ArticleJournal of psychopharmacology (Oxford, England)2021
Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats.
Article in Journal of psychopharmacology (Oxford, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed, 11 citations in OpenAlex.
- Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour.Nature communications · 2025Trial
- Acid sphingomyelinase activity suggests a new antipsychotic pharmaco-treatment strategy for schizophrenia.Molecular psychiatry · 2025Article
- Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models.Psychopharmacology · 2023Article
- Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.Molecular psychiatry · 2021Article
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.
aimsHere we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats.
methodsWe designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors. RESULTS/OUTCOMES: By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3-1.5 mg/kg/day), attenuates psychotic-like behavior in rats. CONCLUSIONS/
interpretationThese findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.
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