White-matter abnormalities in brain during early abstinence from methamphetamine abuse

Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7–13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence. Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior–superior levels parallel to the anterior commissure–posterior commissure (AC–PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine. The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC–PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p’s = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group. The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery

Thalamic glutamate decreases with cigarette smoking.

RationaleFindings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu.ObjectiveTo determine the effects of tobacco smoking on thalamic glutamate levels.MethodsThalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T.ResultsMean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r = -0.64, p = 0.006) and pack-years of smoking (r = -0.66, p = 0.005).ConclusionsConsistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain

Thalamic glutamate decreases with cigarette smoking.

RationaleFindings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu.ObjectiveTo determine the effects of tobacco smoking on thalamic glutamate levels.MethodsThalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T.ResultsMean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r = -0.64, p = 0.006) and pack-years of smoking (r = -0.66, p = 0.005).ConclusionsConsistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain

Deletion of the Fcγ Receptor IIb in Thymic Stromal Lymphopoietin Transgenic Mice Aggravates Membranoproliferative Glomerulonephritis

Engagement of immunoglobulin-binding receptors (FcγR) on leukocytes and other cell types is one means by which immunoglobulins and immune complexes activate effector cells. One of these FcγRs, FcγRIIb, is thought to contribute to protection from autoimmune disease by down-regulation of B-cell responsiveness and myeloid cell activation. We assessed the role of FcγRIIb in a mouse model of cryoglobulin-associated membranoproliferative glomerulonephritis induced by overexpression of thymic stromal lymphopoietin (TSLP). TSLP transgenic mice were crossbred with animals deficient for FcγRIIb on the same genetic background (C57BL/6). Renal pathology was assessed in female and male animals (wild-type, FcγRIIb−/−, TSLP transgenic, and combined TSLP transgenic/FcγRIIb−/− mice) after 50 and 120 days, respectively. FcγRIIb−/− mice had no significant renal pathology, whereas overexpression of TSLP induced a membranoproliferative glomerulonephritis, as previously established. TSLP transgenic FcγRIIb−/− mice appeared sick with increased mortality. Kidney function was significantly impaired in male mice corresponding to aggravated glomerular pathology with increases in glomerular matrix and cellularity. This resulted from both a large influx of infiltrating macrophages and increased cellular proliferation. These results emphasize the important role of FcγRIIb in regulating immune responses and suggest that modulation of Fcγ receptor activation or expression may be a useful therapeutic approach for treating glomerular diseases

Localization of TGF-beta signaling intermediates Smad2, 3, 4, and 7 in developing and mature human and mouse kidney

Smad proteins are signaling intermediates of the TGF-beta superfamily and are involved in a range of biological activities including development and immune responses. We studied the expression of TGF-beta-receptor activated Smads (Smad2 and Smad3), the common partner Smad (Smad4), an inhibitory Smad (Smad7), and the activated (phosphorylated) Smad2 (pSmad2) in developing and adult kidneys of humans and mice. These studies demonstrate associated expression of these Smads in multiple renal cell types in all developmental stages and in mature non-diseased kidneys. Smad expression is in general most widespread at the earliest stages of nephron development and diminishes as components of the nephrons become more differentiated. Paucity of Smad expression in mesangial cells in contrast to widespread expression of these Smads in glomerular visceral epithelial cells in both developing and mature kidneys was remarkable. Divergent and less extensive expression of Smad4, compared with other Smad proteins, was also demonstrated in tubules of human kidneys. Based on the observed expression patterns, these findings demonstrate, for the first time, expression of the TGF-beta-receptor-activated Smad2 and Smad3, the common mediator Smad4, and the inhibitory Smad7 in the developing human fetal kidney, extending observations previously made in rodent systems to humans