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Journal of Neuroscience, Vol 15, 1308-1317, Copyright © 1995 by Society for Neuroscience
Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine
R Kuczenski, DS Segal, AK Cho and W Melega
Psychiatry Department, UC San Diego School of Medicine, La Jolla 92093- 0603.
Microdialysis in behaving animals was used to concomitantly characterize
the dopamine and 5-HT responses in the caudate and the norepinephrine
response in the hippocampus to the D- and L-isomers of amphetamine and
methamphetamine. Doses of all four drugs which promoted similar stereotypy
responses produced a D-amphetamine-like response profile of dopamine and
dopamine metabolites, suggesting that all these drugs interact with
dopamine systems to facilitate the release of transmitter. However, in
contrast to the similar behavioral profiles, the magnitude of the dopamine
responses diverged significantly. In addition, all four drugs increased
extracellular norepinephrine and 5- HT, but the relative responses differed
markedly from dopamine and from each other. The contrasting
structure-activity relationships for these drugs likely reflect their
differential potency at the various neuronal uptake transporters in
promoting either transmitter release, and/or uptake blockade. In addition,
the interaction of each drug at the vesicular transporters, as well as the
availability of a cytoplasmic pool of transmitter likely also contribute to
the neurotransmitter response. Because of the particularly divergent
transmitter response profiles exhibited by L-methamphetamine, its
behavioral and neurotransmitter effects were characterized over a more
extended range of doses. Although the duration of the increase in
extracellular dopamine was clearly proportional to dose, the dose-dependent
increases in the magnitude of the dopamine response did not parallel the
behavioral profiles. The results of these studies indicate that, while the
dopamine, norepinephrine and 5-HT responses to these drugs probably
contribute to the expression of stimulant-induced behaviors, simple
relationships between the neurotransmitter responses and the behavioral
profiles were not evident.
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