The 5-HT1A receptor antagonist WAY-100635 decreases motor/exploratory behaviors and nigrostriatal and mesolimbocortical dopamine D2/3 receptor binding in adult rats

Susanne Nikolaus; Hans-Jörg Wittsack; Markus Beu; Hubertus Hautzel; Christina Antke; Eduards Mamlins; Jens Cardinale; Cvetana Decheva; Joseph P Huston; Gerald Antoch; Frederik L Giesel; Hans-Wilhelm Müller

doi:10.1016/j.pbb.2022.173363

The 5-HT_1A receptor antagonist WAY-100635 decreases motor/exploratory behaviors and nigrostriatal and mesolimbocortical dopamine D_2/3 receptor binding in adult rats

Pharmacol Biochem Behav. 2022 Apr:215:173363. doi: 10.1016/j.pbb.2022.173363. Epub 2022 Feb 26.

Affiliations

¹ Department of Nuclear Medicine, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany. Electronic address: susanne.nikolaus@uni-duesseldorf.de.
² Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany.
³ Department of Nuclear Medicine, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany.
⁴ Clinic for Nuclear Medicine, University Hospital Essen, University Duisburg Essen, Hufelandstraße 55, D-45122 Essen, Germany.
⁵ Center for Behavioural Neuroscience, Institute of Experimental Psychology, Heinrich-Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany.

PMID: 35227734
DOI: 10.1016/j.pbb.2022.173363

Abstract

Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT_1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D_2/3R binding in the rat brain with in vivo imaging methods. D_2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [¹²³I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D_2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.

Keywords: 5-HT(1A) receptor; D(2/3) receptor; WAY-100635; [(123)I]IBZM.

MeSH terms

Animals
Dopamine* / metabolism
Exploratory Behavior* / drug effects
Piperazines* / pharmacology
Pyridines
Rats
Receptor, Serotonin, 5-HT1A
Serotonin 5-HT1 Receptor Antagonists* / pharmacology

Substances

Piperazines
Pyridines
Serotonin 5-HT1 Receptor Antagonists
Receptor, Serotonin, 5-HT1A
N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
Dopamine