Yohimbine prevents morphine-induced changes of glial fibrillary acidic protein in brainstem and α2-adrenoceptor gene expression in hippocampus
ABSTRACT The alpha(2)-adrenoceptor antagonist yohimbine is known to oppose to several pharmacological effects of opioid drugs, but the consequences and the mechanisms involved remain to be clearly established. In the present study we have checked the effects of yohimbine on morphine-induced alterations of the expression of key proteins (glial fibrillary acidic protein, GFAP) and genes (alpha(2)-adrenoceptors) in rat brain areas known to be relevant in opioid dependence, addiction and individual vulnerability to drug abuse. Rats were treated with morphine in the presence or absence of yohimbine. The effects of the treatments on GFAP expression were studied by immunohistochemical staining in Locus Coeruleus (LC) and Nucleus of the Solitary Tract (NST), two important noradrenergic nuclei. In addition, drug effects on alpha(2)-adrenoceptor gene expression were determined by real time RT-PCR in the hippocampus, a brain area that receives noradrenergic input from the brainstem. Morphine administration increased GFAP expression both in LC and NST as it was previously reported in other brain areas. Yohimbine was found to efficiently prevent morphine-induced GFAP upregulation. Chronic (but not acute) morphine downregulated mRNA levels of alpha(2A)- and alpha(2C)-adrenoceptors in the hippocampus, while simultaneously increased the expression of the alpha(2B)-adrenoceptor gene. Again, yohimbine was able to prevent morphine-induced changes in the levels of expression of the three alpha(2)-adrenoceptor genes. These results correlate the well-established reduction of opioid dependence and addiction by yohimbine and suggest that this drug could interfere with the neural plasticity induced by chronic morphine in central noradrenergic pathways.
- SourceAvailable from: Mark R Hutchinson
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- "Importantly , this proinflammatory phenotype induced by morphine has been observed to be brain region specific and in some regions glial cell type specific. For example, astrocytes are activated following chronic morphine administration in the locus ceruleus and nucleus of the solitary tract (Alonso et al., 2007), lateral septal nucleus (Lazriev et al., 2001), ventral tegmental area, nucleus accumbens, dentate gyrus, Cornu ammonis of the hippocampus, dorsal periaqueductal gray, medial prefrontal cortex, ventral periaqueductal gray, caudate putamen, rostral ventromedial medulla and trigeminal nucleus, but not in the dorsal raphe nucleus, caudate nucleus and the substantia nigra (Lazriev et al., 2001; Hutchinson et al., 2009a). In contrast, microglia are only activated by chronic systemic morphine in the ventral tegmental area, dentate gyrus, dorsal periaqueductal gray, ventral periaqueductal gray, caudate putamen, rostral ventromedial medulla and the trigeminal nucleus, but not in the nucleus accumbens, C. ammonis of the hippocampus, substantia nigra, medial prefrontal cortex and dorsal raphe nucleus (Hutchinson et al., 2009a). "
ABSTRACT: In the past two decades a trickle of manuscripts examining the non-neuronal central nervous system immune consequences of the drugs of abuse has now swollen to a significant body of work. Initially, these studies reported associative evidence of central nervous system proinflammation resulting from exposure to the drugs of abuse demonstrating key implications for neurotoxicity and disease progression associated with, for example, HIV infection. However, more recently this drug-induced activation of central immune signaling is now understood to contribute substantially to the pharmacodynamic actions of the drugs of abuse, by enhancing the engagement of classical mesolimbic dopamine reward pathways and withdrawal centers. This review will highlight the key in vivo animal, human, biological and molecular evidence of these central immune signaling actions of opioids, alcohol, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). Excitingly, this new appreciation of central immune signaling activity of drugs of abuse provides novel therapeutic interventions and opportunities to identify 'at risk' individuals through the use of immunogenetics. Discussion will also cover the evidence of modulation of this signaling by existing clinical and pre-clinical drug candidates, and novel pharmacological targets. Finally, following examination of the breadth of central immune signaling actions of the drugs of abuse highlighted here, the current known common immune signaling components will be outlined and their impact on established addiction neurocircuitry discussed, thereby synthesizing a common neuroimmune hypothesis of addiction.Pharmacology [?] Therapeutics 02/2012; 134(2):219-45. DOI:10.1016/j.pharmthera.2012.01.008 · 7.75 Impact Factor
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- "NM_031012). GAPDH was used as a positive control, and the following primers were adopted: GAPDH sense — 5′-TTCAACGGCACAGTCAAGGC-3′, GAPDH anti-sense — 5′-CACCAGCATCACCCCATTTG-3′  (GenBank access no: NM_017008). "
ABSTRACT: Protein (western blotting) and gene (PCR) expressions, catalytic activity of puromycin-insensitive membrane-bound neutral aminopeptidase (APM/CD13) and in situ regional distribution of CD13 and FOS immunoreactivity (ir) were evaluated in the hypothalamus of monosodium glutamate obese (MSG) and/or food deprived (FD) rats in order to investigate their possible interplay with metabolic functions. Variations in protein and gene expressions of CD13 relative to controls coincided in the hypothalamus of MSG and MSG-FD (decreased 2- to 17-fold). Compared with controls, the reduction of hypothalamic CD13 content reflected a negative balance in its regional distribution in the supraoptic, paraventricular, periventricular and arcuate nuclei. CD13-ir increased in the supraoptic nucleus in MSG (2.5-fold) and decreased in the paraventricular nucleus (2-fold) together with FOS-ir (1.5-fold) in FD. In MSG-FD, FOS-ir decreased (7-fold) in the paraventricular nucleus, while CD13-ir decreased in the periventricular (5.6-fold) and the arcuate (3.7-fold) nuclei. It was noteworthy that all these changes of CD13 were not related to catalytic activity of APM. Data suggested that hypothalamic CD13 plays a role in the regulation of energy metabolism not by means of APM enzyme activity.Regulatory Peptides 01/2011; 166(1-3):98-104. DOI:10.1016/j.regpep.2010.09.002 · 2.01 Impact Factor
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- "GAPDH was used as positive control, and the following primers were adopted: GAPDH sense: 5′-TTCAACG- GCACAGTCAAGGC-3′, GAPDH anti-sense: 5′-CACC- AGCATCACCCCATTTG-3′  (GenBank access no. NM_017008). "
ABSTRACT: Proline-specific dipeptidyl peptidases are emerging as a protease family with important roles in the regulation of signaling by peptide hormones related to energy balance. The treatment of neonatal rats with monosodium glutamate (MSG) is known to produce a selective damage on the arcuate nucleus with development of obesity. This study investigates the relationship among dipeptidyl peptidase IV (DPPIV) hydrolyzing activity, CD26 protein, fasting, and MSG model of obesity in 2 areas of the central nervous system. Dipeptidyl peptidase IV and CD26 were, respectively, evaluated by fluorometry, and enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction in soluble (SF) and membrane-bound (MF) fractions from the hypothalamus and hippocampus of MSG-treated and normal rats, submitted or not to food deprivation (FD). Dipeptidyl peptidase IV in both areas was distinguished kinetically as insensitive (DI) and sensitive (DS) to diprotin A. Compared with the controls, MSG and/or FD decreased the activity of DPPIV-DI in the SF and MF from the hypothalamus, as well as the activity of DPPIV-DS in the SF from the hypothalamus and in the MF from the hippocampus. Monosodium glutamate and/or FD increased the activity of DPPIV-DI in the MF from the hippocampus. The monoclonal protein expression of membrane CD26 by enzyme-linked immunosorbent assay decreased in the hypothalamus and increased in the hippocampus of MSG and/or FD relative to the controls. The existence of DPPIV-like activity with different sensitivities to diprotin A and the identity of insensitive with CD26 were demonstrated for the first time in the central nervous system. Data also demonstrated the involvement of DPPIV-DI/CD26 hydrolyzing activity in the energy balance probably through the regulation of neuropeptide Y and β-endorphin levels in the hypothalamus and hippocampus.Metabolism: clinical and experimental 02/2010; 60(2):234-42. DOI:10.1016/j.metabol.2009.12.031 · 3.61 Impact Factor