LB-102 effect on dopamine D2 autoreceptors: Results from a preclinical study evaluating dopamine efflux in rat nucleus accumbens using microdialysis

Introduction

LB-102 is an investigational novel benzamide D₂/D₃/5-HT₇ receptor antagonist under development as a once-daily treatment for schizophrenia, bipolar depression, adjunctive treatment of major depressive disorder, and other neuropsychiatric disorders. Because presynaptic dopamine D₂ autoreceptors exert powerful inhibitory control over dopamine synthesis, release, and extracellular availability, compounds that antagonize these receptors may modulate mesolimbic dopamine signalling in a therapeutically meaningful manner. The nucleus accumbens (NAc) is a key mesolimbic dopamine projection region in the brain implicated in schizophrenia and related disorders. In vivo microdialysis provides a functional assay of presynaptic D₂ autoreceptor activity by measuring the ability of a candidate compound to reverse inhibition of dopamine efflux elicited by quinpirole, a D₂ autoreceptor agonist.

Objectives

To determine whether orally administered LB-102 affects basal dopamine efflux in the NAc in freely moving rats and to test the hypothesis that LB-102 reverses presynaptic D₂ autoreceptor-mediated inhibition of dopamine efflux in the NAc.

Methods

Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc and studied using in vivo microdialysis with high-pressure liquid chromatography/electrochemical detection for dopamine quantification. After stabilization, extracellular dopamine was sampled at 10-minute intervals and normalized to each animal’s pretreatment baseline. Experiment 1: Rats received LB-102 by oral gavage at 1.5, 3.0, or 6.0 mg/kg, and dopamine efflux was monitored for 180 minutes. Experiment 2: Quinpirole (0.1 µM) was infused locally into the NAc by reverse microdialysis over a 3-hour duration to suppress dopamine efflux; LB-102 (vehicle, 1.5, 3.0, or 6.0 mg/kg, oral) was administered 30 minutes after initiation of quinpirole infusion, and dopamine sampling continued for up to 3 hours. Treatment effects were quantified as area-under-the-curve (AUC) of baseline-normalized responses. One-sample t-tests assessed within-group effects, and one-way ANOVA followed by Dunnett’s or Tukey’s multiple-comparison testing evaluated between-group comparisons. Probe placements were histologically verified.

Results

All doses of LB-102 administered orally in the absence of quinpirole produced a moderate and sustained increase in dopamine efflux in the NAc (mean elevations: ~10-15% above baseline across doses tested). Local infusion of quinpirole by reverse microdialysis in the NAc produced a marked and sustained decrease in dopamine efflux in the NAc to ~65% of baseline, confirming robust D₂ autoreceptor-mediated suppression. All doses of LB-102 administered orally 30 minutes after quinpirole gradually reversed the quinpirole-reduced dopamine efflux toward baseline over the course of the study. Though not systematically measured, informal behavioural observations suggested increased arousal and exploration after administration of LB-102 at all doses.

Conclusions

These findings show that LB-102 reverses the quinpirole-induced reduction of dopamine efflux in the NAc of freely moving rats assessed with in vivo microdialysis, and support the hypothesis that LB-102 modulates mesolimbic dopaminergic signalling by functionally interfering with the presynaptic D₂ autoreceptor inhibitory activity. Together, these data confirm that LB-102 keeps dopamine active in the brain by attenuating inhibitory signalling through dopamine autoreceptors that physiologically constrain dopamine release.

References

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