Cortical 5HT2A Receptor Function under Hypoxia in Neonatal Rats: Role of Glucose, Oxygen, and Epinephrine Resuscitation

Abstract

Neonatal hypoxia induces brain injury through alterations in neurotransmitters and its receptors. Molecular processes regulating serotonergic receptors play an important role in the control of respiration under hypoxia. The present study evaluates the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT(2A) receptors and its transporter in the cerebral cortex of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine. Hypoxic stress increased total 5HT and 5HT(2A) receptor number along with an upregulation of 5HT(2A) receptor and 5HT transporter gene in the cortex. The enhanced cortical 5HT(2A) receptors may act as a modulator of ventilatory response to hypoxia. These alterations were reversed to near control by glucose supplementation. Glucose supplementation helped in managing the serotonergic functional alterations. Hypoxia-induced adenosine triphosphate depletion causes a reduction in blood glucose levels which can be encountered by glucose administration, and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.

Pivotal mental states

“…Hypoxia upregulates cortical 5-HT2ARs (Anju et al, 2011) and the 5-HT2AR agonist psychedelic N,N-Dimethyltryptamine (DMT) exerts neuroprotective effects in cells exposed to hypoxic conditions, leading scholars to suggest endogenous DMT may be released as an adaptive response to physiological stress (da Silva Soares et al, 2019; Szabo et al, 2016). A recent study observed increased DMT levels in rat visual cortex following cardiac arrest (Dean et al, 2019), a finding that supports the hypothesized role of endogenous DMT in NDEs (Strassman, 2000; Timmermann et al, 2018).…”

“…Modern therapeutic techniques such as breathwork (Brown and Gerbarg, 2005; Grof and Grof, 2010) and whole-body hyperthermia (Hanusch et al, 2013; Janssen et al, 2016) continue to reinforce the idea that physiological stress or dysregulation can lead to meaningful changes in mental states and have been found to interface with the serotonin system (Anju et al, 2011; Buchanan et al, 2015; Pawlyk et al, 2006). The cross-cultural and recurring practice of asceticism cannot be explained as a purely culturally contingent phenomenon.…”

“…We place special focus on the serotonin system and its 2A receptor (5-HT2AR) subtype in particular, which has been shown to be particularly implicated in biology x environment interactions (Chang et al, 2017; Dressler et al, 2016; Fiocco et al, 2007; Jiang et al, 2016; Jokela et al, 2007; Lebe et al, 2013; Mellman et al, 2009; Parade et al, 2017; Salo et al, 2011). Various acute stressors appear to be reliable and robust inducers of serotonin release (Adell et al, 1997; Amat et al, 1998, 2005; Bastani et al, 2017; Beitia et al, 2005; Bland et al, 2003; Cohen et al, 2015; Ferres-Coy et al, 2013; Fuenmayor and Garcia, 1984; Fujino et al, 2002; Gardner et al, 2005; Hale et al, 2011; Higuchi et al, 2019; Ishida et al, 1997; Ishiwata and Greenwood, 2018; Johnson et al, 2005; Keeney et al, 2006; Kelly et al, 2011; Li et al, 2015; Myers and Beleslin, 1971; Nakajima et al, 2009; Neugebauer, 2020; Paul et al, 2011; Rex et al, 2005; Yoshioka et al, 1995) and different types of stressor, such as sleep deprivation (Elmenhorst et al, 2012; Maple et al, 2015; Zhao et al, 2019), hypoxia (Anju et al, 2011), chronic tryptophan depletion (Cahir et al, 2007), inflammation (Zhang et al, 2001), tonic pain (Kupers et al, 2009), repeated forced swim (Takao et al, 1995), repeated shock (Dwivedi et al, 2005), administration of stress hormones (Jitsuiki et al, 2000; Kuroda et al, 1992, 1994), amygdala stimulation (…”

Therapeutic dissociation: From non-ordinary states to psychological transformation

“…Brouwer and Carhart-Harris name common inducers of stress, including social isolation, starvation, atypical breathing, sleep deprivation, extreme body temperature, pain, alongside canonical stressors such as sleep deprivation (Elmenhorst et al, 2012), hypoxia (Anju et al, 2011), and repeated shock (Dwivedi et al, 2005). Under the PiMS framing, when these stressors are combined with psychedelics, meditation, and other stimuli, a specific mental state capable of causing long-term changes can result.…”

A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex

“…Firstly, chronic stress increases cortical 5-HT2AR expression and sensitivity to signaling ( [177][178][179][180] ; see 173 for a recent review). Such effects can be observed in response to physiological stressors such as deprivation of oxygen 181 , deprivation of sleep [182][183][184] , and inadequate nutrition 185 , and also in response to social/cognitive stress, such as recurring defeat 186 , rearing in isolation [187][188][189] and maternal separation 190,191 . Physiological or social deprivation may be a common factor here,…”