EFFECTS OF PRENATAL AND POSTNATAL TREATMENT WITH A DELTA- OPIOID RECEPTOR LIGAND ON ANXIETY, COGNITION AS WELL AS MESOLIMBIC DOPAMINERGIC AND HIPPOCAMPAL GLUTAMATERGIC NEUROTRANSMISSION IN RATS
Authors: Oravcova *Henrieta , Grinchii Daniil , Romanova Zuzana , Lacinova Lubica , Dremencov Eliyahu , Jezova Daniela 
Published: February 2025

Abstract

Background
Central neurotransmitters are well-known to be involved in the pathophysiological processes leading to mental disorders. It is suggested that activation of delta opioid receptors (DOR) may lead to anxiolytic and antidepressant-like effects. The interaction between these brain regulatory systems is not yet well understood.

Aims & Objectives
We have tested the hypothesis that repeated treatment with the DOR agonist SNC80 induces behavioral changes along with stimulation of the excitability of hippocampal glutamatergic neurons as well as of dopaminergic neurons in the ventral tegmental area (VTA). These effects have been expected following both postnatal and prenatal drug treatments.

Methods
To investigate the impact of postnatal SNC80 treatment, adult rats were injected with SNC80 (1.5 mg/kg, subcutaneously: s.c., twice a day) or vehicle for 14 days. To investigate the consequences of prenatal SNC80 exposure, gestating female rats were pretreated with vehicle or SNC80 (2.5 mg/kg, s.c., once a day, during the days 11-19 of the gestation) and behavioral and electrophysiological experiments were performed on their offspring reaching the adulthood. The anxiety behavior was evaluated using an elevated plus maze (EPM) and open field tests. The cognitive performance was examined using a novel object recognition (NOR) test. The firing activities of glutamatergic and dopaminergic neurons of the VTA were measured using single-unit extracellular electrophysiology in vivo, under isoflurane (for hippocampal glutamatergic neurons) or chloral hydrate (for mesolimbic dopaminergic neurons) anaesthesia.

Results
Postnatal SNC80 treatment resulted in reduced anxiety behavior accompanied by increased locomotor activity. The anxiolytic effects of SNC80 treatment were confirmed by ethological parameters measured in the EPM. Prenatal SNC80 had no effect on anxiety behavior evaluated in adult offspring. Prenatal SNC80, however, increased the recognition index in the NOR test in female, but not in male offspring. Interestingly, postnatal, and prenatal SNC80 had opposite effects on the excitability of the hippocampal glutamate and mesolimbic dopamine neurons: the former increased, while the latter decreased their mean spontaneous firing rates.

Discussion & Conclusion
The stimulatory effect of chronic postnatal SNC80 on hippocampal glutamate neurons is consistent with previous findings obtained under in vitro conditions [1,2]. Observed changes in glutamate and dopamine neurons might be related to positive action of delta-opioid receptor activation by chronic SNC80. Further research is needed to understand mechanisms leading to the suppression of the hippocampal glutamate neuronal firing activity by prenatal SNC80, and its putative linkage with increased cognitive performance. This work was supported by the Slovak Research and Development Agency (grant APVV-20-0202) and Scientific Grant Agency of Ministry of Education of Slovak Republic and Slovak Academy of Sciences (grants VEGA-2/0057/22).

References
1. Moravcikova, L.; Moravcik, R.; Jezova, D.; Lacinova, L.; Dremencov, E., Delta-opioid receptor-mediated modulation of excitability of individual hippocampal neurons: mechanisms involved. Pharmacol Rep 2021, 73, (1), 85-101.
2. Easter, A.; Sharp, T. H.; Valentin, J. P.; Pollard, C. E., Pharmacological validation of a semi-automated in vitro hippocampal brain slice assay for assessment of seizure liability. J Pharmacol Toxicol Methods 2007, 56, (2), 223-33.