minocycline and Anxiety-Disorders

Neuroinflammation is discussed to play a role in specific subgroups of different psychiatric disorders, including anxiety disorders. We have previously shown that a mouse model of trait anxiety (HAB) displays enhanced microglial density and phagocytic activity in key regions of anxiety circuits compared to normal-anxiety controls (NAB). Using minocycline, we provided causal evidence that reducing microglial activation within the dentate gyrus (DG) attenuated enhanced anxiety in HABs. Besides pharmacological intervention, "positive environmental stimuli", which have the advantage of exerting no side-effects, have been shown to modulate inflammation-related markers in human beings. Therefore, we now investigated whether environmental enrichment (EE) would be sufficient to modulate upregulated neuroinflammation in high-anxiety HABs. We show for the first time that EE can indeed attenuate enhanced trait anxiety, even when presented as late as adulthood. We further found that EE-induced anxiolysis was associated with the attenuation of enhanced microglial density (using Iba-1 as the marker) in the DG and medial prefrontal cortex. Additionally, EE reduced Iba1 + CD68+ microglia density within the anterior DG. Hence, the successful attenuation of trait anxiety by EE was associated in part with the normalization of neuro-inflammatory imbalances. These results suggest that pharmacological and/or positive behavioral therapies triggering microglia-targeted anti-inflammatory effects could be promising as novel alternatives or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals predisposed to trait anxiety.

Topics: Adult; Animals; Anxiety; Anxiety Disorders; Disease Models, Animal; Hippocampus; Humans; Mice; Microglia; Minocycline

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia 'inhibitor' in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Mice; Microglia; Minocycline

Activated microglia-induced neuroinflammation can stimulate the hypothalamic- pituitary-adrenal (HPA) axis to release glucocorticoids and suppress astrocyte functions, such as reducing neurotrophin production, which occur in depression. However, the balance between M1 (pro-inflammation) and M2 (anti-inflammation) microglial phenotypes and the interaction between these two glial cells are unclear in the depression. Hence, the chronic unpredictable mild stress (CUMS)-induced depression model was chosen to study depression- and anxiety-like behaviors, the concentration of corticosterone and relevant hippocampal cytokines, mRNA and protein expressions of microglial and astrocyte markers. To demonstrate the role of M1 phenotype activation in depression, the effect of microglial inhibitor minocycline on these aspects was also evaluated. Six weeks after CUMS exposure, behaviors were tested. Compared to the control group, CUMS increased serum corticosterone concentration and depression-like behaviors, like anhedonia, helplessness and anxiety. Moreover, CUMS increased microglia M1 marker CD11b expression and tumor necrosis factor (TNF)-α, interferon (INF)-γ, interleukin (IL)-1β and IL-17 concentrations, but decreased the concentration of M2 cytokines, IL-4, IL-10 and IL-13. Meanwhile, CUMS inhibited the expressions of astrocyte marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrKB. Minocycline (40 mg/kg, 45 days) treatment significantly attenuated CUMS-induced behavioral abnormalities, which were associated with the suppressed M1 response, restored GFAP, BDNF and its receptor expression. In conclusion, CUMS-induced depression- and anxiety-like behavior may result from an imbalance between M1 and M2 and suppressed astrocyte function. Minocycline treatment reversed M1 response, which was associated with behavioral normalization.

Topics: Animals; Antidepressive Agents; Anxiety Disorders; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Female; Hypothalamo-Hypophyseal System; Minocycline; Pituitary-Adrenal System; Rats, Sprague-Dawley; Stress, Psychological

Neuroinflammation induced by stress results in aberrant neurotransmission and dyslipidemia, which can trigger depression- and anxiety-like behaviors. Gamma-aminobutyric acid (GABA) and cholesterol play a crucial role in anxiety-like states, including self-grooming - a common stress-evoked rodent behavior. However, the interaction between neuroinflammation, GABA and cholesterol under stress, and their effects on grooming, remain unclear. Here, we utilize the chronic unpredictable mild stress (CUMS) rat cohort used previously in our Zhang et al. (2019) study, to examine whether CUMS affects grooming behavior, and whether minocycline, a microglia antagonist, can correct these behavioral deficits, accompanied by altering hippocampal neuroinflammation, GABA and serum cholesterol levels. Female Sprague-Dawley rats underwent a 6-week CUMS and received daily minocycline (40 mg/kg, i.p.) during this period, followed by behavioral testing in the open field test. Serum cholesterol, inflammatory cytokines and GABA levels in hippocampus were assayed by ELISA. CUMS significantly decreased locomotion, rearing, central zone entries and time spent in the open field center compared to unstressed controls. CUMS also strongly affected self-grooming behaviors, increasing the frequency of grooming episodes, the number of transitions, interruptions and individual elements of various grooming phases. However, these CUMS-induced behavioral abnormalities were corrected by minocycline. Likewise, CUMS elevated total serum cholesterol and lowered serum high-density lipoprotein cholesterol, whereas minocycline ameliorated these responses. CUMS also lowered hippocampal GABA, whereas minocycline normalized CUMS-induced GABA in the hippocampus. We also found significant correlations between neuroinflammation and GABA, neuroinflammation and cholesterol, GABA and grooming, as well as cholesterol and grooming measures, further implicating stress-evoked neuroinflammation, GABA and cholesterol in the regulation of complex rodent behaviors. In summary, minocycline ameliorated CUMS-induced aberrant self-grooming behaviors in rats by altering hippocampal neuroinflammation, GABA and serum cholesterol levels.

Topics: Animals; Anxiety; Anxiety Disorders; Behavior, Animal; Cholesterol; Depression; Depressive Disorder; Disease Models, Animal; Female; gamma-Aminobutyric Acid; Grooming; Hippocampus; Minocycline; Neuroimmunomodulation; Rats; Rats, Sprague-Dawley; Stress, Psychological

Anxiety disorders are chronic, disabling conditions across the world, and bring a great burden to individuals and society. Although advances have been made in understanding of the pathophysiology of these diseases, no mechanistically new drugs for anxiety disorders have reached the market in the past two decades. Some evidence indicates that stress increases neuroinflammatory signaling, which is related to the development of anxiety and depression. Minocycline, a broad-spectrum tetracycline-antibiotic, has been reported to suppress microglia activation-mediated brain endogenous inflammation. However, it is still unknown whether minocycline can be developed to treat stress-induced anxiety disorders and what is the underlying mechanisms. We chose the anxiety model induced by repeated stress consisting of 2 h of restraint on each of 7 consecutive days. The behavioral test results showed that chronic minocycline treatment, not acute minocycline treatment, increased the time spent in the center area in the open field test and the number of open arm entries and time spent in open arms in the elevated plus maze test, which were comparable with the effect of buspirone. Further mechanism studies demonstrated that chronic minocycline treatment inhibited the microglia activation and decreased the levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). In addition, peroxisome proliferator-activated receptor gamma/ nuclear factor kappa B (PPAR-γ/NF-κB) signaling pathway was also modulated by chronic minocycline treatment. In conclusion, our findings support the hypothesis that immune dysregulation plays an important role in stress-induced anxiety disorders, and minocycline can be developed to be used in these diseases.

Topics: Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior, Animal; Depression; Depressive Disorder; Disease Models, Animal; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Neuroimmunomodulation; NF-kappa B; PPAR gamma; Signal Transduction; Stress, Psychological; Tumor Necrosis Factor-alpha

Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early life inflammation in adulthood.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Anxiety Disorders; Depressive Disorder; Disease Models, Animal; Female; Hippocampus; Hypothalamo-Hypophyseal System; Inflammation; Lactation; Lipopolysaccharides; Male; Mice; Minocycline; Pituitary-Adrenal System

Minocycline is a broad-spectrum tetracycline antibiotic with multiple actions, including anti-inflammatory and neuroprotective effects, that was proposed as novel treatment for several psychiatric disorders including schizophrenia and depression. However, there are contradictory results regarding antidepressant effects of minocycline in rodent models. Additionally, the possible anxiolytic effect of minocycline is still poorly investigated. Therefore, we aimed to clarify in the present study the influence of minocycline on behavioral correlates of mood disorders in standard tests for depression and anxiety, the Porsolt Forced Swim Test (FST), Elevated O-Maze, Dark-Light Box Test and Openfield Test in adult C57BL/6 mice. We found, unexpectedly, that mice treated with minocycline (20-40mg/kg, i.p.) did not display antidepressant- or anxiolytic-like behavioral changes in contrast to mice treated with diazepam (0.5mg/kg, anxiety tests) or imipramine (20mg/kg, depressive-like behavior). These results are relevant for future studies, considering that C57BL/6 mice, the most widely used strain in pharmacological and genetic animal models, did not react as expected to the treatment regime applied.

Topics: Animals; Anti-Anxiety Agents; Anti-Bacterial Agents; Antidepressive Agents; Anxiety Disorders; Depressive Disorder; Diazepam; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Imipramine; Male; Mice, Inbred C57BL; Minocycline; Neuropsychological Tests

Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice induces acute seizures and development of spontaneous recurrent seizures and behavioral comorbidities weeks later. The present studies sought to determine whether acute therapeutic intervention with an anti-inflammatory-based approach could prevent or modify development of TMEV-induced long-term behavioral comorbidities. Valproic acid (VPA), in addition to its prototypical anticonvulsant properties, inhibits histone deacetylase (HDAC) activity, which may alter expression of the inflammasome. Minocycline (MIN) has previously demonstrated an antiseizure effect in the TMEV model via direct anti-inflammatory mechanisms, but the long-term effect of MIN treatment on the development of chronic behavioral comorbidities is unknown.. Mice infected with TMEV were acutely administered MIN (50 mg/kg, b.i.d. and q.d.) or VPA (100 mg/kg, q.d.) during the 7-day viral infection period. Animals were evaluated for acute seizure severity and subsequent development of chronic behavioral comorbidities and seizure threshold.. Administration of VPA reduced the proportion of mice with seizures, delayed onset of symptomatic seizures, and reduced seizure burden during the acute infection. This was in contrast to the effects of administration of once-daily MIN, which did not affect the proportion of mice with seizures or delay onset of acute symptomatic seizures. However, VPA-treated mice were no different from vehicle (VEH)-treated mice in long-term behavioral outcomes, including open field activity and seizure threshold. Once-daily MIN treatment, despite no effect on the maximum observed Racine stage seizure severity, was associated with improved long-term behavioral outcomes and normalized seizure threshold.. Acute seizure control alone is insufficient to modify chronic disease comorbidities in the TMEV model. This work further supports the role of an inflammatory response in the development of chronic behavioral comorbidities and further highlights the utility of this platform for the development of mechanistically novel pharmacotherapies for epilepsy.

Topics: Animals; Anticonvulsants; Anxiety Disorders; Behavior, Animal; Body Weight; Chi-Square Distribution; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Temporal Lobe; Exploratory Behavior; Mice; Minocycline; Motor Activity; Psychomotor Performance; Rotarod Performance Test; Theilovirus; Valproic Acid