Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas

In this study, Whitney et al. used a genetic approach involving site-specific recombinase technology to achieve a nearly total elimination of serotonin (5-HT) synthesis in adult mice. The authors reported a hyperactive behavioral phenotype in adult 5-HT deficiency in both the home cage and novel environment. Also noted was an absence in the normal prolonged break in nocturnal activity, known as siestas and characterized by REM and non-REM sleep. These findings suggest an important role for central 5-HT status in governing activity levels, circadian rhythms, and sleep-wake homeostasis. These animal data accompany emerging evidence of a role of serotonin in human ADHD subjects. Mette et al. (2013) investigated the impact of acute tryptophan depletion (ATD) and the resulting central deficits on 5-HT synthesis on discrimination ability and attentional processes in adult patients with attention-deficit hyperactivity disorder (ADHD) using a double-blind within-subject crossover design. The authors reported that the patients experienced a greater number of omissions and reduced reaction times on a continuous performance test after ATD compared with the tryptophan-balanced control condition, offering preliminary support for a role of serotonergic neurotransmission in the facilitation of attentional deficits in adult ADHD patients. However, a recent report by Bergwerff et al. (2016) indicates a lack of aromatic amino acid (AAA), including tryptophan, deficiencies in children with chronic ADHD symptoms. These differences therefore warrant further inspection on the role of 5-HT in ADHD.

I have recently proposed through empirical methodology (Fluegge and Fluegge, 2016)] and subsequent review (Fluegge, 2016) that the main environmental agent driving increases in the rates of neurodevelopmental disorders like ADHD may be chronic exposure to the widespread and underappreciated air pollutant, nitrous oxide (N2O). In a toxicity study evaluating the effects of chronic, intermittent exposure to N2O in CD-1 mice, Abdul-Kareem et al. (1991) reported modulation of many central neurotransmitters, including 5-HT, norepinephrine, and dopamine. After two-week exposure, significant decreases in 5-HT were noted in the midbrain and cortex at all three doses used. Given the role of serotonergic transmission in respiratory physiology and apnea duration (Donnelly et al., 2016), it follows that low-dose N2O exposure may induce sleep apneas in human adults (Beydon et al., 1997), possibly through a modulation of serotonin efflux. While acute N2O exposure may depress serotonergic activity, significant increases in 5-HT were noted in hypothalamus, midbrain, and cortex after 13-week exposure at the highest dose, which may support the role of N2O as a monoamine oxidase inhibitor. This suggestion by Abdul-Kareem et al. (1991) of a “biphasic response” to N2O exposure is supported with recent clinical evidence indicating a 15% decrease in tryptophan concentration in patients exposed to N2O as part of routine surgery (Nunn et al., 1986), as well as the onset of serotonin syndrome which may have been triggered by a case of polypharmacy involving N2O administration (Volz et al., 2015).

These animal and human data indicate that central serotonergic deficits may be associated with a hyperactive phenotype characterized by disruption in circadian behavioral patterns. Exposure to environmental N2O may significantly modulate central serotonergic activity and disrupt circadian patterns, implicating environmental exposure to N2O as a possible etiological factor in ADHD and related comorbidity (Fluegge, 2016b). Since N2O modulation of serotonergic activity may be “biphasic” (Abdul-Kareem et al., 1991) in nature, it may reveal a competing endogenous feedback mechanism to counter the initial pro-depressant effects of N2O through its role as a MAO inhibitor mimetic after longer term exposure (i.e., 13 weeks) or in cases of polypharmacy. This biphasic serotonergic response to nontoxic doses of N2O supports the ongoing debate in the literature assessing the role of serotonin and its amino acid precursor in neuropsychiatric disorders, like ADHD (chronic versus acute). Therefore, more focus should be paid to environmental N2O as a possible etiologic factor in ADHD and related comorbidities, with a particular focus on the role of serotonergic system.

References

Abdul-Kareem HS, Sharma RP, Drown DB. (1991) Effects of repeated intermittent exposures to nitrous oxide on central neurotransmitters and hepatic methionine synthetase activity in CD-1 mice. Toxicol Ind Health. 7:97–108.

Bergwerff CE, Luman M, Blom HJ, Oosterlaan J. (2016) No Tryptophan, Tyrosine and Phenylalanine Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder. PLoS One. 11:e0151100. doi: 10.1371/journal.pone.0151100.

Beydon L, Goldenberg F, Heyer L, d'Ortho MP, Bonnet F, Harf A, Lofaso F. (1997) Sleep apnea-like syndrome induced by nitrous oxide inhalation in normal men. Respir Physiol. 108(3):215-24.

Donnelly WT, Bartlett D Jr, Leiter JC. (2016) Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats. Exp Physiol. 101(7):946-61. doi: 10.1113/EP085716.

Fluegge K & Fluegge K. (2016) Glyphosate use predicts healthcare utilization for ADHD in the Healthcare Cost and Utilization Project net (HCUPnet): A two-way fixed-effects analysis. Pol J Environ Stud. 25(4): 1489-1503, doi: 10.15244/pjoes/61742

Fluegge K. (2016a) Does environmental exposure to the greenhouse gas, N2O, contribute to etiological factors in neurodevelopmental disorders? A mini-review of the evidence. Environ Toxicol Pharmacol. 47:6-18, doi: 10.1016/j.etap.2016.08.013

Fluegge K. (2016b) A reply to Sleep characteristics in children with attention deficit hyperactivity disorder: systematic review and meta-analyses. J Clin Sleep Med. 12(6): 933, doi: 10.5664/jcsm.5912

Mette C, Zimmermann M, Grabemann M, et al. (2013) The impact of acute tryptophan depletion on attentional performance in adult patients with ADHD. Acta Psychiatr Scand. 128:124-32, doi: 10.1111/acps.12090.

Nunn JF, Sharer NM, Bottiglieri T, Rossiter J. (1986) Effect of short-term administration of nitrous oxide on plasma concentrations of methionine, tryptophan, phenylalanine and S-adenosyl methionine in man. Br J Anaesth. 58:1-10.

Volz LM, Muldowney BL, Trawicki MC. (2016) No laughing matter: nitrous oxide triggers serotonin syndrome in an anxious adolescent. J Clin Anesth. 32:27-8. doi: 10.1016/j.jclinane.2015.11.003.

Whitney MS, Shemery AM, Yaw AM, Donovan LJ, Glass JD, Deneris ES. (2016) Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci. 36(38):9828-42. doi: 10.1523/JNEUROSCI.1469-16.2016.