To understand our ongoing ideas mind and loss of mind and the role of PCO2 and hypercapnia,   please look at our post on     *** a Potential two Step Marker for Bipolar Depressive Illness [to start] and our post on      *** How to Save a Manic Depressive Life.

1] https://ofsoundmind.life/2020/11/09/we-have-a-2-step-marker-for-bipolar-illness/ We have a potential new 2 step biomarker for bipolar illness. Ventilatory issues and [hidden] hypercapnia can cause specific patterns of “odd behaviour”, mood and locomotor activity.    

AND

2]  https://ofsoundmind.life/2020/11/11/how-to-save-a-manic-depressives-life/

At the very least!

To understand our ongoing ideas mind and loss of mind and the role of PCO2 and hypercapnia,   please look at our post on     *** a Potential two Step Marker for Bipolar Depressive Illness [to start] and our post on      *** How to Save a Manic Depressive Life.

1] https://ofsoundmind.life/2020/11/09/we-have-a-2-step-marker-for-bipolar-illness/ We have a potential new 2 step biomarker for bipolar illness. Ventilatory issues and [hidden] hypercapnia can cause specific patterns of “odd behaviour”, mood and locomotor activity.    

AND

2]  https://ofsoundmind.life/2020/11/11/how-to-save-a-manic-depressives-life/

At the very least!

Paula and I have identified a ventilatory injury/defect in that I can be most clearly identified in the  depressive stage of manic depressive insanity.  Kraepelin seems to have identified the same injury/defect over 100+ years ago. This is what is guiding us to new research to connect the dots. It is a lot of fun. It is something that scientists can follow up on. And we think this will make a huge difference in the new updated understanding of the reversible syndrome of bipolar illness and its treatment. this is how we have gotten to learn about adenosine and its ability to inhibit respiration rate in the face of hypercapnia……to be continued.

J Physiol. 2006 Aug 1; 574(Pt 3): 633. doi: 10.1113/jphysiol.2006.115022PMCID: PMC1817737PMID: 16777947

The acid nature of CO₂-evoked adenosine release in the CNS

Nicholas Dale

There is an ever-growing appreciation of the important and universal signalling roles mediated by ATP and adenosine in every major organ system. The brain is no exception, and an effect of adenosine that we experience every day during our normal lives is its action as an endogenous somnogen (Basheer et al. 2004) – adenosine builds up in certain key brain areas during wakefulness and provides an overpowering drive for sleep – hence the wake-promoting properties of coffee as caffeine is a weak adenosine receptor antagonist. However, adenosine has a ‘darker’ side that we experience only when things start to go wrong – it is a major retaliatory metabolite during pathologies such as stroke, apnoea and epileptic seizures. In all of these roles for adenosine, it is fair to say that we still have limited knowledge and evidence as to the mechanisms that lead to its accumulation and release.

In this issue of The Journal of Physiology, Otsuguro et al. (2006) shed new light on this important and vexatious issue. These authors looked at the effect of elevated CO₂ (hypercapnia) on spinal cord function and found a depression of dorsal horn reflexes that was mediated by the release of adenosine acting via A1 receptors. This adenosine release is very unlikely to originate from the prior release of ATP and its subsequent conversion by ectonucleotidases to adenosine in the extracellular space – blockade of the ectonucleotidases had no effect on hypercapnia-induced adenosine release. Hypercapnia not only results in elevated levels of dissolved CO₂ in blood, but also in acidification of blood through the equilibrium between dissolved CO₂, water and bicarbonate. In a fascinating development, the authors have shown that acidification by itself (isocapnic acidosis) is insufficient to cause adenosine release. The key requirement is that the levels of CO₂/HCO₃⁻ should increase (either with or without acidification – respectively, hypercapnic acidosis and isohydric hypercapnia). This firmly suggests that the site for the detection of hypercapnia is inside the cell as CO₂ can readily cross membranes and cause intracellular acidification. This is highly consistent with the next key finding of this study – that hypercapnia inhibits adenosine kinase, a major cytoplasmic enzyme that converts adenosine to AMP, thus ensuring that cytosolic levels of adenosine are normally very low. The authors report a direct inhibitory effect of both hypercapnic acidosis and isohydric hypercapnia but not isocapnic acidosis on adenosine kinase activity. To round things off in a satisfying manner they also show that pharmacological blockade of adenosine kinase is sufficient to depress the spinal reflexes by an A1 receptor-dependent mechanism. Thus the message is clear – hypercapnia causes direct release of adenosine through inhibition of adenosine kinase and equilibrative transport across the membrane.

However, physiology is rarely simple, and in a different area of the brain, the hippocampus, contrasting results on the release of adenosine during hypercapnia have been recently presented by Dulla et al. (2005). These authors also found that hypercapnia caused adenosine release which depressed synaptic transmission in the hippocampus, and additionally demonstrated that hypocapnia caused a reduction in the adenosine tone and a corresponding increase in synaptic transmission. This suggests that P_CO2 exerts a continual and graded influence on excitability and neural function in the hippocampus. Where these results contrast with the report by Otsuguro et al. (2006) is that in hippocampus it appears that it is the extracellular pH rather than intracellular pH that is the key determinant of adenosine production. For hypocapnia, the authors suggest that the extracellular alkalosis results in diminished hydrolysis of extracellular ATP (through an action on the ectoATPase) and hence a fall in the adenosine tone. This is consistent with the recent results of Pascual et al. (2005) demonstrating that the adenosine tone in hippocampus relies on prior release of ATP from the astroglia (and subsequent breakdown in the extracellular space). For hypercapnia, although the evidence suggests an extracellular locus for the action of pH, the adenosine release may not arise from breakdown of extracellular ATP – blockers of the ectonucleotidases are without effect on adenosine levels. Conversely the authors could not prevent the hypercapnic release of adenosine with adenosine transport blockers, leaving the mechanism by which adenosine appears in the extracellular space during hypercapnia a mystery. These intriguing results help to explain why hypo- and hypercapnia, respectively, alter the propensity for seizures and states of consciousness in humans.

In yet a third area of the brain, the medulla oblongata and the respiratory chemosensing areas on its ventral surface, Gourine et al. (2005) have demonstrated directly the release of ATP during hypercapnia. This ATP release forms an important causal link in the adaptive enhancement of ventilation in response to hypercapnia. Whether this is caused by intracellular or extracellular changes in pH and the mechanisms of ATP release remain to be established. The bottom line in these three recent studies looking at the response of the nervous system to hypercapnia seems to be – it depends! Those looking for a single unifying explanation or mechanism may be disappointed; however, the mechanisms underlying adenosine and ATP release in response to hypercapnia appear to differ depending on physiological context and the area of the CNS under consideration.