Rapid Physiological Fluctuations in Nucleus Accumbens Oxygen Levels Induced by Arousing Stimuli: Relationships with Changes in Brain Glucose and Metabolic Neural Activation

Abstract

Proper entry of oxygen from arterial blood into the brain is essential for maintaining brain metabolism under normal conditions and during functional neural activation. However, little is known about physiological fluctuations in brain oxygen and their underlying mechanisms. To address this issue, we employed high-speed amperometry with platinum oxygen sensors in freely moving male rats. Recordings were conducted in the nucleus accumbens (NAc), a critical structure for sensorimotor integration. Rats were exposed to arousing stimuli of different nature (brief auditory tone, a 1-min novel object presentation, a 3-min social interaction with a conspecific, and a 3-min tail-pinch). We found that all arousing stimuli increased NAc oxygen levels. Increases were rapid (4–10-s onset latencies), modest in magnitude (1–3 μM or 5%–15% over baseline) and duration (5–20 min), and generally correlated with the arousing potential of each stimulus. Two strategies were used to determine the mechanisms underlying the observed increases in NAc oxygen levels. First, we showed that NAc oxygen levels phasically increase following intra-NAc microinjections of glutamate (GLU) that excite accumbal neurons. Therefore, local neural activation with subsequent local vasodilation is involved in mediating physiological increases in NAc oxygen induced by arousing stimuli. Second, by employing oxygen monitoring in the subcutaneous space, a highly-vascularized area with no metabolic activity, we determined that physiological increases in NAc oxygen also depend on the rise in blood oxygen levels caused by respiratory activation. Due to the co-existence of different mechanisms governing oxygen entry into brain tissue, NAc oxygen responses differ from fluctuations in NAc glucose, which, within a normal behavioral continuum, are regulated exclusively by neuro-vascular coupling due to glucose’s highly stable levels in the blood. Finally, we discuss the relationships between physiological fluctuations in NAc oxygen, glucose and metabolic brain activation assessed by intra-brain heat production.

Heroin Contaminated with Fentanyl Dramatically Enhances Brain Hypoxia and Induces Brain Hypothermia

“…Therefore, respiratory depression and the subsequent drop in brain oxygen levels are the primary neural effects of these drugs, whereas the succeeding hyperthermia and increases in brain-muscle differentials could be an adaptive brain response caused by brain hypoxia. This pattern of drug-induced changes is drastically different from that occurring under normal physiologic conditions, in which intrabrain oxygen inflow elicited by arousing stimuli is tightly related to metabolic neural activation (Solis et al, 2017a). …”

“…High metabolic activity of the central neurons requires constant and efficient delivery of oxygen that enters the brain extracellular space from the arterial blood via gradient-dependent diffusion (Attwell et al, 2010). Oxygen entry into the brain is enhanced during functional neural activation and this adaptive effect appears to result primarily from neuronal activation that induces local vasodilation and increases local cerebral blood flow (Lecrux and Hamel, 2011; Muoio et al, 2014; Solis et al, 2017a). However, opioid drugs dramatically alter these well-regulated physiological mechanisms by inducing respiratory depression and decreasing blood oxygen levels.…”

“…Surgical procedures for electrochemical experiments are described in detail elsewhere (Kiyatkin and Lenoir, 2012; Solis et al, 2017a). In brief, under general anesthesia (Equithesin, sodium pentobarbital and chloral hydrate mixture), each rat was unilaterally implanted with a BASi guide cannula (Bioanalytical Systems) into which an electrochemical sensor was later inserted.…”

“…These sensors were previously used for assessment of physiological fluctuations in NAc oxygen (Solis et al, 2017a); this publication contains additional details on the use of this technology in awake, freely moving rats.…”

“…Our experimental paradigm allows us to monitor brain oxygen levels following stress- and cue-free intravenous drug injections in awake, freely moving rats and determine the effects of drugs of abuse in the absence of confounding variables such as anesthesia. Using this novel technology, we recently examined physiological fluctuations in brain oxygen levels and established their relationships with metabolic neural activation and local vascular response (Solis et al, 2017a). We also showed that both heroin and fentanyl used within the range of possible human consumption induce rapid, dose-dependent decreases in extracellular oxygen levels in the nucleus accumbens (NAc) of freely moving rats (Solis et al, 2017b,c).…”