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Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat

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Abstract

Rationale

Antagonism at serotonin 5-HT2A and 5-HT2C receptors modulates cortical and striatal dopamine (DA) release and may underlie some aspects of the clinical efficacy of ‘atypical’ antipsychotic compounds. However, it is not known whether 5-HT2A/2C receptor-mediated modulation of DA release can be quantified with non-invasive neurochemical imaging, as would be required for investigation of these processes in man.

Objective

The objective of the study was to perform a feasibility study in the rat in order to determine whether 5-HT2A/2C modulation of DA release can be observed using positron emission tomography (PET) imaging.

Materials and methods

Rats were administered with either vehicle, a combined 5-HT2A/2C antagonist (ketanserin, 3 mg/kg i.p.), or the more selective 5-HT2C antagonist SB 206,553 (10 mg/kg i.p.) 30 min before administration of the PET DA D2 receptor radiotracer [11C]raclopride (∼11 MBq) and were then scanned for 60 min using a quad-high-density avalanche chamber small animal tomograph. Using the same technique, modulation of amphetamine (4 mg/kg)-induced decreases in [11C]raclopride binding by 5-HT2A antagonism (SR 46349B, 0.2 mg/kg i.v.) was also determined.

Results

Consistent with the increase in DA release measured by others using microdialysis, 5-HT2C antagonism markedly reduced striatal [11C]raclopride binding (p < 0.003), while amphetamine-induced reductions in striatal [11C]raclopride binding (p < 0.001) were attenuated by 5-HT2A antagonist administration (p = 0.04).

Conclusions

These results inform the feasibility of monitoring 5-HT2A/2C receptor-mediated modulation of DA systems in man using PET and, more generally, demonstrate that D2 radiotracer PET imaging may be used to monitor the efficacy of new DA modulators in attenuating stimulated DA release.

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Abbreviations

SB 206,553:

5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole hydrochloride

SR 46349B:

(1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene)

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Acknowledgments

The early stages of the work presented here were initiated by Dr Susan P. Hume, and we are very grateful for her important contribution to this research. These investigations were also partly funded by GlaxoSmithKline. A portion of this work has previously been presented in preliminary form (Ahmad et al. 2005; Egerton and Grasby 2007).

Disclosure/conflict of interest

Dr Alice Egerton is funded by GlaxoSmith Kline through Imperial College and reports no competing interests. Rabia Ahmad and Dr Ella Hirani report no competing interests. Prof. Paul M Grasby has served as an occasional consultant to GlaxoSmithKline, Merck, and Pfizer and reports no competing interests.

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Egerton, A., Ahmad, R., Hirani, E. et al. Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat. Psychopharmacology 200, 487–496 (2008). https://doi.org/10.1007/s00213-008-1226-4

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