Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

Rationale: Serotonin (5-Hydroxytryptamine, 5- HT) receptors play an important role in perception, affect regulation and attention. Pharmacological challenge with the 5-HT2A agonist psilocybin (PY) is useful in studying the neurobiological basis of cognition and consciousness. Objective: Investigation of dose-dependent effects of PY on psycho(patho)logical and physiological parameters. Methods: Eight subjects received placebo (PL), and 45 ("very low dose, VLD"), 115 ("low dose, LD"), 215 ("medium dose, MD"), and 315 ("high dose, HD") mg/kg body weight PY. The "Altered States of Consciousness Rating Scale" (5D-ASC), the "Frankfurt Attention Inven- tory" (FAIR), and the "Adjective Mood Rating Scale" (AMRS) were used to assess the effects of PY on psy- cho(patho)logical core dimensions, attention, and mood. A 24-h electrocardiogram (EKG) was recorded and blood pressure was measured. Plasma concentrations of thyroid- stimulating hormone (TSH), prolactin (PRL), cortisol (CORT), adrenocorticotropic hormone (ACTH), and stan- dard clinical chemical parameters were determined. Re- sults: PY dose dependently increased scores of all 5D-ASC core dimensions. Only one subject reacted with transient anxiety to HD PY. Compared with PL, MD and HD PY led to a 50% reduction of performance in the FAIR test. "General inactivation", "emotional excitability", and "dreaminess" were the only domains of the AMRS showing increased scores following MD and HD PY. The mean arterial blood pressure (MAP) was moderately elevated only 60 min following administration of HD PY. Neither EKG nor body temperature was affected by any dose of PY. TSH, ACTH, and CORT plasma levels were elevated during peak effects of HD PY, whereas PRL plasma levels were increased following MD and HD PY. Conclusion: PY affects core dimensions of altered states of consciousness and physiological parameters in a dose-de- pendent manner. Our study provided no cause for concern that PY is hazardous with respect to somatic health.

/pdf/acute-psychological-and-physiological-effects-of-psilocybin-4jqwv06qj0.pdf

Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose?effect study

Background Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have reported evidence that inflammation and release of inflammatory cytokines affect circuitry relevant to both reward and threat sensitivity to contribute to behavioral change. Of relevance to mood and anxiety-related disorders, biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of patients with major depressive disorder (MDD), bipolar disorder, anxiety disorders and post-traumatic stress disorder (PTSD). Methods This review summarized clinical and translational work demonstrating the impact of peripheral inflammation on brain regions and neurotransmitter systems relevant to both reward and threat sensitivity, with a focus on neuroimaging studies involving administration of inflammatory stimuli. Recent translation of these findings to further understand the role of inflammation in mood and anxiety-related disorders is also discussed. Results Inflammation was consistently found to affect basal ganglia and cortical reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including amygdala, insula and anterior cingulate cortex, which may result from cytokine effects on monoamines and glutamate. Similar relationships between inflammation and altered neurocircuitry have been observed in MDD patients with increased peripheral inflammatory markers, and such work is on the horizon for anxiety disorders and PTSD. Conclusion Neuroimaging effects of inflammation on reward and threat circuitry may be used as biomarkers of inflammation for future development of novel therapeutic strategies to better treat mood and anxiety-related disorders in patients with high inflammation.

Imaging the Role of Inflammation in Mood and Anxiety-related Disorders

Context Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. Objectives To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. Design Cross-sectional and longitudinal studies. Setting Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. Patients Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. Main Outcome Measures Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa–induced depression, anhedonia, fatigue, and neurotoxicity. Results Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. Conclusions These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/1370458/yoa110072_1044_1053.pdf

Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward During Interferon Alfa Administration

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine.

Regional changes occur in the sympathetic innervation of the heart after myocardial infarction (MI), including loss of norepinephrine (NE) uptake and depletion of neuronal NE. This apparent denervation is accompanied by increased cardiac NE spillover. One potential explanation for these apparently contradictory findings is that the sympathetic neurons innervating the heart are exposed to environmental stimuli that alter neuronal function. To understand the changes that occur in the innervation of the heart after MI, immunohistochemical, biochemical, and molecular analyses were carried out in the heart and stellate ganglia of control and MI rats. Immunohistochemistry with panneuronal markers revealed extensive denervation in the left ventricle (LV) below the infarct, but sympathetic nerve fibers were retained in the base of the heart. Western blot analysis revealed that tyrosine hydroxylase (TH) expression (normalized to a panneuronal marker) was increased significantly in the base of the heart and in the stellate ganglia but decreased in the LV below the MI. NE transporter (NET) binding sites, normalized to total protein, were unchanged, except in the LV, where [3H]nisoxetine binding was decreased. TH mRNA was increased significantly in the left and right stellate ganglia after MI, while NET mRNA was not. In the base of the heart, increased TH coupled with no change in NET may explain the increase in extracellular NE observed after MI. Coupled with substantial denervation in the LV, these changes likely contribute to the onset of cardiac arrhythmias.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00768.2003

Infarction alters both the distribution and noradrenergic properties of cardiac sympathetic neurons

Although the sympathetic neurons innervating the heart are exposed to the inflammatory cytokines cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) after myocardial infarction, the effects of these cytokines on noradrenergic function are not well understood. We used cultured sympathetic neurons to investigate the effects of these cytokines on catecholamine content, the tyrosine hydroxylase co-factor, tetrahydrobiopterin (BH4), and norepinephrine (NE) uptake. CT-1, but not IL-6 or TNFalpha, suppressed NE uptake and catecholamines in these neurons, whereas CT-1 and, to a lesser extent, IL-6 decreased BH4 content. CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. The neurons innervating the heart are also activated by the central nervous system after myocardial infarction. We examined the combined effect of depolarization and cytokines on noradrenergic function. In CT-1-treated cells, depolarization caused a small increase in BH4 and NE uptake, and a large increase in catecholamines. These changes were accompanied by increased TH, GCH and NE transporter mRNAs. CT-1 and depolarization regulate expression of noradrenergic properties in an opposing manner, and the combined treatment results in elevated cellular catecholamines and decreased NE uptake relative to control cells.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2003.01890.x

Regulation of noradrenergic function by inflammatory cytokines and depolarization

During development, sympathetic neurons innervating rodent sweat glands undergo a target-induced change in neurotransmitter phenotype from noradrenergic to cholinergic. Although the sweat gland innervation in the adult mouse is cholinergic and catecholamines are absent, these neurons continue to express tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. The developmental suppression of noradrenergic function in these mouse sympathetic neurons is not well understood. We investigated whether the downregulation of the enzyme aromatic l-amino acid decarboxylase (AADC) or the TH cofactor tetrahydrobiopterin (BH4) could account for the loss of catecholamines in these neurons. AADC levels did not decrease during development, and adult cholinergic sympathetic neurons were strongly immunoreactive for AADC. In contrast, BH4 levels dropped significantly in murine sweat gland-containing footpads during the time period when the gland innervation was switching from making norepinephrine to acetylcholine. Immunoreactivity for the rate-limiting BH4 synthetic enzyme GTP cyclohydrolase (GCH) became undetectable in the sweat gland neurons during this phenotypic conversion, suggesting that sweat glands reduce BH4 levels by suppressing GCH expression during development. Furthermore, extracts from sweat gland-containing footpads suppressed BH4 in cultured mouse sympathetic neurons, and addition of the BH4 precursor sepiapterin rescued catecholamine production in neurons treated with footpad extracts. Together, these results suggest that the mouse sweat gland-derived cholinergic differentiation factor functionally suppresses the noradrenergic phenotype during development by inhibiting production of the TH cofactor, BH4. These data also indicate that GCH expression, which is often coordinately regulated with TH expression, can be controlled independently of TH during development.

https://www.jneurosci.org/content/jneuro/22/21/9445.full.pdf

Developmental Regulation of Neurotransmitter Phenotype through Tetrahydrobiopterin

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Infarction alters both the distribution and noradrenergic properties of cardiac sympathetic neurons

Regulation of noradrenergic function by inflammatory cytokines and depolarization

Developmental Regulation of Neurotransmitter Phenotype through Tetrahydrobiopterin