Activation of 5-hydroxytryptamine2C (5-HT 2C ) receptors by the 5-HT 2 receptor agonist m-chlorophenylpiperazine (m-CPP) elicits anxiety in humans and anxiety-like behavior in animals. We compared the effects of m-CPP with the anxiogenic GABA A receptor inverse agonist N-methyl-␤-carboline-3-carboxamide (FG-7142) on both anxiety-like behavior and regional brain activation using functional magnetic resonance imaging (fMRI) in the rat. We also determined whether the selective 5-HT 2C receptor antagonist SB 242084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] would blunt m-CPP or FG-7142-induced neuronal activation. Both m-CPP (3 mg/kg i.p.) and FG-7142 (10 mg/kg i.p.) elicited anxiety-like behavior when measured in the social interaction test, and pretreatment with SB 242084 (1 mg/kg i.p.) completely blocked the behavioral effects of both anxiogenic drugs. Regional brain activation in vivo in response to anxiogenic drug challenge was determined by blood oxygen level-dependent (BOLD) fMRI using a powerful 9.4T magnet. Region of interest analyses revealed that m-CPP and FG-7142 significantly increased BOLD signals in brain regions that have been linked to anxiety, including the amygdala, dorsal hippocampus, and medial hypothalamus. These BOLD signal increases were blocked by pretreatment with SB 242084. In contrast, injection of m-CPP and FG-7142 resulted in BOLD signal decreases in the medial prefrontal cortex that were not blocked by SB 242084. In conclusion, the brain activation signals produced by anxiogenic doses of both m-CPP and FG-7142 are mediated at least partially by the 5-HT 2C receptor, indicating that this receptor is a key component in anxiogenic neural circuitry.The 5-hydroxytryptamine 2C (5-HT 2C ) receptor has been implicated in mood and anxiety disorders and is a target for development of novel anxiolytic drugs (Wood, 2003). Selective and nonselective 5-HT 2C receptor antagonists reduce anxiety-like behavior in several animal models of anxiety (Stutzmann et al., 1991;Kennett et al., 1995;Griebel et al., 1997). (Charney et al., 1987;Lowy and Meltzer, 1988;Kahn and Wetzler, 1991;Gatch, 2003;de Mello Cruz et al., 2005). For example, m-CPP administration to mice resulted in less time spent on the open arms of an elevated plus maze (Benjamin et al., 1990), and in rats, anxiety-like behavior has been reported in the This study was supported by National Institutes of Health Grants T32 GM07628, RO1 MH34007, and R01 EB02326 and a predoctoral fellowship from the PhRMA foundation (to E.A.H.).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.113357. 2C , 5-hydroxytryptamine2C; m-CPP, m-chlorophenylpiperazine; FG-7142, N-methyl-␤-carboline-3-carboxamide; SB 242084, 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride; fMRI, functional magnetic resonance imaging; BOLD, blood oxygen level-dependent;...

This study evaluates the intra- and inter- subject variability of digit maps in area 3b of anesthetized squirrel monkeys. Maps were collected using high field Blood Oxygenation Level Dependent (BOLD) fMRI. BOLD responses to individual digit stimulations were mapped and their response properties (location, area of activation, % signal change, time to peak response) were compared within and across imaging sessions separated by up to 20 months. During single digit stimulation using a block design, the spatio-temporal response of the BOLD signal for individual runs within and across sessions and animals was well conserved, with a time to peak BOLD response of 20 ± 4 sec. The variability in the center of BOLD activation in area 3b was 0.41 ± 0.24 mm (mean ± SD) across individual 5–7 minutes runs within a scanning session and 0.55 ± 0.15 mm across sessions. The average signal change across all animals, runs and sessions was 0.62 ± 0.38 %, and varied 32% within and 40% across sessions. In a comparison of the stability and reproducibility of the area of single digit activation obtained using three approaches, use of a fixed statistical threshold (p<10−5) yielded an average area of 4.8 ± 3.5 mm2 (mean ± SD), adaptive statistical thresholding 1.32 ± 1.259 mm2 (mean ± SD), and combined fixed statistical and adaptive BOLD signal amplitude 4.4 ± 2.5 mm2 (mean ± SD) across image runs and sessions. The somatotopic organization was stable within animals across sessions, while across animals, there was some variation in overall activation pattern and inter-digit distances. These results confirm that BOLD activation maps of single digits in area 3b as characterized by activation center, signal amplitudes, and temporal profile are very stable. The activation sizes determined by various criteria are the most variable measure in this preparation, but adaptive statistical thresholding appears to yield the most stable and reproducible maps. This study serves as a baseline assessment of the limits imposed on the detection of plastic changes by experimental variations of the digit BOLD fMRI activation maps in normal animals, and as an indicator of the likely performance limits in human studies.

Spatial independent component analysis (ICA) was used to study the temporal stationarity and spatial consistency of structured functional MRI (fMRI) noise. Spatial correlations have been used in the past to generate filters for the removal of structured noise for each time-course in an fMRI dataset. It would be beneficial to produce a multivariate filter based on the same principles. ICA is examined to determine if it has properties that are beneficial for this type of filtering. Six fMRI baseline datasets were decomposed via spatial ICA. The time-courses associated with each component were tested for wide-sense stationarity using the wide sense stationarity quotient (WSS). Each dataset was divided into three subsets and each subset was decomposed. The components of first and third subset were matched by the strength of their correlation. The components produced by ICA were found to have largely nonstationary time-courses. Despite the temporal nonstationarity in the data, ICA was found to produce consistent spatial components. The degree of correlation among components differed depending on the amount of dimension reduction performed on the data. It was found that a relatively small number of dimensions produced components that are potentially useful for generating a spatial fMRI filter.