Prior methamphetamine self-administration attenuates serotonergic deficits induced by subsequent high-dose methamphetamine administrations.
BACKGROUND
Pre-clinical studies indicate that high-dose, non-contingent methamphetamine (METH) administration both rapidly and persistently decreases serotonergic neuronal function. Despite research indicating the hippocampus plays an important role in METH abuse and is affected by METH use, effects of METH self-administration on hippocampal serotonergic neurons are not well understood, and were thus an important focus of the current study. Because humans often administer METH in a binge-like pattern, effects of prior METH self-administration on a subsequent "binge-like" METH treatment were also examined.


METHODS
Rats were treated as described above, and sacrificed 1 or 8d after self-administration or 1h or 7d after the final binge METH or saline exposure. Hippocampal serotonin (5-hydroxytryptamine; 5HT) content and transporter (SERT) function were assessed.


RESULTS
METH self-administration per se had no persistent effect on hippocampal 5HT content or SERT function. However, this treatment attenuated the persistent, but not acute, hippocampal serotonergic deficits caused by a subsequent repeated, high-dose, non-continent METH treatment administered 1 d the last self-administration session. No attenuation in persistent deficits were seen when the high-dose administration of METH occurred 15d after the last self-administration session.


CONCLUSIONS
The present findings demonstrate that METH self-administration alters serotonergic neurons so as to engender "tolerance" to the persistent serotonergic deficits caused by a subsequent METH exposure. However, this "tolerance" does not persist. These data provide a foundation to investigate complex questions including how the response of serotonergic neurons to METH may contribute to contingent-related disorders such as dependence and relapse.
Department of Pharmacology and Toxicology University of Utah, Salt Lake City, UT 84112, USA.
Lisa M
LM
McFadden
Madison M
MM
Hunt
Paula L
PL
Vieira-Brock
Janice
J
Muehle
Shannon M
SM
Nielsen
Scott C
SC
Allen
Glen R
GR
Hanson
Annette E
AE
Fleckenstein
D019969:Amphetamine-Related Disorders / Q000523:psychology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid