Abstract
Patients with eating disorders exhibit problems with appetitive impulse control. Interactions between dopamine and serotonin (5-HT) neuron in this setting are poorly characterized. Here we examined 5-HT receptor-mediated changes in extracellular dopamine during impulsive appetitive behavior in rats. Rats were trained to perform a cued lever-press (LP) task for a food reward such that they stopped experiencing associated dopamine increases. Trained rats were administered the mixed 5-HT1B/2C-receptor antagonist metergoline, the 5-HT2A/2C-receptor antagonist ketanserin, and p-chlorophenylalanine (PCPA). We measured dopamine changes in the ventral striatum using voltammetry and examined the number of premature LPs, reaction time (RT), and reward acquisition rate (RAR). Compared with controls, metergoline increased premature LPs and shortened RT significantly; ketanserin decreased premature LPs and lengthened RT significantly; and PCPA decreased premature LPs, lengthened RT, and decreased RAR significantly. Following metergoline administration, rats exhibited a fast phasic dopamine increase for 0.25–0.75 s after a correct LP, but only during LP for an incorrect LP. No dopamine increases were detected with ketanserin or PCPA, or in controls. After LP task completion, metergoline also caused dopamine to increase slowly and remain elevated; in contrast, ketanserin caused dopamine to increase slowly and decrease rapidly. No slow dopamine increase occurred with PCPA. Inhibition of 5-HT1B- and 5-HT2C-receptors apparently induced dual modes of extracellular dopamine increase: fast phasic, and slow long-lasting. These increases may be associated with the suppression of acquired prediction learning and retention of high motivation for reward, leading to impulsive excessive premature LPs.
Highlights
Impulsive appetitive behavior is a key symptom in autism spectrum disorder, eating disorders, and obsessive–compulsive disorders (OCD)
Our present study investigated the neuronal mechanisms of eating disorders by examining the interaction between DA and 5-HT neurons during impulsive appetitive behavior in rats
When multiple LPs were performed between a correct LP and the cue tone, they were recorded as premature LPs
Summary
Impulsive appetitive behavior is a key symptom in autism spectrum disorder, eating disorders, and obsessive–compulsive disorders (OCD). Miyazaki et al (2012a, b) demonstrated that patience to wait for rewards requires serotonin (5-HT) neurons. 5-HT reuptake inhibitors (SSRIs) are useful for treating pathologic impulsive aggression (Armenteros and Lewis 2002; Hollander et al 2000), suggesting that 5-HT-mediated processes are involved in controlling impulse-related behavior. The 5-HT1B-R reportedly plays a highly selective role in the modulation of offensive aggression (Olivier 2004), and 5-HT1B-R knock-out mice exhibit impulsive behavior (Bouwknecht et al 2001; Saudou et al 1994). In animal models of OCD, 5-HT2C-R activation can induce compulsive behavior (Flaisher-Grinberg et al 2008; Graf et al 2003; Tsaltas et al 2005); other reports demonstrate that 5-HT2C-R activation decreases cocaine-seeking behavior (Cunningham et al 2011) and reduces impulsivity in studies of anxiety (Martin et al 2002). A 5-HT2A-R antagonist suppresses impulsivity in the 5-choice task, while a 5-HT2C-R antagonist leads to
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