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.
Previous work in this project has demonstrated that self-administered cocaine has both positive (rewarding) and negative (anxiogenic/aversive) properties. The current proposal is aimed at identifying the underlying neurobiological and neurochemical systems mediating the opponent-process actions of cocaine the understanding of which is essential for the development of effective treatments for cocaine abuse.
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