Dual-mode dopamine increases mediated by 5-HT1B and 5-HT2C receptors inhibition, inducing impulsive behavior in trained rats

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.