The question of whether nicotine, the neuroactive compound of tobacco, is addictive has been open to considerable scientific and public discussion. Although it can serve as a positive reinforcer in several animal species, including man, nicotine is thought to be a weak reinforcer in comparison with addictive drugs such as cocaine and heroin, and has been argued to be habit forming but not addictive. Here we report that intravenous nicotine in the rat, at doses known to maintain self-administration, stimulates local energy metabolism, as measured by 2-deoxyglucose autoradiography, and dopamine transmission, as estimated by brain microdialysis, in the shell of the nucleus accumbens. These neurochemical and metabolic effects are qualitatively similar to those of other drugs, such as cocaine, amphetamine and morphine, which have strong addictive properties. Our results provide functional and neurochemical evidence that there are specific neurobiological commonalities between nicotine and addictive drugs.

Both ionotropic and metabotropic glutamate receptors (mGluRs) are involved in the behavioral effects of pyschostimulants; however, the specific contributions of individual mGluR subtypes remain unknown. Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice. These results demonstrate a significant contribution of mGlu5 receptors to the behavioral effects of cocaine, and suggest that they may be involved in cocaine addiction.

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Migraine is a common and disabling neurological disease. The pathomechanism that underlies the disorder is not entirely understood, and reliable biomarkers are missing. In the current analysis we looked for microstructural alterations of the brain white matter in migraine patients by means of diffusion-weighted magnetic resonance imaging. The measurements were carried out with a novel approach based on fine-tuned nonlinear registration and nonparametric permutation test in an alignment-invariant tract representation (Tract-Based Spatial Statistics). We found reduced fractional anisotropy in the right frontal white matter cluster of migraine patients. In the same region we also found increased mean diffusivity and increased radial diffusivity. The probabilistic tractography showed connection of this cluster to other parts of the pain network (orbitofrontal cortex, insula, thalamus, dorsal midbrain). We speculate that these findings reflect maladaptive plastic changes or white matter disintegration.

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The mGlu2/3 receptor agonists 4-carboxy-3-hydroxyphenylglycine (4C3HPG) and LY379268 attenuated NMDA toxicity in primary cultures containing both neurons and astrocytes. Neuroprotection was abrogated by PD98059 and LY294002, which inhibit the mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI-3-K) pathways, respectively. Cultured astrocytes lost the ability to produce transforming growth factor-b1 (TGF-b1) in response to mGlu2/3 receptor agonists when co-incubated with PD98059 or LY294002. As a result, the glial medium was no longer protective against NMDA toxicity. Activation of the MAPK and PI-3-K pathways in cultured astrocytes treated with 4C3HPG or LY379268 was directly demonstrated by an increase in the phosphorylated forms of ERK-1/2 and Akt. Similarly to that observed in the culture, intracerebral or systemic injections of mGlu2/3 receptor agonists enhanced TGF-b1 formation in the rat or mouse caudate nucleus, and this effect was reduced by PD98059. PD98059 also reduced the ability of LY379268 to protect striatal neurons against NMDA toxicity. These results suggest that activation of glial mGlu2/3 receptors induces neuroprotection through the activation of the MAPK and PI-3-K pathways leading to the induction of TGF-b. Keywords: astrocytes, MAP kinase, mGlu receptors, neuroprotection, phosphatidylinositol-3-kinase, TGF-b1.The low success of ionotropic glutamate receptor antagonists in clinical trials (reviewed by Lee et al. 1999) has switched the interest toward metabotropic glutamate (mGlu) receptors as targets for neuroprotective drugs. These receptors form a family of eight subtypes divided into three groups on the basis of sequence homology, pharmacological pro®le and transduction mechanisms. Group-I includes mGlu1 and -5 receptors, which are coupled to polyphosphoinositide hydrolysis and selectively activated by 3,5-dihydroxyphenylglycine (DHPG). Group-II includes mGlu2 and -3 receptors, which are coupled to G i proteins in heterologous expression systems. Compounds are now available that activate these two receptor subtypes with high potency and selectivity, such as (1)-2- Abbreviations used: l-AP4, l-2-amino-4-phosphonobutanoate; 4C3HPG, 4-carboxy-3-hydroxyphenylglycine; DHPG, 3,5-dihydroxyphenylglycine; DIV, days in vitro; GAD, glutamate decarboxylase; GCM, glial conditioned medium; LY354740, (1)-2-aminobicyclo[3,1,0]hexane-2,6-dicarboxylic acid; LY379268, (±)-2-oxa-4-aminobicyclo[3,1,0]hexane-4,6-dicarboxylic acid; LY389795, (±)-2-thia-4-aminobicyclo[3,1,0]hexane-4,6-dicarboxylic acid; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; mGlu, metabotropic glutamate; MAPK, mitogen activated protein kinase; MS, medium stock; PI-3-K, phosphatidylinositol-3-kinase; PPG, 4-phosphonophenylglycine; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; TGF-b1, transforming growth factor-b1. R e t r a c t e d

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The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers.