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Mesolimbic System (mesolimbic + system)
Selected AbstractsPRECLINICAL STUDY: FULL ARTICLE: Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependenceADDICTION BIOLOGY, Issue 3 2010Saturnino Spiga ABSTRACT Cannabinoid withdrawal produces a hypofunction of mesencephalic dopamine neurons that impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment with two structurally different cannabinoid agonists, ,9 -tetrahydrocannabinol and CP55 940 (CP) rats were withdrawn spontaneously and pharmacologically with the CB1 antagonist SR141716A (SR). In these two conditions, evaluation of tyrosine hydroxylase (TH)-positive neurons revealed significant morphometrical reductions in the ventrotegmental area but not substantia nigra pars compacta of withdrawn rats. Similarly, confocal analysis of Golgi,Cox-stained sections of the nucleus accumbens revealed a decrease in the shell, but not the core, of the spines' density of withdrawn rats. Administration of the CB1 antagonist SR to control rats, provoked structural abnormalities reminiscent of those observed in withdrawal conditions and support the regulatory role of cannabinoids in neurogenesis, axonal growth and synaptogenesis by acting as eu-proliferative signals through the CB1 receptors. Further, these measures were incorporated into a realistic computational model that predicts a strong reduction in the excitability of morphologically altered MSN, yielding a significant reduction in action potential output. These pieces of evidence support the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system and provide direct morphological evidence for functional abnormalities associated with cannabinoid dependence at the level of dopaminergic neurons and their postsynaptic counterpart and are coherent with recent hypothesis underscoring a hypodopaminergic state as a distinctive feature of the ,addicted brain'. [source] Genes Associated With Alcohol Abuse and Tobacco Smoking in the Human Nucleus Accumbens and Ventral Tegmental AreaALCOHOLISM, Issue 7 2010Traute Flatscher-Bader Background:, The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown, but interactions between these drugs have important implications for the development of and recovery from drug dependence. Methods:, We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the 2 behaviors on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by factorial ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Applying real-time PCR differential expression of candidate genes was confirmed in the nucleus accumbens and explored further in a second core region of the mesolimbic system, the ventral tegmental area. Results:, Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from nonalcoholics with the exception of 1 control case. All smokers were distinguished from nonsmokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism, and signaling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodeling, proliferation, and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway "regulation of the actin cytoskeleton" was induced in response to alcohol and tobacco co-abuse and included. Alcohol abuse elevated the expression of candidate genes in this pathway in the nucleus accumbens and ventral tegmental area, while smoking comorbidity blunted this induction in the ventral tegmental area. Conclusions:, The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system. [source] Contribution of perospirone and risperidone to reduce delirium in senile patientsPSYCHOGERIATRICS, Issue 1 2008Michikazu USHIJIMA Abstract Background:, Serotonin,dopamine antagonists (SDAs) inhibit dopaminergic transmission in the mesolimbic system less than in the nigrostriatal dopaminergic pathway, which relates to the extrapyramidal side-effects of these drugs. The SDAs seem to have an adequate receptor binding profile for the management of the behavioral and psychiatric symptoms of dementia. However, clinicians are discouraged from prescribing SDAs for elderly patients because of an advisory statement from the US Food and Drug Administration that warns about an increased mortality rate among elderly patients treated with atypical antipsychotics. Methods:, We conducted a retrospective study involving 16 elderly patients (mean age 84.9 years; range 67,94 years) with delirium who were treated with one of two SDAs, namely perospirone (4,12 mg/day) or risperidone (1,2 mg/day). The time-course of their psychiatric symptoms was assessed using subcategories of the Delirium Rating Scale (DRS) before treatment and on Days 10 and 24 of treatment. Results:, Total DRS scores were significantly decreased from baseline in both treatment groups. Both agents led to significant improvements from baseline in psychomotor behavior and lability of mood. Of interest, perospirone decreased hallucinations and delusions and improved sleep,awake cycle disturbances compared with baseline. No serious side-effects were seen with either drug. Conclusions:, Both perospirone and risperidone are effective in the management of delirium in elderly patients. The improvement in the sleep,awake cycle with perospirone may be derived from its short pharmacological half-life. [source] The endocannabinoid system in brain reward processesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008M Solinas Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB1 receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB1 receptors by plant-derived, synthetic or endogenous CB1 receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB1 receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes. British Journal of Pharmacology (2008) 154, 369,383; doi:10.1038/bjp.2008.130; published online 14 April 2008 [source] Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol inPKC,-deficient miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000M. Foster Olive Abstract There is increasing evidence that individual protein kinase C (PKC) isozymes mediate specific effects of ethanol on the nervous system. In addition, multiple lines of evidence suggest that the mesoaccumbens dopamine reward system is critically involved in the rewarding and reinforcing effects of ethanol. Yet little is known about the role of individual PKC isozymes in ethanol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKC,) show reduced operant ethanol self-administration and an absence of ethanol-induced increase in extracellular dopamine levels in the nucleus accumbens. PKC, null mice exhibited a 53% decrease in alcohol-reinforced operant responses under basal conditions, as well as following ethanol deprivation. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKC, null mice demonstrated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis experiments showed that, in contrast to wild-type mice, PKC, null mice exhibited no change in extracellular levels of dopamine in the nucleus accumbens following acute administration of ethanol (1 and 2 g/kg i.p.), while mesolimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (100 m m) in these mice were comparable with that of wild-types. These data provide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKC, may be useful in the treatment of alcohol dependence. [source] Stoichiometry of Tyrosine Hydroxylase Phosphorylation in the Nigrostriatal and Mesolimbic Systems In VivoJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Effects of Acute Haloperidol, Related Compounds Abstract ; Electrical stimulation of the medial forebrain bundle increases 32P incorporation into striatal tyrosine hydroxylase (TH) at Ser 19, Ser31, and Ser40. In the present studies, the effects of acute haloperidol and related drugs on sitespecific TH phosphorylation stoichiometry (PS) in the nigrostriatal and mesolimbic systems were determined by quantitative blot immunolabeling using phosphorylation statespecific antibodies. The striatum (Str), substantia nigra (SN), nucleus accumbens (NAc), and ventral tegmental area (VTA) from Sprague-Dawley rats were harvested 30-40 min after a single injection of either vehicle, haloperidol (2 mg/kg), raclopride (2 mg/kg), clozapine (30 mg/kg), or SCH23390 (0.5 mg/kg). In vehicle-injected control rats, Ser19 PS was 1.5- to 2.5-fold lower in Str and NAc than in SN and VTA, Ser31 PS was two-to fourfold higher in Str and NAc than in SN and VTA, and Ser40 PS was similar between the terminal field and cell body regions. After haloperidol, Ser40 PS increased twofold in Str and NAc, whereas a smaller increase in SN and VTA was observed. The effects of haloperidol on Ser19 PS were similar to those on Ser40 in each region ; however, haloperidol treatment increased Ser31 PS at least 1.6-fold in all regions. The effects of raclopride on TH PS were comparable to those of haloperidol, whereas clozapine treatment increased TH PS at all sites in all regions. By contrast, the effects of SCH23390 on TH PS were relatively small and restricted to the NAc. The stoichiometries of site-specific TH phosphorylation in vivo are presented for the first time. The nigrostriatal and mesolimbic systems have common features of TH PS, distinguished by differences in TH PS between the terminal field and cell body regions and by dissimilar increases in TH PS in the terminal field and cell body regions after acute haloperidol. [source] | |||||||||||||