Journal
PSYCHOPHARMACOLOGY
Volume 200, Issue 4, Pages 487-496Publisher
SPRINGER
DOI: 10.1007/s00213-008-1226-4
Keywords
positron emission tomography; dopamine; serotonin
Categories
Funding
- GlaxoSmithKline
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Rationale Antagonism at serotonin 5-HT(2A) and 5-HT(2C) 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-HT(2A/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 5HT(2A/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-HT(2A/2C) antagonist ( ketanserin, 3 mg/kg i.p.), or the more selective 5-HT(2C) antagonist SB 206,553 (10 mg/kg i.p.) 30 min before administration of the PET DA D2 receptor radiotracer [(11)C] raclopride (similar to 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 [(11)C] raclopride binding by 5-HT(2A) 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-HT(2C) antagonism markedly reduced striatal [(11)C] raclopride binding ( p<0.003), while amphetamine-induced reductions in striatal [ 11C] raclopride binding (p<0.001) were attenuated by 5HT(2A) antagonist administration (p = 0.04). Conclusions These results inform the feasibility of monitoring 5-HT(2A/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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