Activation of locus coeruleus heme oxygenase-carbon monoxide pathway promoted an anxiolytic-like effect in rats

Abstract

The heme oxygenase-carbon monoxide pathway has been shown to play an important role in many physiological processes and is capable of altering nociception modulation in the nervous system by stimulating soluble guanylate cyclase (sGC). In the central nervous system, the locus coeruleus (LC) is known to be a region that expresses the heme oxygenase enzyme (HO), which catalyzes the metabolism of heme to carbon monoxide (CO). Additionally, several lines of evidence have suggested that the LC can be involved in the modulation of emotional states such as fear and anxiety. The purpose of this investigation was to evaluate the activation of the heme oxygenase-carbon monoxide pathway in the LC in the modulation of anxiety by using the elevated plus maze test (EPM) and light-dark box test (LDB) in rats. Experiments were performed on adult male Wistar rats weighing 250-300 g (n=182). The results showed that the intra-LC microinjection of heme-lysinate (600 nmol), a substrate for the enzyme HO, increased the number of entries into the open arms and the percentage of time spent in open arms in the elevated plus maze test, indicating a decrease in anxiety. Additionally, in the LDB test, intra-LC administration of heme-lysinate promoted an increase on time spent in the light compartment of the box. The intracerebroventricular microinjection of guanylate cyclase, an sGC inhibitor followed by the intra-LC microinjection of the heme-lysinate blocked the anxiolytic-like reaction on the EPM test and LDB test. It can therefore be concluded that CO in the LC produced by the HO pathway and acting via cGMP plays an anxiolytic-like role in the LC of rats.

The role of brain gaseous neurotransmitters in anxiety

“…for 11 weeks Rat Anxiolytic EPM, MWM tests [ 115 ] NaHS 1.68 or 5.6 mg/kg i.p. for a week Rat/Mse Anxiolytic EPM and FST tests [ 113 ] CO donors Heme lysinate 600 nmol Intra LC inj Rat Anxiolytic EPM and LDB tests [ 127 ] CORM-2 5 mg/kg i.p. for 10 days Rat Anxiolytic EPM and LDB tests [ 133 ] CORM-3 4 mg/kg i.v.…”

“…The endogenous production of CO occurs through the activity of heme oxygenase (HOCO, HOs) responsible for the cleavage of heme molecule into biliverdin, free iron (Fe 2+ ) and CO. Two independent isoforms of this enzyme are known: an inducible heme oxygenase 1 (HO-1) and a constitutive form, heme oxygenase 2 (HO-2) [ 24 ]. A third probably inactive isoform HO-3 was cloned from rat brain tissue but its functions remains unknown [ 127 , 128 ]. The expression of HO-1 is detected in the selective small cellular assemblies of the brain (both neural and glial) while distribution of HO-2 is rather ubiquitous [ 129 ].…”

“…One of the few pioneer studies on CO and anxiety was conducted by Carvalho-Costa et al [ 127 ]. This important report showed that anxiolytic effect of CO in rats was evoked by cGMP-dependent heme oxygenase pathway in the rat locus coeruleus (LC), the main center of brain noradrenegic signaling [ 127 ].…”

Effects of Exogenous Biliverdin Treatment on Neurobehaviors in Mice

“…The significant neuroprotective effects of HO and its derivatives have been well investigated. 9,10) The experiment concurrently shows that the HO-CO system has the function of relieving anti-anxiety and epileptic seizures. 11,12) The BVD reductase/HO-1 system is also associated with Alzheimer's disease.…”

Participação da via HO-CO em áreas encefálicas do sistema límbico na modulação da dor: recrutamento de receptores µ e δ opióides, fatores de transcrição, neurotróficos e oxidativos

“…Estudos anteriores mostraram que o CO atua na antinocicepção aguda não inflamatória avaliada no teste de retirada de cauda em ratos (Carvalho et al, 2011), na dor inflamatória induzida por adjuvante completo de Freund (CFA) no teste de von Frey (Carcolé et al, 2014), na dor neuropática induzida por diabetes (Castany et al, 2016) e por constrição de nervo ciático (Jurga et al, 2016). Além disso, estudo recente evidenciou que o CO participa da modulação do comportamento emocional (Carvalho-Costa, et al, 2016) em ratos avaliados no labirinto em cruz elevado e no teste claro-escuro, promovendo efeito ansiolítico. Entretanto, o envolvimento do CO na modulação da dor para além dos aspectos sensoriais ainda necessita de mais esclarecimentos.…”