Affective disorders and the loudness dependence of the auditory evoked potential: Serotonin and beyond.

Identifying additional noninvasive biomarkers for affective disorders, such as unipolar major depressive disorder (MDD) and bipolar disorder (BD), could aid in the diagnosis and treatment of these prevalent and debilitating neuropsychiatric conditions. One such candidate biomarker is the loudness dependence of the auditory evoked potential (LDAEP), an event-related potential that measures responsiveness of the auditory cortex to different intensities of sound. The LDAEP has been associated with MDD and BD, including therapeutic response to particular classes of antidepressant drugs, while also correlating with several other neuropsychiatric disorders. It has been suggested that increased values of the LDAEP indicate low central serotonergic neurotransmission, further implicating this EEG measure in depression. Here, we briefly review the literature on the LDAEP in affective disorders, including its association with serotonergic signaling, as well as with that of other neurotransmitters such as dopamine. We summarize key findings on the LDAEP and the genetics of these neurotransmitters, as well as prediction of response to particular classes of antidepressants in MDD, including SSRIs versus noradrenergic agents. The possible relationship between this EEG measure and suicidality is addressed. We also briefly analyze acute pharmacologic studies of serotonin and/or dopamine precursor depletion and the LDAEP. In conclusion, the existing literature suggests that serotonin and norepinephrine may modulate the LDAEP in an opposing manner, and that this event-related marker may be of use in predicting response to chronic treatment with particular pharmacologic agents in the context of affective disorders, such as MDD and BD, including in the presence of suicidality.

Neural hyperexcitability in Angelman syndrome: Genetic factors and pharmacologic treatment approaches.

Angelman syndrome (AS) is a rare neurodevelopmental disorder that is typically caused by deletion or a loss-of-function mutation of the maternal copy of the ubiquitin ligase E3A (UBE3A) gene. The disorder is characterized by severe intellectual disability, deficits in speech, motor abnormalities, altered electroencephalography (EEG) activity, spontaneous epileptic seizures, sleep disturbances, and a happy demeanor with frequent laughter. Regarding electrophysiologic abnormalities in particular, enhanced delta oscillatory power and an elevated excitatory/inhibitory (E/I) ratio have been documented in AS, with E/I ratio especially studied in rodent models. These electrophysiologic characteristics appear to relate with the greatly elevated rates of epilepsy in individuals with AS, and associated hypersynchronous neural activity. Here we briefly review findings on EEG, E/I ratio, and epileptic seizures in AS, including data from rodent models of the disorder. We summarize pharmacologic approaches that have been used to treat behavioral aspects of AS, including neuropsychiatric phenomena and sleep disturbances, as well as seizures in the context of the disorder. Antidepressants such as SSRIs and atypical antipsychotics are among the medications that have been used behaviorally, whereas anticonvulsant drugs such as valproic acid and lamotrigine have frequently been used to control seizures in AS. We end by suggesting novel uses for some existing pharmacologic agents in AS, including noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists) and cholinesterase inhibitors, where these various classes of drugs may have the ability to ameliorate both behavioral disturbances and seizures.

Is There a Novel Biosynthetic Pathway in Mice That Converts Alcohol to Dopamine, Norepinephrine and Epinephrine?

Previous studies in animals and humans have shown multiple types of interaction between alcohol (ethanol) intake and the catecholamine signaling molecules: dopamine, norepinephrine and epinephrine. This literature suggests that the administration of alcohol to rodents affects the central and peripheral (blood plasma) levels of these catecholamines. Two prior publications (Fitzgerald 2012, 2020) put forth the hypothesis that there may be a currently unidentified biosynthetic pathway, in a range of organisms, that actually converts alcohol to dopamine, norepinephrine and epinephrine. This publication describes the details for how to test this hypothesis in mice. Mice can be systemically injected with an intoxicating dose of commercially available stable isotope-labeled ethanol (ethanol-1-13C), and blood plasma samples and brains can be collected approximately two to 24 h post-injection. Liquid chromatography-mass spectrometry analysis can then be used to test whether some of the labeled ethanol molecules have been incorporated into new dopamine, norepinephrine, and epinephrine molecules, in plasma and brain samples. If confirmed, this hypothesis may have broadly reaching implications both for basic neuroscience and our understanding of alcohol abuse and alcoholism.

Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo.

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

Major depressive disorder (MDD) remains a significant public health problem worldwide, and revised treatment strategies are therefore urgently needed, including the creation of novel antidepressant compounds or using existing molecular entities in new ways. Etiologic theories of MDD from decades ago have suggested that synaptic deficiencies of monoaminergic neurotransmitters play a causative role in this neuropsychiatric disorder, and that boosting monoamines with drugs such as SSRIs, SNRIs, TCAs, and MAOIs has antidepressant effects and in some individuals can even induce hypomania or mania. While other factors, such as various intracellular molecular pathways and hippocampal neurogenesis, undoubtedly also play a role in MDD, monoaminergic boosting drugs nonetheless have clearly demonstrated antidepressant properties. There is also, however, a body of studies in the preclinical literature suggesting that monoaminergic transmission reducing drugs, including noradrenergic ones, also have antidepressant-like behavioral properties in rodents. Given that there is increasing evidence that the monoamines have u-shaped or Janus-faced dose-response properties, in which a mid-range value is "optimal" in a variety of behavioral and physiological processes, it is plausible that either too much or too little synaptic norepinephrine in key circuits may exacerbate MDD in some individuals. Here we briefly review rodent depression-related behavioral data, focusing on the forced swim test, from three major classes of noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists), and find much support for the hypothesis that they have antidepressant-like properties. Whether these drugs are antidepressants in human subjects remains to be determined.

Norepinephrine May Oppose Other Neuromodulators to Impact Alzheimer's Disease.

While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer's disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological "balance" between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.

An electrophysiological model of major depression: Relevance to clinical subtyping and pharmacological management.

We present a neurochemical model of unipolar major depressive disorder that makes predictions for optimizing pharmacological treatment of this debilitating neuropsychiatric disorder. We suggest that there are two principal electrophysiological subtypes of depression, with the more common one involving a high excitatory/inhibitory (E/I) electrophysiological ratio, and a less common low E/I subtype. The high E/I subtype is paradoxically a variant of previous conceptions of atypical depression, whereas the low E/I subtype is a variant of melancholic depression. We focus on the ratio of norepinephrine (NE) to serotonin (5HT) as primary determinants of E/I ratio, which have opposing effects on mood regulation. We suggest that high NE/5HT (or E/I) ratio depressions should be treated with pharmacological agents that boost 5HT (such as SSRIs) and/or drugs that reduce noradrenergic transmission (such as clonidine, guanfacine, propranolol, prazosin). In contrast, low NE/5HT (or E/I) depressions should be treated with agents that boost NE (such as most tricyclics) and/or drugs that reduce serotonergic transmission. Our model predicts that the rapidly acting antidepressant ketamine (and possibly scopolamine), which has an acutely excitatory electrophysiological profile that may be followed by sustained increased inhibition, should improve the high NE/5HT subtype and worsen the low subtype.

Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

The anesthetic drug ketamine has been successfully repurposed as an antidepressant in human subjects. This represents a breakthrough for clinical psychopharmacology, because unlike monoaminergic antidepressants, ketamine has rapid onset, including in Major Depressive Disorder (MDD) that is resistant to conventional pharmacotherapy. This rapid therapeutic onset suggests a unique mechanism of action, which continues to be investigated in reverse translational studies in rodents. A large fraction of rodent and human studies of ketamine have focused on the effects of only a single administration of ketamine, which presents a problem because MDD is typically a persistent illness that may require ongoing treatment with this drug to prevent relapse. Here we review behavioral studies in rodents that used repeated dosing of ketamine in the forced swim test (FST), with an eye toward eventual mechanistic studies. A subset of these studies carried out additional experiments with only a single injection of ketamine for comparison, and several studies used chronic psychosocial stress, where stress is a known causative factor in some cases of MDD. We find that repeated ketamine can in some cases paradoxically produce increases in immobility in the FST, especially at high doses such as 50 or 100 mg/kg. Several studies however provide evidence that repeated dosing is more effective than a single dose at decreasing immobility, including behavioral effects that last longer. Collectively, this growing literature suggests that repeated dosing of ketamine has prominent depression-related effects in rodents, and further investigation may help optimize the use of this drug in humans experiencing MDD.

Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test.

There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.

Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.

The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test.

Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention. Furthermore, the classically engaged monoaminergic neurotransmitter systems in depression treatment-serotonin, norepinephrine, and dopamine-interact directly at times with cholinergic signaling. Here we investigate in greater detail how the cholinergic system may impact depression-related behavior, by administering widely ranging doses of the cholinesterase inhibitor drug, donepezil, to C57BL/6J mice in the forced swim test. First, we confirm prior findings that this drug, which is thought to boost synaptic acetylcholine, promotes depression-like behavior at a high dose (2.0 mg/kg, i.p.). But we also find paradoxically that it has an antidepressant-like effect at lower doses (0.02 and 0.2 mg/kg). Further this antidepressant-like effect is not due to generalized hyperactivity, since we did not observe increased locomotor activity in the open field test. These data support a novel antidepressant-like role for donepezil at lower doses as part of an overall u-shaped dose-response curve. This raises the possibility that donepezil could have antidepressant properties in humans suffering from MDD.

Serious infection may systemically increase noradrenergic signaling and produce psychological effects.

Serious infection elicits inflammatory processes that act through a range of molecular pathways, including cytokine signaling. It is not established however that noradrenaline (NA), a widely distributed neurotransmitter in the brain that is also a principal output molecule of the sympathetic nervous system, can produce psychological effects associated with infection. This paper puts forth the hypothesis that through neural-immune crosstalk, serious infection increases noradrenergic signaling, both in the central nervous system and in peripheral organs. In this manner, elevated noradrenergic transmission may help produce basic symptoms of infection such as fever, fatigue, aches and pains (including headache), nausea, and loss of appetite. NA may also promote cognitive impairment, major depression, unipolar mania, and even epileptic seizures in some cases. The paper focuses on three major types of infection: influenza (viral), tuberculosis (bacterial), malaria (parasitic), while also summarizing the potential relationship between NA and human immunodeficiency virus (HIV) infection. Four lines of evidence are used to test association between NA and influenza, tuberculosis, and malaria: direct measures of NA and its metabolites; and incidence of hypertension, bipolar mania, and epileptic seizures, since the latter three conditions may be associated with elevated NA. In addition, heart rate variability data are examined with respect to a number of infectious diseases, since those data provide information on sympathetic nervous system activity. While the data do not unequivocally support elevated noradrenergic signaling promoting psychological symptomatology with infection, many studies are consistent with this view.

Neurodining: Common dietary factors may be substrates in novel biosynthetic pathways for monoaminergic neurotransmitters.

It is not established that there are multiple endogenous mechanisms for synthesizing each of the three major monoamine neurotransmitters: serotonin, norepinephrine, and dopamine. Having multiple biosynthetic pathways for each of these important signaling molecules would provide greater assurance that they are available in sufficient quantities for their various physiological roles in the body. This paper puts forth the hypothesis that a number of common dietary factors-including sucrose and glucose, fats, plant components, and even ethanol-are substrates in novel biosynthetic pathways for the monoamines. A major aspect of this hypothesis is that in a range of multicellular organisms, D-glucose in particular may participate in novel biosynthetic pathways for the monoamines, where this sugar has already been linked with synthesis of the neurotransmitters acetylcholine, glutamate, and GABA through the tricarboxylic acid cycle. Another major aspect of the hypothesis is that phenol or polyphenol molecules, found in various plants, may combine with particular fats or even ethanol to form dopamine, which can then be converted to norepinephrine through the already established step involving the enzyme dopamine beta-hydroxylase. If such a biosynthetic pathway exists for converting ethanol to dopamine in humans, it could be a major factor in substance abuse, including early onset alcoholism. Further, if the above biosynthetic pathways exist in a range of organisms, they may be associated with appetitive processes regulating consumption of particular dietary factors, such as fruits and vegetables, to maintain internal "set points" of, for example, elevated noradrenergic signaling. In this scenario, exposure to psychological stress, which could eventually deplete neurotransmitters such as norepinephrine, may result in craving for sucrose, fats, or alcohol to help replenish the depleted cellular levels of this signaling molecule. An alternative to the overall biosynthetic hypothesis put forth here is that animal cells do not possess these pathways, but the animal microbiome harbors bacteria that do carry out these reactions and helps supply the body with monoamines and other signaling molecules.

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.

Rodent ketamine depression-related research: Finding patterns in a literature of variability.

Discovering that the anesthetic drug ketamine has rapidly acting antidepressant effects in many individuals with major depression is one of the most important findings in clinical psychopharmacology in recent decades. The initial report of these effects in human subjects was based on a foundation of rodent preclinical studies carried out in the 1990s, and subsequent investigation has included both further studies in individuals with depression, as well as reverse translational experiments in animal models, especially rodents. While there is general agreement in the rodent literature that ketamine has rapidly-acting, and generally sustained, antidepressant-like properties, there are also points of contention across studies, including the precise mechanism of action of this drug. In this review, we briefly summarize prominent yet variable findings regarding the mechanism of action. We also discuss a combination of similarities and variances in the rodent literature in the antidepressant-like effects of ketamine as a function of dose, species and strain, test, stressor, and presumably sex of the experimenter. We then present previously unpublished mouse strain comparison data suggesting that subanesthetic ketamine does not have robust antidepressant-like properties in unstressed animals, and may actually promote depression-like behavior, in contrast to widely reported findings. We conclude that the data best support the notion of ketamine action principally via NMDA receptor antagonism, transiently boosting glutamatergic (and possibly other) signaling in diverse brain circuits. We also suggest that future studies should address in greater detail the extent to which antidepressant-like properties of this drug are stress-sensitive, in an effort to better model major depression present in humans.

In vivo electrophysiological recordings of the effects of antidepressant drugs.

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.