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Histamine H3 receptor antagonist JNJ-39220675 modulates locomotor responses but not place conditioning by dopaminergic drugs

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Abstract

Rationale

Brain histaminergic system is involved in the regulation of the dopaminergic circuitry. The role of histamine H3 receptor (H3R) in behaviors linked to amphetamine addiction and other behaviors induced by dopaminergic compounds has remained unclear.

Objective

Our aim was to study whether H3R antagonist JNJ-39220675 inhibits amphetamine-induced stimulation and reward. The effects of JNJ-39220675 on dopamine D2-like receptor (D2R-like) agonist quinpirole-induced behaviors were also investigated in order to clarify whether the possible effects of H3R antagonists are D2R-like dependent.

Methods

The effects of JNJ-39220675 on amphetamine and quinpirole-induced behavioral responses in mice were studied assessing the locomotor activation after both acute and repeated administrations of amphetamine and quinpirole. The place conditioning paradigm was also used as a measure of reward or aversion.

Results

JNJ-39220675 inhibited amphetamine-induced stimulation acutely but not after repeated administrations. Amphetamine (2 mg/kg) induced conditioned place preference that was not affected by either of the tested doses of JNJ-39220675 (1 and 10 mg/kg). Quinpirole (0.5 mg/kg) induced conditioned place aversion to which the pretreatment by JNJ-39220675 (10 mg/kg) had no effect. In repeated administration, JNJ-39220675 did, however, inhibit quinpirole-induced tolerance to hypokinesia.

Conclusions

Our results show that although H3R antagonists inhibit ethanol reward, they may not possess the same ability on psychostimulants, such as amphetamine. However, if H3R antagonists will become clinically available, it is of importance that these compounds potentiate neither the rewarding nor aversive effects of other drugs.

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Abbreviations

H3R:

Histamine H3 receptor

CPA:

Conditioned place aversion

CPP:

Conditioned place preference

DAT:

Dopamine transporter

D1R:

Dopamine D1 receptor

D2R:

Dopamine D2 receptor

D2R-like:

Dopamine D2-like receptor

MSN:

Medium spiny neuron

VMAT2:

Vesicular monoamine transporter 2

VTA:

Ventral tegmental area

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Acknowledgments

This work was supported by the Finnish Graduate School of Neuroscience (FGSN), doctoral program Brain & Mind, and grants from the Academy of Finland (Grant No 118547 and 253416), Magnus Ehrnrooth’s Foundation, Finska Läkaresällskapet, and Finnish Fund for Alcohol Research. We thank Janssen Research & Development, LLC, for JNJ-39220675 and Prof. Esa Korpi for the d-amphetamine.

Conflict of interest

The authors declare no conflict of interest.

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  1. Saara Nuutinen

    Present address: Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), 00014, Helsinki, Finland

Authors and Affiliations

  1. Neuroscience Center and Institute of Biomedicine/Anatomy, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014, Helsinki, Finland

    Jenni Vanhanen, Marja Kinnunen, Saara Nuutinen & Pertti Panula

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  1. Jenni Vanhanen
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Vanhanen, J., Kinnunen, M., Nuutinen, S. et al. Histamine H3 receptor antagonist JNJ-39220675 modulates locomotor responses but not place conditioning by dopaminergic drugs. Psychopharmacology 232, 1143–1153 (2015). https://doi.org/10.1007/s00213-014-3751-7

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