Biology Ph.D. Dissertations

Behavioral characterization of substituted amphetamines and their synthetic cathinone analogues in the rusty crayfish (Orconectes rusticus)

Date of Award

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Biological Sciences

First Advisor

Robert Huber (Advisor)

Second Advisor

Moira Van Staaden (Committee Member)

Third Advisor

Jon Sprague (Committee Member)

Fourth Advisor

Andrea Kalinoski (Committee Member)

Fifth Advisor

Verner Bingman (Committee Member)

Sixth Advisor

Arthur Samel (Other)

Abstract

The functional and evolutionary conservation of neural circuits of reward is an essential component of survival. Drugs of abuse are known to “hijack” natural reward systems to produce their euphoric and reinforcing effects. Recently, synthetic cathinones have gained popularity among the drug users due to low cost, potency and widespread availability resulting from unclear legal regulatory status. Sharing a chemical structure with amphetamines, synthetic cathinones are likely to pose a significant public health threat. Even though synthetic cathinones have been in use for over a decade, the neuropharmacology, behavioral and physiological effects still remain obscure. This gap in knowledge needs to be urgently addressed in order to understand the basic pharmacological effects, development of treatment/therapy against synthetic cathinone addiction and to define a consistent legal framework to assure regulatory control. Due to the ease of experimental manipulations, modularly organized nervous system, absence of blood-brain barrier and well-characterized behavioral paradigms for drug addiction-like behaviors, crayfish continues to be an ideal model to study the addictive potential of any drug. With highly stereotyped behaviors, and a modularly organized nervous system, crustaceans offer productive research models to study proximate mechanisms of a wide range of behavioral phenomena. The current project has harnessed the advantages of this model system to investigate the behavioral effects of synthetic cathinone in comparison to known stimulants: 4-methylmethamphetamine (4-MMA) vs. mephedrone and 3,4-methylenedioxymethamphetamine (MDMA) vs. methylone. We explored the unconditioned behavioral effects, locomotor activity, sensitization of locomotor response, reward potential and termination effects of the above mentioned drugs at doses of 1, 3, and 10 µg/g. Our results show that all the drugs generate significant locomotor effects in crayfish. When crayfish were exposed to these drugs for the first time, increase in locomotion was seen over a brief period of time which faded eventually over the course of trial. Our study indicates that apart from already known exploratory behaviors, unique unconditioned behaviors such as claw waving and circling are observed following drug injections. Typically, these drugs were able to produce psychostimulation at lower doses (1 µg/g) where as depression of locomotion was seen at higher doses (10 µg/g). Initial exposure of these drugs increased locomotion during the infusion itself while repeated drug injections produced psychostimulation that lasted for longer durations. Using the conditioned place preference (CPP) paradigm, we demonstrated that crayfish seek out a particular tactile environment that had previously been paired with the drug. All the drugs at 10 µg/g show preference for the substrate which was paired with the drug. Furthermore, the preference for drug-paired environment persists even after the extinction pairing sessions (when the initially drug-paired compartment was paired with saline). We also investigated the termination effects of the drug to pinpoint withdrawal like behaviors. Termination of drug resulted in production of withdrawal-like behaviors and significant differences in locomotion. This study demonstrates that crayfish offer a comparative and complementary approach in addiction research. The current study contributes an evolutionary context to our understanding of a key component in learning and of natural reward as an important life-sustaining process.

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