Characterization of Drug Reward in an Invertebrate Model System Using Operant Conditioning Paradigms

Chapter I: Natural reward circuits are fundamental components of learning as they allow the experience of an event to be associated with a perception of its value. By promoting affective states of eagerness and directed purpose, natural reward also serves as an essential generator of all forms of motivated behavior. Drugs of abuse are able to artificially trigger both the circuitry for reward and the incentive labeling of surrounding cues, as they lead to abnormal learning processes in taxa ranging from planarians to humans. Crayfish, with their modularly organized nervous systems and confirmed vulnerabilities to human drugs of abuse, have recently emerged as a valid model for the study of addiction. Confirmed drug effects in crayfish include psychostimulant properties, sensitization, withdrawal, reinstatement, and drug reward in conditioned place preference paradigms. Here we extend this work with an operant, self-administration paradigm to obtain direct measures of drug reward, along with a characterization of dose response and time course of reward conditioning. In a spatially contingent task individuals learned that entry into a specific substrate quadrant will deliver a bolus of drug. The use of yoked controls allowed quantification of unconditioned drug effects where the drug is presented in a non-contingent fashion. With application of amphetamine close to the brain, crayfish significantly increased operant responding as they readily learned to navigate the paradigm. Infusion into the general circulation followed a similar pattern but proved less effective. The establishment of an effective self-administration paradigm in crayfish provides a unique, comparative perspective on the neural mechanisms of drug-sensitive reward and the phylogenetically conserved vulnerabilities to addictive plant alkaloids. Chapter II: The field of addiction research has recently shown increased interest in the use of invertebrate systems. The crayfish model is at the forefront of this movement, with its accessible, modular nervous system, and demonstrated sensitivity to drugs of abuse. The present study of invertebrate reward employs an instrumental conditioning paradigm to investigate the stimulation of exploratory drive by amphetamine injection directly into the head ganglion. To obtain amphetamine reward, treated animals were required to execute side-specific antennal movements. Yoked controls, receiving the drug on the same temporal pattern as the treated animal, but independent of their own antennal movements, provide a measure of the unconditioned psychostimulant effects. The effect of reward contingency on changes in behavior was assayed at three different drug doses. Comparison of the levels of operant responding in treatment versus yoked controls revealed an increase in operant responding at the highest dose tested (1.0 µg/infusion). Moreover, dose dependent stimulation of antennal movements, behaviors typically associated with active exploration, suggests that amphetamine enhances exploratory drive, most likely through the activation of the seeking system, and supports the use of antennal measurements as a sensitive assay for drug-associated psychostimulation