Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways

Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n=788; 83% African American), 206 genetic variants across the mGluR–eEF2–AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value <0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3′-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P<0.05). Importantly, the association between several genetic variants within the mGluR–eEF2–AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n=1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P<0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P<0.05) and EEF2 (empirical P<0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR–eEF2–AMPAR pathway

4D flow imaging with 2D‐selective excitation

PURPOSE: 4D flow MRI permits to quantify non-invasively time-dependent velocity vector fields, but it demands long acquisition times. 2D-selective excitation allows to accelerate the acquisition by reducing the FOV in both phase encoding directions. In this study, we investigate 2D-selective excitation with reduced FOV imaging for fast 4D flow imaging while obtaining correct velocity quantification. METHODS: Two different 2D-selective excitation pulses were designed using spiral k-space trajectories. Further, their isophase time point was analyzed using simulations that considered both stationary and moving spins. On this basis, the 2D-selective RF pulses were implemented into a 4D flow sequence. A flow phantom study and seven 4D flow in vivo measurements were performed to assess the accuracy of velocity quantification by comparing the proposed technique to non-selective and conventional 1D slab-selective excitation. RESULTS: The isophase time point for spiral 2D-selective RF pulses was found to be located at the end of excitation for both stationary and moving spins. Based on that, 2D-selective excitation with reduced FOV allowed us to successfully quantify velocities both in a flow phantom and in vivo. In a flow phantom, the velocity difference Δv = (0.8 ± 5.3)cm/s between the smaller reduced FOV and the reference scan was similar to the inter-scan variability of Δv = (−1.0 ± 2.3)cm/s . In vivo, the differences in flow (P = 0.995) and flow volume (P = 0.469) between the larger reduced FOV and the reference scan were non-significant. By reducing the FOV by two-thirds, acquisition time was halved. CONCLUSION: A reduced field-of-excitation allows to limit the FOV and therefore shorten 4D flow acquisition times while preserving successful velocity quantification