UNIGE document Scientific Article
previous document  unige:147475  next document
add to browser collection
Title

Effect of 5-HT2A receptor antagonism on levels of D2/3 receptor occupancy and adverse behavioral side-effects induced by haloperidol: a SPECT imaging study in the rat

Authors
Published in Translational psychiatry. 2021, vol. 11, no. 1, 51
Abstract Several studies suggested that 5-HT2A receptor (5-HT2AR) blockade may provide a more favorable efficacy and side-effect profile to antipsychotic treatment. We hypothesized that a combined haloperidol (a D2/3 receptor (D2/3R) antagonist) and MDL-100,907 (a 5-HT2AR antagonist) treatment would reverse the side effects and the neurochemical alterations induced by haloperidol alone and would potentialize its efficacy. We thus chronically treated male Mdr1a knock-out rats with several doses of haloperidol alone or in combination with a saturating dose of a MDL-100,907. Receptor occupancy at clinically relevant levels was validated with a dual-radiotracer in-vivo SPECT imaging of D2/3R and 5-HT2AR occupancy. Experimental tests of efficacy (dizocilpine-disrupted prepulse inhibition (PPI) of the startle reflex) and side effects (catalepsy, vacuous chewing movements) were performed. Finally, a second dual-radiotracer in-vivo SPECT scan assessed the neurochemical changes induced by the chronic treatments. Chronic haloperidol failed to reverse PPI disruption induced by dizocilpine, whilst administration of MDL-100,907 along with haloperidol was associated with a reversal of the effect of dizocilpine. Haloperidol at 0.5 mg/kg/day and at 1 mg/kg/day induced catalepsy that was significantly alleviated (by ~50%) by co-treatment with MDL-100,907 but only at 0.5 mg/kg/day dose of haloperidol. Chronic haloperidol treatment, event at doses as low as 0.1 mg/kg/day induced a significant upregulation of the D2/3R in the striatum (by over 40% in the nucleus accumbens and over 20% in the caudate-putamen nuclei), that was not reversed by MDL-100,907. Finally, an upregulation of 5-HT2AR after chronic haloperidol treatment at a moderate dose only (0.25 mg/kg/day) was demonstrated in frontal cortical regions and the ventral tegmental area. Overall, a partial contribution of a 5-HT2AR antagonism to the efficacy and side-effect profile of antipsychotic agents is suggested.
Identifiers
PMID: 33446643
Full text
Article (Published version) (1.6 MB) - public document Free access
Appendix (179 Kb) - public document Free access
Other version: http://www.nature.com/articles/s41398-020-01179-5
Structures
Research groups Imagerie de la transmission dopaminergique dans les troubles addictifs (989)
Neuroimagerie moléculaire en psychiatrie (983)
Project
Swiss National Science Foundation: 310030_156829
Citation
(ISO format)
TSARTSALIS, Stergios et al. Effect of 5-HT2A receptor antagonism on levels of D2/3 receptor occupancy and adverse behavioral side-effects induced by haloperidol: a SPECT imaging study in the rat. In: Translational Psychiatry, 2021, vol. 11, n° 1, p. 51. doi: 10.1038/s41398-020-01179-5 https://archive-ouverte.unige.ch/unige:147475

353 hits

108 downloads

Update

Deposited on : 2021-01-18

Export document
Format :
Citation style :