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 reduced 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-DHT into the ventral hippocampus, which produced a 83% decrease 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 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, ip.) or saline for 2 weeks, and at 2 weeks withdrawal, were infused with the selective serotonin reuptake inhibitor paroxetine (0.5 μM) 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 is critical for regulating anxiety behavior. Increasing 5-HT levels during withdrawal may be an effective strategy for reducing anxiety-induced drug relapse.

Preconception Alcohol Increases Offspring Vulnerability to Stress

“…Moreover, although increased corticosterone signaling is associated with increased anxiety-like behavior in the EPM and OF, behavior in these tests are likely a manifestation of effects on multiple hormonal and neural substrates. The OF and EPM tests are also known to be heavily regulated by the GABAergic and serotonergic systems (Osborn et al, 1998;Tu et al, 2014), which were not investigated in these studies and might be explored in future studies using our PCAE model. Finally, another factor in the observed sex difference in behavior might be the modulating effects of ovarian hormones on behavioral testing, as, in the LPS study, females were only used in diestrus, whereas in the behavior studies, estrus cycle was not restricted to diestrus, and some females were likely in estrus and proestrus during testing.…”

Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress

“…Amphetamine withdrawal is associated with anxiety and hypersensitivity to stressors in humans (Cleck and Blendy, 2008; Shoptaw et al, 2009) and rodents (Barr et al, 2010; Li et al, 2014; Russig et al, 2006; Tu et al, 2014; Vuong et al, 2010) that can induce relapse in humans (Gossop, 2009) and maintains the cycle of addiction (Koob et al, 2014; Shoptaw et al, 2009). …”

“…Stress induces serotonin release in the ventral hippocampus, which has been implicated in reducing anxiety and stress responsiveness (Graeff et al, 1996; Herman et al, 2003; Li et al, 2014; Tu et al, 2014). We have previously found that rats in the second week of withdrawal from repeated amphetamine exposure show heightened behavioral anxiety (Barr et al, 2010; Reinbold et al, 2014; Tu et al, 2014; Vuong et al, 2010), enhanced behavioral measures of stress-induced arousal (Li et al, 2014), and severely blunted stress-induced serotonin release in the ventral hippocampus (Li et al, 2014), which is known to cause increased behavioral anxiety (Tu et al, 2014).…”

“…We have previously found that rats in the second week of withdrawal from repeated amphetamine exposure show heightened behavioral anxiety (Barr et al, 2010; Reinbold et al, 2014; Tu et al, 2014; Vuong et al, 2010), enhanced behavioral measures of stress-induced arousal (Li et al, 2014), and severely blunted stress-induced serotonin release in the ventral hippocampus (Li et al, 2014), which is known to cause increased behavioral anxiety (Tu et al, 2014). Therefore, it is important to understand the mechanism by which amphetamine withdrawal alters stress-induced serotonin levels in the ventral hippocampus.…”

“…For instance, stress-induced corticosterone levels in the dorsal hippocampus have been found to increase up to 200% from baseline in drug-naïve rats (Droste et al, 2008; Keeney et al, 2006). Therefore, it is conceivable that stress-induced levels of corticosterone in the ventral hippocampus are reduced or absent during amphetamine withdrawal, lowering corticosterone availability and contributing to the lack of glucocorticoid receptor-dependent stress-induced serotonin release in this region (Li et al, 2014) and to the resultant heightened anxiety states (Tu et al, 2014). This possibility was addressed by the current study, using the same amphetamine treatment and withdrawal regime previously shown to produce heightened behavioral anxiety (Barr et al, 2010; Reinbold et al, 2014; Tu et al, 2014; Vuong et al, 2010), enhanced stress-induced behavioral arousal (Li et al, 2014), and blunted stress-induced serotonin release in the ventral hippocampus (Li et al, 2014).…”