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 8. d after self-administration or 1. h or 7. d 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 15. d 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.