Effects of local application of methamphetamine and its para-hydroxylated metabolites on central monoaminergic systems
Creators: name: Matsuda, Lisa Asako
Publisher: name: University of Utah
Year: 2012
Subjects: subject: Drug Effects
subject: Pharmacokinetics
subject: Physiology
subject: FOS: Biological sciences

description: Within minutes after treatment, a single systemic dose of methamphetamine (METH) decreases the activity of tryptophan hydroxylase (TPH) in the central nervous system of the rat.  However, direct applications of large doses of METH into the neostriatum do not alter TPH activity.  The experiments performed in this study examined two possible reasons for the absence of a METH-induced decrease in TPH activity observed in rats which were treated with METH intrastriatally.  One possible explanation for the effects produced by systemic versus intrastriatal administrations of METH is that decreases of TPH activity are produced by the interaction of numerous neuronal systems which are influenced by METH in multiple brain areas.  However, METH given intraventricularly or into two other brain regions, in addition to the striatum (the substantia nigra or lateral midbrain), failed to decrease significantly striatal TPH activity.  An alternative explanation for these and the previous findings is that, following intracerebral injections, TPH activity remains unchanged due to rapid clearance of METH, away from the site of injection(s).  This alternative was tested by examining the neurochemical response to the analogs of AMPH, p-hydroxyamphetamine (pOHA) and p-hydroxynorephedrine (pOHNor).  While these compounds demonstrate pharmacodynamics profiles which are quite similar to that of METH (i.e., marked enhancement of dopamine release) their clearance from neural tissues is substantially slower.  Following intrastriatal injection, local concentration of dopamine and its major metabolites were decreased by pOHA or pOHNor in a dose-dependent manner; neither compound, however, reduced TPH activity in this area of the brain.  Intrastriatally administered pOHA or pOHNor also decreased local concentrations of serotonin, although stores of this monoaminergic amine were less sensitive to the depleting actions of these compounds.  Systemically administered pOHA also effectively reduced concentrations of dopamine and serotonin in specific brain regions.  The pOHA-induced depletion of striatal dopamine was reversible and , following systemic administration, was attenuated significantly by the dopamine uptake blocker, amfonelic acid.  These findings suggest that a brief duration of exposure of brain tissues, to METH-like compounds, does not explain the absence of decreased TPH activity in rats treated with a cerebral injection of METH.  It is possible, however, that along with the ability to release dopamine, other actions of these para-hydroxylated compounds may simultaneously prevent subsequent changes in TPH activity.  Addition studies, therefore, are necessary to not only elucidate the underlying mechanisms involved in the immediate METH-induced effects on TPH activity, but also to understand further the actions of  these para-hydroxylated compounds on central monoaminergic systems.