Yohimbine prevents morphine-induced changes of glial fibrillary acidic protein in brainstem and alpha2-adrenoceptor gene expression in hippocampus.
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.
Alonso
Elba
E
Lab. Pharmacology and Toxicology, Universidad San Pablo CEU, 28668 Boadilla del Monte, Madrid, Spain.
Garrido
Elisa
E
Díez-Fernández
Carmen
C
Pérez-García
Carmen
C
Herradón
Gonzalo
G
Ezquerra
Laura
L
Deuel
Thomas F
TF
Alguacil
Luis F
LF
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D017776:Autonomic Pathways / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D009294:Narcotics; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D009020:Morphine