation or access to an alternative reinforcer such as orally-delivered G+S or ethanol (8%). Other groups will be given pharmacological treatments throughout, such as buprenorphine,an opiate mixed agonist-antagonist, and fluoxetine, serotonin reuptake blocker, which have some efficacy in reducing cocaine self- administration in animals and humans. For comparison, a serotonin antagonist, metergoline, will be administered, and neuropeptide Y, a drug that induces feeding, will also be tested. Each of these agents antagonist, metergoline, will be administered, and neuropeptide Y, a drug that induces feeding, will also be tested. Each of these agents will be given in several doses in separate groups of rats. An additional group will be given a combination of a behavioral and pharmacological interventions to determine whether the combined strategies reduce cocaine intake in an additive manner. Selective experiments will be replicated with groups that are self-administering fentanyl, a synthetic opiate and methamphetamine, a longer acting psychomotor stimulant. In addition, an attempt will be made to establish fluoxetine as a reinforcer using the autoshaping or a cocaine-induced reward. Two competing reinforcers will be tested, G+S and ethanol, under a range of concurrent fixed-ratio (FR) schedules. A behavioral economic analysis will be conducted to quantify demand for cocaine as a function of the effort required to obtain the alternative reinforcer. The third experiment will consist of a thorough examination of performance deficits that occur during cocaine abstinence. Separate groups will be tested under different FR schedules for G+S and ethanol, under a range of concurrent fixed-ratio (FR) schedules. A behavioral economic analysis will be conducted to quantify demand for cocaine as a function of the effort required to obtain the alternative reinforcer. The third experiment will consist of a thorough examination of performance deficits that occur during cocaine abstinence. Separate groups will be tested under different FR schedules for G+S and ethanol, under a range of concurrent fixed-ratio (FR) schedules. A behavioral economic analysis will be conducted to quantify demand for cocaine as a function of the effort required to obtain the alternative reinforcer. The third experiment will consist of a thorough examination of performance deficits that occur during cocaine abstinence. Separate groups will be tested under different FR schedules for G+S delivery. Initial work indicates that the protracted disruptions in operant behavior during drug abstinence are highly dependent upon the performance requirement s, with greater deficits occurring with higher response costs. This experiment will extend initial work and define important parameters for further study with behavioral and pharmacological interventions. Successful strategies for altering behavior in all phases of drug addiction would have considerable health related consequences for the prevention of initial illicit drug use, in treatment and in the prevention of relapse in human drug users.
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