Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats
| Autor: | Eva-Maria Weiss, Taygun C Uzuneser, Jonas Kaindl, Jan Hellmann, Stefan Löber, Teja W. Grömer, Christian P. Müller, Jana Dahlmanns, Christian Alzheimer, Harald Hübner, Peter Gmeiner, Liubov S. Kalinichenko, Davide Amato, Johannes Kornhuber |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Presynaptic Terminals Pharmacology Inhibitory postsynaptic potential Hippocampus 03 medical and health sciences 0302 clinical medicine Drug Delivery Systems Postsynaptic potential Dopamine receptor D2 Haloperidol medicine Animals Pharmacology (medical) ddc:610 Antipsychotic Cells Cultured 030304 developmental biology 0303 health sciences business.industry behavior Receptors Dopamine D2 medicine.disease Original Papers Rats schizophrenia Psychiatry and Mental health Dopamine D2 Receptor Antagonists Inhibitory Postsynaptic Potentials Psychotic Disorders Schizophrenia Synaptic Vesicles business 030217 neurology & neurosurgery presynaptic accumulation medicine.drug Antipsychotic Agents |
| Zdroj: | Journal of Psychopharmacology (Oxford, England) |
| ISSN: | 1461-7285 0269-8811 |
| Popis: | Background:The 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.Aims:Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats.Methods:We 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/interpretation:These 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. |
| Databáze: | OpenAIRE |
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