title: Influence of chronic amphetamine treatment and acute withdrawal on serotonin synthesis and clearance mechanisms in the rat ventral hippocampus.
abstract: Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis (in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal.
authors.affiliation: Neuroscience Group, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barr
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Scholl
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Solanki
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Renner
authors.forename: Gina L
authors.initials: GL
authors.lastname: Forster
mesh_terms: D000661:Amphetamine / Q000009:adverse effects / Q000633:toxicity*; D000818:Animals; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D009435:Synaptic Transmission; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D027701:Organic Cation Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D000661:Amphetamine; D014365:Tryptophan Hydroxylase