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Effects of chronic delta-opioid receptor agonist on the excitability of hippocampal glutamate and brainstem monoamine neurons, anxiety, locomotion, and habituation in rats

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Abstract

Background

Short-term treatment with non-peptide agonists of delta-opioid receptors, such as agonist SNC80, induced behavioral effects in rodents, which could be modulated via changes in central neurotransmission. The present experiments aimed at testing the hypothesis that chronic treatment with SNC80 induces anxiolytic effects associated with changes in hippocampal glutamate and brainstem monoamine pathways.

Methods

Adult male Wistar rats were used in experiments. Rats were treated with SNC80 (3 mg/kg/day) for fourteen days. Neuronal excitability was assessed using extracellular in vivo single-unit electrophysiology. The behavioral parameters were examined using the elevated plus maze and open field tests.

Results

Chronic SNC80 treatment increased the excitability of hippocampal glutamate and ventral tegmental area dopamine neurons and had no effect on the firing activity of dorsal raphe nucleus serotonin cells. Chronic SNC80 treatment induced anxiolytic effects, which were, however, confounded by increased locomotor activity clearly confirmed in an open field test. The ability to cope with stressful situations and habituation processes in a novel environment was not influenced by chronic treatment with SNC80.

Conclusion

Our study suggests that the psychoactive effects of SNC80 might be explained by its ability to stimulate hippocampal glutamate and mesolimbic dopamine transmission.

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Data availability

Original experimental data are available upon request.

Abbreviations

SNC80:

( +)-4-[(Alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide

DPDPE:

(D-Pen2,5)-enkephalin

RM ANOVA:

Analysis of variance for repeated measures

CA1/3:

Cornu Ammonis 1/3

DOR:

Delta-opioid receptor

DRN:

Dorsal raphe nucleus

EPM:

Elevated plus maze

HD:

Head dipping

HCl:

Hydrochloric acid

5-HT:

Serotonin

NaCl:

Sodium chloride

NaOH:

Sodium hydroxide

SAP:

Stretch attend postures

VTA:

Ventral tegmental area

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Acknowledgements

This work was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic and Slovak Academy of Sciences (grant No 2/0057/22; ED) Slovak Research and Development Agency (APVV-18-0283; DJ and partly APVV-19-0435; LL and APVV-20-0202; ED) and the Neuron Era Net UNMET project (NEURON-051; DJ). The funding agencies had no further role in study design; in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. The authors thank Dr Michal Dubovický for his valuable advice with respect to the measurements of habituation processes.

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Authors and Affiliations

  1. Institute of Molecular Physiology and Genetics, Center of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia

    Eliyahu Dremencov, Daniil Grinchii & Lubica Lacinova

  2. Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia

    Eliyahu Dremencov, Zuzana Romanova, Pavol Chomanic & Daniela Jezova

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Bratislava, Slovakia

    Zuzana Romanova & Pavol Chomanic

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  1. Eliyahu Dremencov
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Contributions

ED, LL, and DJ planned the study and formulated the working hypothesis. DG, ZR, and PC conducted the experiments. ED, DG, ZR, and PC analyzed the results. ED, ZR, and DJ wrote the manuscript. All authors critically proofread the manuscript and approved it for publication.

Corresponding author

Correspondence to Eliyahu Dremencov.

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The authors declare no conflict of interest.

Ethical standards

Experiments with Animals: All experimental procedures were approved by the Animal Health and Animal Welfare Division of the State Veterinary and Food Administration of the Slovak Republic (Permit number Ro 3592/15-221) and confirmed to the Directive 2010/63/EU of the European Parliament and of the Council on the Protection of Animals Used for Scientific Purposes.

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Dremencov, E., Grinchii, D., Romanova, Z. et al. Effects of chronic delta-opioid receptor agonist on the excitability of hippocampal glutamate and brainstem monoamine neurons, anxiety, locomotion, and habituation in rats. Pharmacol. Rep 75, 585–595 (2023). https://doi.org/10.1007/s43440-023-00485-1

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