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Delta(9) tetrahydrocannabinol (THC) through its action on cannabinoid type 1 receptor (CB(1)R) is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB(1)R and DA D(2) receptors (D(2)R) suggests that D(2)R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated in rodents the effects of chronic exposure to THC (1 mg/kg/day; 21 days) on D(2)R and D(3)R availabilities using the D(2)R prefering antagonist and the D(3)R preferring agonist radiotracers [(1)(8)F]fallypride and [(3)H] (+) PHNO respectively. At 24 h after the last THC dose D(2)R and D(3)R densities were significantly increased in midbrain. In caudate/putamen (CPu) THC exposure was associated with increased densities of D(2)R with no change in D(2)R mRNA expression whereas in nucleus accumbens (NAcc) both D(3)R binding and mRNA levels were upregulated. These receptor changes which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation correlated with an increased functionality of D(2)/(3)R in vivo based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D(2)/(3)R controlling DA synthesis and release in midbrain with the concurrent development of postsynaptic D(2)/(3)R supersensitivity in NAcc and CPu. Such D(2)/(3)R neuroadaptations may contribute to the reinforcing and habit forming properties of THC.

The pharmacokinetic properties of radiotracers are crucial for successful in vivo single-photon emission computed tomographic (SPECT) imaging. Our goal was to determine if MDR1A-deficient animals could allow better SPECT imaging outcomes than wild-type (WT) animals for a selection of serotoninergic radioligands. Thus, we compared the performances of 123I-p-MPPI, 123I-R91150, 123I-SB207710, and 123I-ADAM radioligands, for imaging of their respective targets (5-hydroxytryptamine [5-HT]1A, 5-HT2A, 5-HT4, and serotonin transporter [SERT]), in WT and Mdr1a knockout (KO) rats. With 123I-SB207710, virtually no SPECT signal was recorded in the brain of WT or KO animals. For 123I-p-MPPI, low nondisplaceable binding potentials (BPND, mean ± SD) were observed in WT (0.49 ± 0.25) and KO (0.89 ± 0.52) animals. For 123I-ADAM, modest imaging contrast was observed in WT (1.27 ± 0.02) and KO (1.31 ± 0.09) animals. For 123I-R91150, the BPND were significantly higher in Mdr1a KO (3.98 ± 0.65) animals compared to WT animals (1.22 ± 0.26). The pharmacokinetics of 123I-SB207710 and 123I-p-MPPI do not make them ideal tracers for preclinical SPECT neuroimaging. 123I-ADAM showed adequate brain uptake regardless of Mdr1a expression and appeared suitable for preclinical SPECT neuroimaging in both animal strains. The use of Mdr1a KO animals significantly improved the brain penetration of 123I-R91150, making this animal strain an interesting option when considering SPECT neuroimaging of 5-HT2A receptors in rat.

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635), labelled in the O-methyl group with carbon-11 (t(1/2) = 20.4 min), is a promising radioligand for application with positron emission tomography (PET) to the study of 5-HT1A receptors in living human brain. An understanding of the metabolism of this new radioligand is crucial to the development of a biomathematical model for the interpretation of the kinetics of radioactivity uptake in brain in terms of receptor-binding parameters. After intravenous injection of [O-methyl-C-11]WAY-lO0635 into humans, radioactivity was found to clear rapidly from blood and plasma, By using established methods for the analysis of radioactivity in plasma, it was found that intravenously injected [O-methyl-C-11]WAY-lO0635 is rapidly metabolised to more polar radioactive compounds in a cynomolgus monkey and in humans. Thus, at 60 min postinjection, parent radioligand represented 40% and 5% of the radioactivity in monkey and human plasma, respectively. In monkey and human, one of the radioactive metabolites was identified as the descyclohexanecarbonyl analogue of the parent radioligand, namely [O-methyl-C-11]WAY-100634. This compound is known to have high affinity for 5-HT1A receptors and alpha(1)-adrenoceptors. In a PET experiment it was demonstrated that, after IV injection of [O-methyl-C-11]WAY-100634 into a cynomolgus monkey, radioactivity was avidly taken up by brain. Uptake of radioactivity was higher in 5-HT1A receptor-rich frontal cortex than in cerebellum, which is devoid of 5-HT1A receptors. Polar radioactive metabolites appeared in plasma. The results suggest that the use of WAY-100635 labelled with carbon-ii in its cyclohexanecarbonyl moiety may provide enhanced signal contrast in PET studies and a possibility to develop a simple biomathematical model for regional brain radioactivity uptake.