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The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity

Korte, S. M., Prins, J., Van den Bergh, F. S., Oosting, R. S., Dupree, R., Korte-Bouws, G. A. H., Westphal, K. G. C., Olivier, B., Denys, D. A., Garland, A. & Guentuerkuen, O., 5-Jan-2017, In : European Journal of Pharmacology. 794, p. 257-269 13 p.

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  • The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity

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DOI

  • S. Mechiel Korte
  • Jolanda Prins
  • Filip S. Van den Bergh
  • Ronald S. Oosting
  • Rudy Dupree
  • Gerdien A. H. Korte-Bouws
  • Koen G. C. Westphal
  • Berend Olivier
  • Damiaan A. Denys
  • Alexis Garland
  • Onur Guentuerkuen

The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward.

How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms.

Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task.

The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distoinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.

Original languageEnglish
Pages (from-to)257-269
Number of pages13
JournalEuropean Journal of Pharmacology
Volume794
Publication statusPublished - 5-Jan-2017

    Keywords

  • Eltoprazine, 5-HT1A/1B-receptor, Microdialysis, Monoamines, Prefrontal cortex, Impulsivity, VENTRAL TEGMENTAL AREA, SIGNAL REACTION-TIME, BRAIN-STIMULATION REWARD, RAPHE SEROTONIN NEURONS, 5-HYDROXYTRYPTAMINE(1A) RECEPTOR ACTIVATION, DEFICIT HYPERACTIVITY DISORDER, ENHANCES COCAINE REINFORCEMENT, FREELY-MOVING RATS, 5-HT1A RECEPTOR, LOCUS-COERULEUS

ID: 97529863