Anxiolytics antagonize yohimbine-induced central noradrenergic activity: a concomitant in vivo voltammetry-electrophysiology model of anxiety.
It has been shown that increased cerebral noradrenergic activity is closely related to anxiety-related behaviours. Furthermore, the noradrenergic alpha-2 receptor antagonist yohimbine (YOH) increases noradrenaline- (NA) cell firing and release in discrete brain areas involved in the modulation of anxiety such as the locus coeruleus (LC) and amygdala (AMY). In addition, YOH is highly anxiogenic in both humans and laboratory animals. Here we used an in vivo dual methodology to measure concomitantly the extracellular levels of catecholamines in AMY with voltammetry and the cell firing rate in LC with field electrophysiology in anaesthetized rats to characterize the pharmacological effects of YOH. We found that systemic administration of YOH increases both noradrenergic cell firing in the LC and catecholamines release in the AMY. Prior administration of the alpha-2 agonist clonidine prevents these effects on both the electrophysiological and the voltammetric signals, suggesting that YOH effects are mainly mediated by the alpha-2 adrenoceptors. In addition, we found that pre-treatment with the behaviourally active doses of the benzodiazepine (BDZ) anxiolytic chlordiazepoxide (CDE, Librium: BDZ very similar to diazepam) and of the non-BDZ buspirone counteract the effects of YOH on catecholamines release and cell firing. This suggests that the neurochemical and physiological effects of YOH measured in this study might be related to the anxiogenic effects of the drug. Thus, the presented electrophysiological-voltammetric-YOH study may be proposed as in vivo real time model of anxiety and this approach might be suitable for the evaluation of the neurochemical and physiological effects of new anxiolytic compounds.
Biology Dept, Neurosciences CEDD GlaxoSmithKline, Medicines Research Centre, via Fleming 4, 37135 Verona, Italy. Francesco.M.Crespi@GSK.com
Francesco
F
Crespi
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001008:Anxiety Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002065:Buspirone / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004594:Electrophysiology / Q000379:methods*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009480:Neuropharmacology / Q000379:methods*; D009482:Neurophysiology / Q000379:methods; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D015016:Yohimbine / Q000037:antagonists & inhibitors*
D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D002707:Chlordiazepoxide; D002065:Buspirone; D009638:Norepinephrine