Year of Publication

2006

Document Type

Dissertation

College

Medicine

Department

Anatomy and Neurobiology

First Advisor

Greg A. Gerhardt

Abstract

Stimulant medications such as D-amphetamine, mixed-salts (75% D- and25% L-) amphetamine; Adderall®, and methylphenidate are first-line treatmentsfor Attention-Deficit/Hyperactivity Disorder (ADHD). In vivo studies havepredominantly focused on these stimulants in the context of drug abuse, andtheir therapeutic mechanistic properties are only theoretical. Previously, in vivotechniques have been limited by poor temporal and spatial resolution, andcharacterizations of these medications in rodent models have not been possibleat low, clinically relevant levels. In order to address these issues, our laboratoryused in vivo high speed chronoamperometric microelectrodes to characterize theeffects of local applications of D-amphetamine, L-amphetamine, D,Lamphetamine,and Adderall® at low levels in the striatum and nucleusaccumbens of 3-6 month old, male Fischer 344 (F344) rats. Our results showedsignificant differences between the faster kinetics of dopamine (DA) releasesignals caused by D,L-amphetamine and the slower kinetics resulting from Damphetamine.These data support that resulting DA concentrations evoked by DandD,L-amphetamine are correlated with the amount of D-amphetamine in thedrug and only the time courses of the signals are affected by L-amphetamine.Additionally, locally applied D- and L-amphetamine caused DA release signalswith similar amplitudes or concentrations of evoked DA; however, the signalswere significantly faster for L-amphetamine. Adderall® caused significantlygreater DA release that lasted over a longer time course compared to DA releasecaused by D- or D,L-amphetamine. These data support the hypothesis thatamphetamine isomers, alone or in combination, interact differently with the DAtransporter (DAT) to subsequently cause reversal of transport of DA out ofpresynaptic membranes of DA neuronal projections. Finally, reversemicrodialysis studies were carried out to assess low levels of D-amphetamine,Adderall® (75% D-, 25% L-amphetamine), methylphenidate, and a new mixedsaltsamphetamine that we referred to as Reverse Adderall (75% L-, 25% Damphetamine)in the striatum of F344 rats. These data reveal a stimulantconcentration-response curve for DA with double plateaus that may be explainedby dual mechanisms of reverse transport of DA through the DAT. In addition,reverse microdialysis of methylphenidate caused DA overflow similar to theeffects of the other stimulants.

Share

COinS