ATP is released during hypoxia from the ventrolateral medulla (VLM) and activates purinergic P2 receptors (P2Rs) at unknown loci to offset the secondary hypoxic depression of breathing. In this study, we used rhythmically active medullary slices from neonatal rat to map, in relation to anatomical and molecular markers of the pre-Bötzinger complex (preBötC) (a proposed site of rhythm generation), the effects of ATP on respiratory rhythm and identify the P2R subtypes responsible for these actions. Unilateral microinjections of ATP in a three-dimensional grid within the VLM revealed a "hotspot" where ATP (0.1 mM) evoked a rapid 2.2 +/- 0.1-fold increase in inspiratory frequency followed by a brief reduction to 0.83 +/- 0.02 of baseline. The hotspot was identified as the preBötC based on histology, overlap of injection sites with NK1R immunolabeling, and potentiation or inhibition of respiratory frequency by SP ([Sar9-Met(O2)11]-substance P) or DAMGO ([D-Ala2,N-MePhe4,Gly-ol5]-enkephalin), respectively. The relative potency of P2R agonists [2MeSADP (2-methylthioadenosine 5'-diphosphate) approximately = 2MeSATP (2-methylthioadenosine 5'-triphosphate) approximately = ATPgammas (adenosine 5'-[gamma-thio]triphosphate tetralithium salt) approximately = ATP > UTP approximately = alphabeta meATP (alpha,beta-methylene-adenosine 5'-triphosphate)] and attenuation of the ATP response by MRS2179 (2'-deoxy-N6-methyladenosine-3',5'-bisphosphate) (P2Y1 antagonist) indicate that the excitation is mediated by P2Y1Rs. The post-ATP inhibition, which was never observed in response to ATPgammas, is dependent on ATP hydrolysis. These data establish in neonatal rats that respiratory rhythm generating networks in the preBötC are exquisitely sensitive to P2Y1R activation, and suggest a role for P2Y1Rs in respiratory motor control, particularly in the P2R excitation of rhythm that occurs during hypoxia.
"Thus, LC purinergic signaling appears to play a role in the CO2 drive to breathe, specifically through the activation of P2 receptors, accelerating the ventilatory response to hypercapnia. This observation was probably due to P2X activation of noradrenergic neurons, triggering further NA and ATP release which in turn activate rhythm-generating circuits and medullary respiratory neurons in one or more of the following brainstem nuclei: RTN, RVLM, prepositus hypoglossi nucleus, and NTS (Aston-Jones et al., 1986, 1991b; Astier et al., 1990; Pieribone and Aston-Jones, 1991; Vulchanova et al., 1997; Llewellyn-Smith and Burnstock, 1998; Kanjhan et al., 1999; Thomas and Spyer, 2000; Yao et al., 2000; Gourine et al., 2003; Lorier et al., 2007, 2008; Huxtable et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: The locus coeruleus (LC) is a dorsal pontine region, situated bilaterally on the floor of the fourth ventricle. It is considered to be the major source of noradrenergic innervation in the brain. These neurons are highly sensitive to CO2/pH, and chemical lesions of LC neurons largely attenuate the hypercapnic ventilatory response in unanesthetized adult rats. Developmental dysfunctions in these neurons are linked to pathological conditions such as Rett and sudden infant death syndromes, which can impair the control of the cardio-respiratory system. LC is densely innervated by fibers that contain glutamate, serotonin, and adenosine triphosphate, and these neurotransmitters strongly affect LC activity, including central chemoreflexes. Aside from neurochemical modulation, LC neurons are also strongly electrically coupled, specifically through gap junctions, which play a role in the CO2 ventilatory response. This article reviews the available data on the role of chemical and electrical neuromodulation of the LC in the control of ventilation.
Frontiers in Physiology 08/2014; 5:288. DOI:10.3389/fphys.2014.00288 · 3.53 Impact Factor
"ATP excites the preBötC in vitro in rats (Huxtable et al., 2009; Zwicker et al., 2011) through the activation of P2Y-receptors (Lorier et al., 2007; Huxtable et al., 2009). Interestingly, blockade of endogenous activation of P2-receptors with suramin reduced inspiratory frequency in the slice preparation, while Cu2+, an allosteric modulator of purinergic receptors, produced the opposite effect (Lorier et al., 2007, 2008). "
[Show abstract][Hide abstract] ABSTRACT: The generation of neural network dynamics relies on the interactions between the intrinsic and synaptic properties of their neural components. Moreover, neuromodulators allow networks to change these properties and adjust their activity to specific challenges. Endogenous continuous ("tonic") neuromodulation can regulate and sometimes be indispensible for networks to produce basal activity. This seems to be the case for the inspiratory rhythm generator located in the pre-Bötzinger complex (preBötC). This neural network is necessary and sufficient for generating inspiratory rhythms. The preBötC produces normal respiratory activity (eupnea) as well as sighs under normoxic conditions, and it generates gasping under hypoxic conditions after a reconfiguration process. The reconfiguration leading to gasping generation involves changes of synaptic and intrinsic properties that can be mediated by several neuromodulators. Over the past years, it has been shown that endogenous continuous neuromodulation of the preBötC may involve the continuous action of amines and peptides on extrasynaptic receptors. I will summarize the findings supporting the role of endogenous continuous neuromodulation in the generation and regulation of different inspiratory rhythms, exploring the possibility that these neuromodulatory actions involve extrasynaptic receptors along with evidence of glial modulation of preBötC activity.
Frontiers in Physiology 07/2012; 3:253. DOI:10.3389/fphys.2012.00253 · 3.53 Impact Factor
"Interestingly, a reduction in locomotor burst frequency contrasts the excitatory effects of ATP on the respiratory rhythm in mice (Lorier et al. 2007) and locomotor rhythm in Xenopus tadpoles (Dale and Gilday 1996). However, in both of these systems, adenosine derived from the breakdown of ATP has inhibitory effects. "
[Show abstract][Hide abstract] ABSTRACT: The activation of purinergic receptors modulates central pattern generators controlling rhythmic motor behaviors, including respiration in rodents and swimming in frog tadpoles. The present study aimed to determine whether purinergic signaling also modulates the mammalian locomotor central pattern generator. This was investigated by using isolated spinal cord preparations obtained from neonatal mice in which locomotor-related activity can be induced pharmacologically. The application of either ATP or adenosine led to a reduction in the frequency of locomotor activity recorded from ventral roots. ATP had no effect when applied in the presence of both the adenosine receptor antagonist theophylline and the ectonucleotidase inhibitor ARL67156, demonstrating that the effects of ATP application result from the breakdown of ATP to adenosine and subsequent activation of adenosine receptors. The application of theophylline or the A(1)-specific antagonist cyclopentyl dipropylxanthine, but not the A(2A)-receptor antagonist SCH58261, caused an increase in locomotor burst frequency, demonstrating that endogenously derived adenosine activates A(1) receptors during locomotor network activity. Furthermore, theophylline had no effect in the presence of the ectonucleotidase inhibitor ARL67156 or the glial toxins methionine sulfoximine or ethyl fluoracetate, suggesting that endogenous adenosine is derived from ATP, which is released from glia. Finally, adenosine had no effect on slow rhythmic activity recorded upon blockade of all inhibitory transmission, suggesting that adenosine may act via the modulation of inhibitory transmission. Together, these data highlight endogenous purinergic gliotransmission, involving activation of A(1) receptors, as an important intrinsic modulatory system controlling the frequency of activity generated by spinal locomotor circuitry in mammals.
Journal of Neurophysiology 12/2011; 107(7):1925-34. DOI:10.1152/jn.00513.2011 · 2.89 Impact Factor
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