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There appear to be huge variations and aberrations in the reported data in COVID-19 2 years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases, and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

Long COVID refers to the lingering symptoms which persist or appear after the acute illness. The dominant long COVID symptoms in the two years since the pandemic began (2020-2021) have been depression, anxiety, fatigue, concentration and cognitive impairments with few reports of psychosis. Whether other symptoms will appear later on is not yet known. For example, dopamine-dependent movement disorders generally take many years before first symptoms are seen. Post-stroke depression and anxiety may explain many of the early long COVID cases. Hemorrhagic, hypoxic and inflammatory damages of the central nervous system, unresolved systematic inflammation, metabolic impairment, cerebral vascular accidents such as stroke, hypoxia from pulmonary damages and fibrotic changes are among the major causes of long COVID. Glucose metabolic and hypoxic brain issues likely predispose subjects with pre-existing diabetes, cardiovascular or lung problems to long COVID as well. Preliminary data suggest that psychotropic medications may not be a danger but could instead be beneficial in combating COVID-19 infection. The same is true for diabetes medications such as metformin. Thus, a focus on sigma-1 receptor ligands and glucose metabolism is expected to be useful for new drug development as well as the repurposing of current drugs. The reported protective effects of psychotropics and antihistamines against COVID-19, the earlier reports of reduced number of sigma-1 receptors in post-mortem schizophrenic brains, with many antidepressant and antipsychotic drugs being antihistamines with significant affinity for the sigma-1 receptor, support the role of sigma and histamine receptors in neuroinflammation and viral infections. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

Prevention of deterioration of brain function over time is important in the long-term management of chronic brain disorders such as dementia, schizophrenia, and mood disorders. Although the possibility of neurogenesis in the adult human brain is attractive, and there are psychiatric drugs proven to be effective inducers of neurogenesis in animals, we have yet to see their utility in clinical practice. The terms neurodegeneration and neuroregeneration are often used in a nonspecific manner. Neuroregeneration may mean neurogenesis, dendritogenesis, spinogenesis, or axonogenesis. The term "neuroprotection" is attractive clinically and may involve different mechanisms. Many causative and protective factors of neurodegeneration and neuroregeneration have been proposed. However, the specificity of these factors and agents and differential neuronal vulnerability factors have generally been ignored in past studies. It is also hard to separate disease-modifying from "neuroprotective" effects of a drug. The application of stringent long-term neuroanatomical, neurochemical, neurophysiological, and therapeutic efficacy criteria should improve future research in this important area., (© 2017 S. Karger AG, Basel.)

Objective: The literature has shown that cognitive and emotional changes may occur after chronic treatment with glucocorticoids. This might be caused by the suppressive effect of glucocorticoids on hippocampal neurogenesis and cell proliferation. Paroxetine, a selective serotonin reuptake transporter, is a commonly used antidepressant for alleviation of signs and symptoms of clinical depression. It was discovered to promote hippocampal neurogenesis in the past few years and we wanted to investigate its interaction with glucocorticoid in this study., Methods: Adult rats were given vehicle, corticosterone, paroxetine, or both corticosterone and paroxetine for 14 d. Cell proliferation in the dentate gyrus was quantified using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry., Results: The corticosterone treatment suppressed while paroxetine treatment increased hippocampal cell proliferation. More importantly, paroxetine treatment could reverse the suppressive effect of corticosterone on hippocampal cell proliferation., Conclusion: This may have clinic application in preventing hippocampal damage after glucocorticoid treatment.

Purpose: Major depressive disorder is often associated with elevated glucocorticoid levels, which in turn suppress cell proliferation and neurogenesis in the hippocampus. Increasing evidence supports that antidepressants induce hippocampal neurogenesis and this induces speculation that decrease in hippocampal neurogenesis has causal relationship with depression. There is, however, a lack of information about neurogenic effects of antidepressants on the subventricular zone, which is another CNS region with continuous neurogenesis throughout adulthood. In the present study, we investigated whether corticosterone and the SSRI paroxetine, have effects on SVZ cell proliferation., Methods: Rats were treated with the corresponding drugs for 14 days and the proliferating cells were labeled with bromodeoxyuridine (BrdU). BrdU labeled cells in the SVZ were quantified and analyzed., Results: In the corticosterone-treatment group, cell proliferation was decreased by 18% compared to vehicle-treatment group. Paroxetine-treatment group, in contrast, shows a 34% increase in cell proliferation. The decreased cell proliferation caused by corticosterone was prevented by paroxetine., Conclusions: Although corticosterone and antidepressants were found to affect cell proliferation in hippocampus, this is the first report to demonstrate that 1) corticosterone decreases cell proliferation in SVZ; 2) paroxetine promotes SVZ cell proliferation and 3) the suppressive effect on SVZ cell proliferation by corticosterone could be attenuated by paroxetine. These findings provide new insights into basic mechanisms of antidepressants, potential impact of steroid therapy on CNS neurogenesis, antidepressant mechanisms of action and potential involvement of the olfactory system in depression.

Initial investigations on dopamine D4 receptors generated much interest in the role of this receptor in schizophrenia and other aspects of human behavior, as well as new opportunities for novel therapeutics. However, attempts to treat patients suffering from schizophrenia with dopamine D4 agents have failed to yield satisfactory results so far. An examination of the dopamine D4 literature shows that contrasting and conflicting data seemed to be the norm in this field of research. This paper reviews the literature on the dopamine D4 receptor and discusses many of the associated methodological problems that might have contributed to the paradoxical findings.

1-Benzyl-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-amino-piperidine ([3H]U-101958), a dopamine D4 receptor ligand, was found to bind to a large sigma1 receptor-like component in human cerebellum and SK-N-MC neuroblastoma cells with high affinity (2-4 nM Kd). By contrast, binding to dopamine D4 receptors represented 10% or less of the sigma1 receptor-like site. Considering that U-101958 has been characterized as either a dopamine D4 receptor agonist or antagonist, depending on the system under study, the observation that U-101958 also binds to sigma1 receptor-like sites is important for accurate interpretation of the pharmacological actions of this compound. [3H]U-101958 may be a useful radioligand for sigma1 rather than dopamine D4 receptor sites.

Calcium abnormalities are some of the more consistent findings in platelets of affective disorder patients. While medication status does not correlate with this finding, antidepressants do modulate intracellular calcium. This, in combination with reports that calcium channel inhibitors may have antidepressant potential, suggests that calcium may play an important role in this disorder. This paper reviews the specificity of calcium abnormalities for the affective disorders and also discusses possible mechanisms of action.

Serotonin uptake in human platelets was inhibited by cytochrome P450 inhibitors such as miconazole and econazole but not clotrimazole. There was a correlation between inhibition of serotonin uptake and inhibition of imipramine binding, suggesting that these P450 inhibitors may inhibit serotonin uptake via direct binding to the transporter. P450 inhibitor effects on serotonin uptake did not seem to be related to the effects of these compounds on intracellular calcium mobilization. Additionally, nitric oxide pathway stimulation does not appear to be involved.

The difference between the binding of [3H]nemonapride and [3H]raclopride has been used to quantify dopamine D4 receptors in postmortem schizophrenic brain studies. Recent work, however, has suggested that at least part of the differential between [3H]nemonapride and [3H]raclopride binding may represent sigma rather than D4 receptor sites. We applied the nemonapride-raclopride subtraction method to postmortem, non-schizophrenic human striatum to examine the variation in dopaminergic receptor binding labeled by these ligands. Variation in sigma receptor binding labeled by [3H]nemonapride was studied in frontal cortex, striatum and cerebellum. Specific binding was defined by sulpiride (dopamine receptor ligand), PPAP (sigma receptor ligand) and haloperidol (mixed dopaminergic/sigma agent), respectively. Haloperidol defined a combination of sites, which were approximately the sum of the dopaminergic and sigma components defined by sulpiride and PPAP, respectively. Significant inter-individual variation in the amount of specific binding for dopaminergic and sigma receptor sites was observed. However, no significant nor consistent observation of striatal dopamine D4 receptors or D4-like binding sites was observed in the striatum even though two independent sets of tissues, with different dissections were used. The inconsistencies in some previous postmortem studies appear to be at least partially explained by the inclusion of both sigma and dopaminergic components in [3H]nemonapride binding and the inherent high inter-individual variability of the different components.

[3H]-Nemonapride has been the ligand of choice to label D4 dopamine receptors. Its specificity was questioned when it was discovered that sigma (sigma) sites were also labeled by [3H]-nemonapride. To further characterize the binding of [3H]-nemonapride, three areas of calf brain (striatum, frontal cortex and cerebellum) were examined. In all three areas, [3H]-nemonapride labeled multiple sites. Dopaminergic and sigma sites were the most prominent. The sigma binding profile was sigma-1 like with a Ki binding profile as follows (in order of decreasing potency): haloperidol, PPAP, pentazocine, DTG, U-50488, R(+)-3-PPP. Experiments using sulpiride and pentazocine to block striatal dopaminergic and sigma sites, respectively, revealed additional, not previously characterized binding sites for [3H]-nemonapride. One component which was present in striatum but not in frontal cortex or cerebellum, had affinity for some neuroleptics and WB-4101, but not for typical serotonergic agents. Thus, [3H]-nemonapride has no selectivity for dopamine receptors unless stringent experimental conditions are met.

[3H]Nemonapride differentially defines sigma and dopamine receptor sites depending upon assay conditions. In post-mortem schizophrenic brain tissues, [3H]nemonapride-labeled sigma receptor binding is decreased compared to match normal controls. No striatal dopamine D4/D4-like receptor differential was observed between the schizophrenic or control tissues, using the [3H]nemonapride minus [3H]raclopride subtraction method.

Uptake of tritiated serotonin into human platelets was found to be rapidly inhibited by the tyrosine kinase inhibitors, genistein and methyl 2,5-dihydroxycinnamate. Binding studies indicated that uptake inhibition did not correlate with direct binding of these inhibitors to the transporter. Chelation of mobilizable intracellular Ca2+ did not inhibit the effects of genistein on uptake. These results suggest a more direct, non-Ca2+ mediated effect of tyrosine kinase inhibitors on uptake.

The serotonin uptake inhibitors sertraline, paroxetine and fluoxetine were compared with imipramine and the calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) and calmidazolium, for their effects on intracellular Ca2+ mobilization in human platelets. All serotonin uptake inhibitors and calmodulin antagonists augmented thrombin-mediated increases in intracellular Ca2+. Sertraline, calmidazolium and W-7 also caused large dose-dependent increases in baseline levels of intracellular Ca2+. There was a rough correlation between the ability to elevate intracellular Ca2+ and potencies for inhibition of calmodulin. Neomycin, an inhibitor of inositol trisphosphate (IP3) generation, significantly inhibited the effects of sertaline. This is consistent with a role of IP3 and calmodulin in the effects of these drugs.

Effects of kinase inhibitors and activators on the binding of tritiated imipramine and inhibition of serotonin uptake were tested in platelets. The majority of compounds inhibited specific [3H]imipramine binding and serotonin uptake with affinities similar to those reported for their action on protein kinases themselves. Many of these compounds are derivatives with modified naphthalenesulfonamide or isoquinolinesulfonamide structures, which appear to compete directly with imipramine for binding to the serotonin transporter. This is of great importance for studies involving kinase regulation since at these concentrations, the inhibitors and activators were previously thought to interact virtually exclusively with protein kinases.

Lectin affinity chromatography was used to demonstrate the glycoprotein nature of the serotonin (5-HT) transporter. The human platelet transporter protein was solubilized with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), labelled with [3H]cyanoimipramine and chromatographed on lectin columns. Wheat germ, gorse seed and lentil lectin-agarose columns specifically retained 5-HT transporter. Peanut and horse gram lectins were ineffective. Concanavalin A showed high non-specific adsorption. Binding of [3H]imipramine to platelet membranes or solubilized 5-HT transporter was not affected by lectins. These data suggest that the lectin interaction with 5-HT transporter is extrinsic to the antidepressant binding site.

The antidepressants mianserin and amoxapine, and the neuroleptic loxapine caused significant decreases in the number of rat frontal cortex S2-serotonergic receptors after a single acute injection. The affinity of serotonin for this site was also decreased after acute mianserin. Daily injections of loxapine and amoxapine for 2, 7 or 28 days resulted in decreased receptor density but no change in Kd. Down-regulation of S2 sites by mianserin was not dependent on endogenous serotonin stores or occupation of the S2 recognition site since chronic PCPA or acute ketanserin preadministration did not affect the mianserin-induced decreases. The results suggest that mianserin may be acting on other sites which it does not share in common with other S2-antagonists such as ketanserin.

In order to examine the potential relation between behaviour elicited by apomorphine and the density of catecholamine receptors, we studied stereotypy and the binding of [3H]spiperone to D2-(or neuroleptic/dopamine) receptors, of [3H]WB-4101 to alpha1-adrenoceptors, and [3H]clonidine to alpha2-adrenoceptors in two strains of rats. The F344 rats exhibited significantly more stereotypy to apomorphine than the Buffalo strain of rats. Other F344 rats which did not receive apomorphine and 34% more D2-receptors in the striatum and 50% more D2-receptors in the olfactory tubercle. Alpha2-Receptors in the frontal cortex were 20% higher in F344 rats when compared to the Buffalo strain, while alpha 1-receptors were the same across both strains. These results suggest a relation between D2-dopamine/neuroleptic receptor density and behavioural responsiveness to the direct-acting and specific dopamine agonist, apomorphine.

Opioid receptors have been solubilized from human striatal and rat whole-brain membranes by use of 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). Tritiated human beta-endorphin (3H-beta h-EP) binding revealed high-affinity competition by morphine, naloxone, and various beta-EP analogues, suggesting predominantly mu-type binding. Lack of high-affinity competition by (+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneaceta mide methanesulfonate (U50-488, Upjohn) indicated that kappa sites were not labeled by 3H-beta h-EP under these conditions. Affinities were similar in both soluble and membrane preparations except for [Met]enkephalin, which appears to be rapidly degraded by the solubilized extract. Size differences between human and rat solubilized 3H-beta h-EP-receptor complexes were revealed by exclusion chromatography.

Two inbred strains of rats (F344 and Buffalo) were tested for differences in spontaneous and apomorphine-induced inhibition of locomotor activity. F344 rats showed greater percentage decreases in locomotion after apomorphine (0.25, 1.0 and 2.5 mg/kg) compared to the Buffalo strain. F344 rats also showed higher levels and slower habituation of spontaneous locomotor activity. F344 rats had previously been shown to have significantly higher densities of D2-dopamine receptors in the striatum and olfactory tubercle and also more apomorphine-induced stereotypy when compared to Buffalo rats. These results confirm and extend previous studies suggesting that genetic differences in brain D2-dopamine receptors can predict behavioral differences in locomotor activity.

Two analogs of human beta-endorphin (beta-EP) which contain cystine bridges, [Cys15-Cys26,Phe27,Gly31]-beta-EP (I) and [Cys16-Cys26,Phe27,Gly31]-beta-EP (II), were synthesized by the solid-phase method. Peptides I and II were shown to contain 2-2.5 times the opiate receptor binding activity of beta-endorphin. We also synthesized two analogs with reduced alkylated cysteine residues and these peptides, [Arg9,19,24,28,29 Cys(Cam)11,26,Phe27,Gly31] and [Arg9,19,24,28,29,Cys-(Cam)12,26,Phe27,Gly31], were shown to have approximately the same opiate receptor activity as beta-endorphin.

The relationship between brain D2 dopamine receptors and locomotor response to amphetamine was investigated in eight strains of mice. The D2 receptor is defined as that dopaminergic site with high affinity (nanomolar) for neuroleptics and low affinity (micromolar) for agonists. D2 receptors were measured in the striatum and olfactory tubercle using [3H]spiperone and 10 microM sulpiride to define specific binding. Four inbred strains of mice (CBA/J; C57BL/6J; DBA/2J; SEC/1ReJ) had low receptor densities of about 380 and 160 fmoles/mg protein in the striatum and olfactory tubercle, respectively; all these mice were essentially nonresponsive (i.e., locomotion) to low doses of amphetamine (0.5 and 1.0 mg/kg i.p.) or showed hyperlocomotion to high doses (5 mg/kg). Three other mouse strains (BALB/cJ; A/J; C3H/HeJ) had higher densities of about 600 and 230 fmoles/mg protein in the striatum and olfactory tubercle, respectively, and these mice all responded with hypolocomotion to the low doses and hyperlocomotion to the high dose of amphetamine. The two genetically different populations, one of which responded to amphetamine with hypolocomotion while the other did not, are analogous to hyperactive children, only 70% of whom respond to amphetamine-like drugs. Thus, the mice with high receptor density may serve as a model for studying the hyperactivity syndrome which may be associated with dopaminergic dysfunction.

The effects of some antidepressants on brain total 3-methoxy-4-hydroxyphenylglycol (MHPG) were studied in the rat. Desipramine decreased and mianserine increased the brain total MHPG concentration while the other antidepressants had no effect. They were also the only antidepressants that attenuated the lowering action of clonidine on brain total MHPG, but possibly through different mechanisms. Two tertiary amine tricyclic antidepressants, amitriptyline and imipramine, appeared to enhance the lowering action of clonidine on brain total MHPG. The results suggest that antidepressants are heterogeneous in their action on brain noradrenergic mechanisms in the rat.

Mianserin stereoselectively decreases rat cortical S2 binding, the (+)enantiomer having higher potency. This and other data suggest that an alpha-2 receptor is unlikely to contribute to the mechanism of rapid S2 down-regulation by mianserin. Yohimbine, an alpha-2 antagonist which enhances desipramine-induced S2 decreases, was not dependent on NE or 5-HT release for its effect. Depletion of NE by 75% or 5-HT by 94% did not alter the ability of yohimbine and desipramine to decrease binding. These results raise previously unsuspected mechanisms involved in acute down-regulation of S2 binding by mianserin and yohimbine.

Characterization of temperature-sensitive [3H]serotonin (5-HT) binding sites (1 and 4 nM Kd sites) revealed complex inhibition by neuroleptics and serotonin antagonists. There was no simple correlation with affinities for S1 and S2 receptors. In vivo pretreatment (48 h before) with mianserin did not alter Bmax or Kd for the 1 nM Kd [3H]5-HT site, although [3H]ketanserin (S2) densities were decreased by 50%. This suggested that possible S2 components of [3H]5-HT binding must be negligeable, even though ketanserin competed with high affinity (IC50 = 3 nM) for a portion of the 1 nM Kd [3H]5-HT site. Low concentrations of mianserin inhibited the 1 nM Kd [3H]5-HT site in a non-competitive manner, as shown by a decrease in Bmax with no change in Kd after in vitro incubation. The complex inhibition data may therefore represent indirect interactions through another site.

The effect of clonidine withdrawal on the brain norepinephrine system was studied in the rat. Clonidine suppresses brain total 3-methoxy-4-hydroxyphenylglycol (MHPG) significantly and no tolerance to this effect was observed up to 21 days. Cessation of clonidine treatment resulted in an elevation in the level of brain total MHPG. The suitability of the clonidine withdrawal syndrome as a model of bipolar depression is discussed.

Low doses of d-amphetamine (1.0 mg/kg) can reduce the spontaneous hyperactivity of BALB/cJ mice. Amphetamine-induced hypolocomotion can be antagonized by NCA and sulpiride pretreatment, suggesting that this is a dopaminergic phenomenon. However, behaviorally active doses of NCA do not alter brain D2 dopamine receptor binding in either mice or rats. NCA also did not induce stereotypy/catalepsy or affect apomorphine-induced stereotypy. The results suggest that another type of dopamine receptor may mediate the behavioral effects of amphetamine and NCA.

A radioligand suitable for crosslinking studies to opioid receptors has been obtained by radioiodination and purification of the monoiodotyrosine-27 derivative of the synthetic human beta-endorphin (beta h-endorphin) analogue [5-leucine]beta h-endorphin. The derivative, [27-[125I]monoiodotyrosine,5-leucine]beta h-endorphin, was crosslinked to human striatal (caudate and putamen) and NG108-15 neuroblastoma-glioma cell membranes by using disuccinimidyl suberate. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis under reducing conditions revealed four specifically labeled bands at 68, 40, 30, and 25 kDa for both human caudate and putamen, whereas NG108-15 cell membranes gave specifically labeled bands at 92, 56, 38, and 23 kDa.

The effect of acute (single dose), short-term (4 days), and chronic treatment (21 days) with two tricyclic antidepressants desipramine and amitriptyline on brain 3-methoxy-4-hydroxyphenylglycol (MHPG) was examined in the rat. Amitriptyline had no effect on brain total MHPG irrespective of the duration of the treatment and did not interfere with the lowering effect of clonidine on brain total MHPG. Acute and short-term desipramine treatment decreased brain total MHPG in rats, while chronic desipramine treatment increased it. The differential effect of acute and chronic treatment of desipramine on the brain total MHPG was further demonstrated by the lack of interference with the lowering effect of clonidine on brain total MHPG by one single dose of desipramine; partial interference after 4 days and complete interference after 21 days of desipramine treatment.