title: Serotonin in the ventral hippocampus modulates anxiety-like behavior during amphetamine withdrawal.
abstract: Withdrawal from amphetamine is associated with increased anxiety and sensitivity to stressors which are thought to contribute to relapse. Rats undergoing amphetamine withdrawal fail to exhibit stress-induced increases in serotonin (5-HT) release in the ventral hippocampus and show heightened anxiety-like behaviors. Therefore, we tested the hypothesis that reducing 5-HT levels in the ventral hippocampus is a causal mechanism in increasing anxiety-like behaviors during amphetamine withdrawal. First, we tested whether reducing 5-HT levels in the ventral hippocampus directly increases anxiety behavior. Male rats were bilaterally infused with 5,7-dihydroxytryptamine (5,7-DHT) into the ventral hippocampus, which produced a 83% decrease in ventral hippocampus 5-HT content, and were tested on the elevated plus maze (EPM) for anxiety-like behavior. Reducing ventral hippocampus 5-HT levels decreased the time spent in the open arms of the maze, suggesting that diminished ventral hippocampus 5-HT levels increases anxiety-like behavior. Next, we tested whether increasing 5-HT levels in the ventral hippocampus reverses anxiety behavior exhibited by rats undergoing amphetamine withdrawal. Rats were treated daily with either amphetamine (2.5-mg/kg, i.p.) or saline for 2weeks, and at 2weeks withdrawal, were infused with the selective serotonin reuptake inhibitor paroxetine (0.5μM) bilaterally into the ventral hippocampus and tested for anxiety-like behavior on the EPM. Rats pre-treated with amphetamine exhibited increased anxiety-like behavior on the EPM. This effect was reversed by ventral hippocampus infusion of paroxetine. Our results suggest that 5-HT levels in the ventral hippocampus are critical for regulating anxiety behavior. Increasing 5-HT levels during withdrawal may be an effective strategy for reducing anxiety-induced drug relapse.
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tu
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cook
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Scholl
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mears
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Center for Brain and Behavior Research, Biology Department, University of South Dakota, 414 East Clark Street, Vermillion, SD, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Renner
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, 414 East Clark Street, Vermillion, SD, USA. Electronic address: gforster@usd.edu.
authors.forename: G L
authors.initials: GL
authors.lastname: Forster
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000494:pharmacology; D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D019969:Amphetamine-Related Disorders / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000517:prevention & control; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D018490:Serotonin Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D017374:Paroxetine; D000661:Amphetamine
keywords: anxiety; hippocampus; psychostimulant; rat; serotonin; withdrawal