The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury.

BACKGROUND: Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex. METHODS: This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined. RESULTS: Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (ß ± SE = - 0.12 ± 0.06, p = 0.034 and ß ± SE = 0.08 ± 0.04, p = 0.026, respectively). CONCLUSIONS: Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

Early TNF-Dependent Regulation of Excitatory and Inhibitory Synapses on Striatal Direct Pathway Medium Spiny Neurons in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin gene. Neurodegeneration first occurs in the striatum, accompanied by an elevation in inflammatory cytokines. Using the presymptomatic male YAC128 HD model mouse, we examined the synaptic input onto the striatal medium spiny neurons to look for early changes that precede degeneration. We observed an increase in excitatory synaptic strength, as measured by AMPA/NMDA ratios, specifically on direct pathway D1 receptor expressing medium spiny neurons, with no changes on indirect pathway neurons. The changes in excitation were accompanied by a decrease in inhibitory synaptic strength, as measured by the amplitude of miniature inhibitory synaptic currents. The pro-inflammatory cytokine tumor necrosis factor alpha (TNF) was elevated in the striatum of YAC128 at the ages examined. Critically, the changes in excitatory and inhibitory inputs are both dependent on TNF signaling, as blocking TNF signaling genetically or pharmacological normalized synaptic strength. The observed changes in synaptic function are similar to the changes seen in D1 medium spiny neurons treated with high levels of TNF, suggesting that saturating levels of TNF exist in the striatum even at early stages of HD. The increase in glutamatergic synaptic strength and decrease in inhibitory synaptic strength would increase direct pathway neuronal excitability, which may potentiate excitotoxicity during the progress of HD.SIGNIFICANCE STATEMENT The striatum is the first structure to degenerate in Huntington's disease, but the early changes that presage the degeneration are not well defined. Here we identify early synaptic changes in the YAC128 mouse model of Huntington's disease specifically on a subpopulation of striatal neurons. These neurons have stronger excitatory synapses and weaker inhibitory inputs, and thus would increase the susceptibility to excitotoxicity. These changes are dependent on signaling by the pro-inflammatory cytokine TNFα. TNF is elevated even at early presymptomatic stages, and blocking TNF signaling even acutely will reverse the synaptic changes. This suggests early intervention could be important therapeutically.

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients.

The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment. Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients' disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups. Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82-157) at baseline to 89 (45-138) at endpoint (-18.98; 95%CI= -26.95 to -11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment. The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

Correction: Bar-Sela et al. Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome. Cancers 2020, 12, 2447.

In the original article [...].

Sex differences in medical cannabis-related adverse effects.

ABSTRACT: Studies have shown that women are more susceptible to adverse effects (AEs) from conventional drugs. This study aimed to investigate the differences of medical cannabis (MC)-related AEs between women and men in patients with chronic noncancer pain (CNCP). This is a cross-sectional study of adult patients licensed for MC treatment who were also diagnosed as patients with CNCP by a physician. Data included self-reported questionnaires and comprehensive MC treatment information. Simultaneously, identification and quantification of phytocannabinoids and terpenoids from the MC cultivars were performed. Comparative statistics were used to evaluate differences between men and women. Four hundred twenty-nine patients with CNCP (64% males) reported fully on their MC treatment. Subgrouping by sex demonstrated that the weight-adjusted doses were similar between men and women (0.48 [0.33-0.6] gr for men and 0.47 [0.34-0.66] gr for women). Nonetheless, women reported more than men on MC-related AEs. Further analysis revealed that women consumed different MC cultivar combinations than men, with significantly higher monthly doses of the phytocannabinoids CBD and CBC and significantly lower monthly doses of the phytocannabinoid 373-15c and the terpenoid linalool. Our findings demonstrate sex differences in MC-related AEs among patients with CNCP. Women are more susceptible to MC-related AEs, presumably because of both the inherent sex effect and the consumption of specific phytocannabinoid compositions in the MC cultivar(s). The understanding of these differences may be crucial for planning MC treatments with safer phytocannabinoid and terpenoid compositions and to better inform patients of expected AEs.

Prolonged Medical Cannabis Treatment is Associated With Quality of Life Improvement and Reduction of Analgesic Medication Consumption in Chronic Pain Patients.

Introduction: Chronic non-cancer pain (CNCP) is one of the most prevalent indications for medical cannabis (MC) treatment globally. In this study, we investigated CNCP parameters in patients during prolonged MC treatment, and assessed the interrelation between CNCP parameters and the chemical composition of MC chemovar used. Methods: A cross-sectional questionnaire-based study was performed in one-month intervals for the duration of six months. Subjects were adult patients licensed for MC treatment who also reported a diagnosis of CNCP by a physician. Data included self-reported questionnaires. MC treatment features included administration route, cultivator, cultivar name and monthly dose. Comparison statistics were used to evaluate differences between the abovementioned parameters and the monthly MC chemovar doses at each time point. Results: 429, 150, 98, 71, 77 and 82 patients reported fully on their MC treatment regimens at six one-month intervals, respectively. Although pain intensities did not change during the study period, analgesic medication consumption rates decreased from 46 to 28% (p < 0.005) and good Quality of Life (QoL) rates increased from 49 to 62% (p < 0.05). These changes overlapped with increase in rates of (-)-Δ9-trans-tetrahydrocannabinol (THC) and α-pinene high dose consumption. Conclusion: Even though we observed that pain intensities did not improve during the study, QoL did improve and the rate of analgesic medication consumption decreased alongside with increasing rates of high dose THC and α-pinene consumption. Understanding MC treatment composition may shed light on its long-term effects.

Specific phytocannabinoid compositions are associated with analgesic response and adverse effects in chronic pain patients treated with medical cannabis.

Medical cannabis (MC) treatment for chronic pain is increasing, but evidence regarding short- and long-term efficacy and associated adverse effects (AEs) of the different cannabis plant components is limited. Most reports focus on two phytocannabinoids, (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This study, aimed to identify patterns of phytocannabinoid compositions associated with MC treatment response and with related AEs. Participants in this multicenter prospective cohort were patients with chronic non-cancer pain that were prescribed MC by physicians. Data was collected before MC treatment, at one month (short-term) and at 12 months (long-term). Simultaneously, liquid chromatography mass spectrometry identification and quantification of phytocannabinoids from the cultivars were performed. The monthly dose of each phytocannabinoid for each patient was z-scaled and clustered into ten groups to assess the difference in analgesic treatment response (≥30%/50% pain intensity reduction) and AEs rates. We identified ten clusters that had similar analgesic treatment response rates. However, there were significant differences in AEs rates both at short- and long-term. We identified specific phytocannabinoid compositions that were associated with overall AEs rates (5% compared to 53% at short-term and 44% at long-term) and with specific AEs rates such as MC related central nervous system, gastrointestinal and psychological AEs. To conclude, Evaluating only Δ9-THC or CBD is insufficient to find associations with MC related AEs. Therefore, comprehensive profiling of phytocannabinoids is needed to discover associations to related AEs and help physicians prescribe safer cannabis with less AEs while still relieving pain.

Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients.

In the last decade the use of medical cannabis (MC) for palliative cancer treatment has risen. However, the choice between products is arbitrary and most patients are using Tetrahydrocannabinol (THC)-dominant cannabis products. In this study, we aimed to assess the short-term outcomes of MC treatment prescribed by oncologists in relation to the type of cannabis they receive. A comparative analysis was used to assess the differences in treatment effectiveness and safety between THC-dominant (n = 56, 52%), cannabidiol (CBD)-dominant (n = 19, 18%), and mixed (n = 33, 30%) MC treatments. Oncology patients (n = 108) reported on multiple symptoms in baseline questionnaires, initiated MC treatment, and completed a one-month follow-up. Most parameters improved significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden. There was no significant difference between the three MC treatments in the MC-related safety profile. Generally, there were no differences between the three MC treatments in pain intensity and in most secondary outcomes. Unexpectedly, CBD-dominant oil treatments were similar to THC-dominant treatments in their beneficial effects for most secondary outcomes. THC-dominant treatments showed significant superiority in their beneficial effect only in sleep duration compared to CBD-dominant treatments. This work provides evidence that, though patients usually consume THC-dominant products, caregivers should also consider CBD-dominant products as a useful treatment for cancer-related symptoms.

Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome.

Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients' overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy.

Cannabinoidomics - An analytical approach to understand the effect of medical Cannabis treatment on the endocannabinoid metabolome.

Increasing evidence for the therapeutic potential of Cannabis in numerous pathological and physiological conditions has led to a surge of studies investigating the active compounds in different chemovars and their mechanisms of action, as well as their efficacy and safety. The biological effects of Cannabis have been attributed to phytocannabinoid modulation of the endocannabinoid system. In-vitro and in-vivo studies have shown that pure phytocannabinoids can alter the levels of endocannabinoids and other cannabimimetic lipids. However, it is not yet understood whether whole Cannabis extracts exert variable effects on the endocannabinoid metabolome, and whether these effects vary between tissues. To address these challenges, we have developed and validated a novel analytical approach, termed "cannabinoidomics," for the simultaneous extraction and analysis of both endogenous and plant cannabinoids from different biological matrices. In the methodological development liquid chromatography high resolution tandem mass spectrometry (LC/HRMS/MS) was used to identify 57 phytocannabinoids, 15 major phytocannabinoid metabolites, and 78 endocannabinoids and cannabimimetic lipids in different biological matrices, most of which have no analytical standards. In the validation process, spiked cannabinoids were quantified with acceptable selectivity, repeatability, reproducibility, sensitivity, and accuracy. The power of this analytical method is demonstrated by analysis of serum and four different sections of mouse brains challenged with three different cannabidiol (CBD)-rich extracts. The results demonstrate that variations in the minor phytocannabinoid contents of the different extracts may lead to varied effects on endocannabinoid concentrations, and on the CBD metabolite profile in the peripheral and central systems. We also show that the Cannabis challenge significantly decreases the levels of several endocannabinoids in specific brain sections compared to the control group. This effect is extract-specific and suggests the importance of minor, other-than CBD, phytocannabinoid or non-phytocannabinoid compounds.

Migraine Frequency Decrease Following Prolonged Medical Cannabis Treatment: A Cross-Sectional Study.

BACKGROUND: Medical cannabis (MC) treatment for migraine is practically emerging, although sufficient clinical data are not available for this indication. This cross-sectional questionnaire-based study aimed to investigate the associations between phytocannabinoid treatment and migraine frequency. METHODS: Participants were migraine patients licensed for MC treatment. Data included self-reported questionnaires and MC treatment features. Patients were retrospectively classified as responders vs. non-responders (≥50% vs. <50% decrease in monthly migraine attacks frequency following MC treatment initiation, respectively). Comparative statistics evaluated differences between these two subgroups. RESULTS: A total of 145 patients (97 females, 67%) with a median MC treatment duration of three years were analyzed. Compared to non-responders, responders (n = 89, 61%) reported lower current migraine disability and lower negative impact, and lower rates of opioid and triptan consumption. Subgroup analysis demonstrated that responders consumed higher doses of the phytocannabinoid ms_373_15c and lower doses of the phytocannabinoid ms_331_18d (3.40 95% CI (1.10 to 12.00); p < 0.01 and 0.22 95% CI (0.05-0.72); p < 0.05, respectively). CONCLUSIONS: These findings indicate that MC results in long-term reduction of migraine frequency in >60% of treated patients and is associated with less disability and lower antimigraine medication intake. They also point to the MC composition, which may be potentially efficacious in migraine patients.

Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect.

The therapeutic effect of the Cannabis plant largely depends on the presence and specific ratio of a spectrum of phytocannabinoids. Although prescription of medicinal Cannabis for various conditions constantly grows, its consumption is mostly limited to oral or respiratory pathways, impeding its duration of action, bioavailability, and efficacy. Herein, a long-acting formulation in the form of melt-printed polymeric microdepots for full-spectrum cannabidiol (CBD)-rich extract administration is described. When injected subcutaneously in mice, the microdepots facilitate sustained release of the encapsulated extract over a two-week period. The prolonged delivery results in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to Cannabis extract injection. A direct analysis of the microdepots retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. As a proof of concept, we compare the long-term efficacy of a single administration of the microdepots to a single administration of Cannabis extract in a pentylenetetrazol-induced convulsion model. One week following administration, the microdepots reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic-clonic seizures by 170%. These results suggest that a long-term full-spectrum Cannabis delivery system may provide new form of Cannabis administration and treatments.

Cannabinoid and Terpenoid Doses are Associated with Adult ADHD Status of Medical Cannabis Patients.

OBJECTIVE: The aim of this cross-sectional questionnaire-based study was to identify associations between the doses of cannabinoids and terpenes administered, and symptoms of attention deficit hyperactivity disorder (ADHD). METHODS: Participants were adult patients licensed for medical cannabis (MC) treatment who also reported a diagnosis of ADHD by a physician. Data on demographics, ADHD, sleep, and anxiety were collected using self-report questionnaires. Data collected on MC treatment included administration route, cultivator, cultivar name, and monthly dose. Comparison statistics were used to evaluate differences in reported parameters between low (20-30 g, n=18) and high (40-70 g, n=35) MC monthly dose and low adult ADHD self-report scale (ASRS, 0-5) score (i.e. ≤3.17 score, n=30) or high ASRS score (i.e. ≥3.18 score, n=29) subgroups. RESULTS: From the 59 patients that answered the questionnaire, MC chemovar could be calculated for 27 (45%) of them. The high MC monthly dose group consumed higher levels of most phyto-cannabinoids and terpenes, but that was not the case for all of the cannabis components. The high dose consumers and the ones with lower ASRS score reported a higher occurrence of stopping all ADHD medications. Moreover, there was an association between lower ASRS score subgroup and lower anxiety scores. In addition, we found an association between lower ASRS score and consumption of high doses of cannabinol (CBN), but not with Δ-9-tetrahydrocannabinol (THC). CONCLUSION: These findings reveal that the higher-dose consumption of MC components (phyto-cannabinoids and terpenes) is associated with ADHD medication reduction. In addition, high dosage of CBN was associated with a lower ASRS score. However, more studies are needed in order to fully understand if cannabis and its constituents can be used for management of ADHD.

The heterogeneity and complexity of Cannabis extracts as antitumor agents.

The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant's therapeutic effects. Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins. We first utilized our novel electrospray ionization liquid chromatography mass spectrometry method to analyze the phytocannabinoid contents of 124 Cannabis extracts. We then monitored the effects of 12 chosen different Cannabis extracts on 12 cancer cell lines. Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis. Our findings showed that pure (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ9-THC produced significantly different effects on the survival of specific cancer cells. In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line. Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract's composition as well as on certain characteristics of the targeted cells.

A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis.

Most clinical studies of Cannabis today focus on the contents of two phytocannabinoids: (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), regardless of the fact that the plant contains over 100 additional phytocannabinoids whose therapeutic effects and interplay have not yet been fully elucidated. This narrow view of a complex Cannabis plant is insufficient to comprehend the medicinal and pharmacological effects of the whole plant. In this study we suggest a new ESI-LC/MS/MS approach to identify phytocannabinoids from 10 different subclasses, and comprehensively profile the identified compounds in diverse medical Cannabis plants. Overall, 94 phytocannabinoids were identified and used for profiling 36 of the most commonly used Cannabis plants prescribed to patients in Israel. In order to demonstrate the importance of comprehensive phytocannabinoid analysis before and throughout medical Cannabis clinical trials, treatments, or experiments, we evaluated the anticonvulsant effects of several equally high-CBD Cannabis extracts (50% w/w). We found that despite the similarity in CBD contents, not all Cannabis extracts produced the same effects. This study's approach for phytocannabinoid profiling can enable researchers and physicians to analyze the effects of specific Cannabis compositions and is therefore critical when performing biological, medical and pharmacological-based research using Cannabis.

Microglial TNF-α Suppresses Cocaine-Induced Plasticity and Behavioral Sensitization.

Repeated administration of cocaine results in the development of behavioral sensitization, accompanied by a decrease in excitatory synaptic strength in the nucleus accumbens (NAc) through an unknown mechanism. Furthermore, glial cells in the NAc are activated by drugs of abuse, but the contribution of glia to the development of addictive behaviors is unknown. Tumor necrosis factor alpha (TNF-α), an inflammatory cytokine released by activated glia, can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons. Here we show that repeated administration of cocaine activates striatal microglia and induces TNF-α production, which in turn depresses glutamatergic synaptic strength in the NAc core and limits the development of behavioral sensitization. Critically, following a period of abstinence, a weak TLR4 agonist can reactivate microglia, increase TNF-α production, depress striatal synaptic strength, and suppress cocaine-induced sensitization. Thus, cytokine signaling from microglia can regulate both the induction and expression of drug-induced behaviors.

Astrocytic TNFα regulates the behavioral response to antidepressants.

Recent studies have suggested that cytokines, and in particular tumor necrosis factor alpha (TNFα), have a role in modulating antidepressant efficacy. To directly test this idea, we compared the response of TNFα(-/-) mice and astrocyte-specific TNFα(-/-) mice to the antidepressants fluoxetine and desipramine. Using standard behavior models for measuring antidepressant efficacy, the forced swim test (FST) and tail suspension test (TST), we determined that TNFα(-/-) mice were essentially normal in basal behavior in the FST and TST. However, TNFα(-/-) mice showed no behavioral response to a standard dose of chronic antidepressant treatment, in sharp contrast to wildtype mice. Similar results were seen with acute antidepressant treatment, but TNFα(-/-) mice did respond to a very high-dose acute antidepressant treatment. We also assessed in vitro and in vivo effects of fluoxetine on TNFα expression. Glia responded to serotonin in vitro and fluoxetine in vivo by upregulating TNFα mRNA. Consistent with this source of TNFα, mice with an astrocyte-specific deletion of TNFα also did not respond to standard chronic antidepressant treatment. These data suggest that astrocytic TNFα is important to the sensitivity of the behavioral response to administration of antidepressants.

An adaptive role of TNFα in the regulation of striatal synapses.

Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFα drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFα drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFα signaling appears to be adaptive in nature, as TNFα is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFα is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.

Vaccination as a novel approach for treating depressive behavior.

BACKGROUND: Depressive behavior in animals is often associated with reduced levels of brain-derived neurotrophic factor (BDNF) and impaired neurogenesis in the hippocampus. Recent studies showed that T cells recognizing central nervous system (CNS)-specific antigens can regulate adult hippocampal neurogenesis and expression of BDNF. On the basis of these findings, we hypothesized that controlling CNS specific immune activity by immunization with a myelin-related peptide may have an antidepressant effect. METHODS: We investigated the impact of immunization with a CNS related peptide, on the behavioral and cellular outcomes of chronic mild stress (CMS; an animal model for depression) in rats. RESULTS: Immunization with a weak agonist of a myelin-derived peptide ameliorated depressive behavior such as anhedonia (measured by sucrose preference), induced by CMS in rats. The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis. CONCLUSIONS: The results of this study introduce a novel approach of immunization with CNS-related antigens as a therapeutic means for fighting depression. Vaccination, as an antidepressant therapy, may invoke several molecular and cellular pathways that are known to be regulated by antidepressant drugs. Therefore, we suggest that immune-based therapies should be considered for treatment of depression.

Reducing post-traumatic anxiety by immunization.

Trafficking of T lymphocytes to specific organs, such as the skin and lungs, is part of the body's defense mechanism following acute psychological stress. Here we demonstrate that T lymphocytes are also trafficking to the brain in response to psychological stress and are needed to alleviate its negative behavioral consequences. We show that short exposure of mice to a stressor (predator odor) enhanced T-cell infiltration to the brain, especially to the choroid plexus, and that this infiltration was associated with increased ICAM-1 expression by choroid plexus cells. Systemic administration of corticosterone could mimic the effects of psychological stress on ICAM-1 expression. Furthermore, we found that the ability to cope with this stress is interrelated with T-cell trafficking and with the brain and hippocampal BDNF levels. Immunization with a CNS-related peptide reduced the stress-induced anxiety and the acoustic startle response, and restored levels of BDNF, shown to be important for stress resilience. These results identified T cells as novel players in coping with psychological stress, and offers immunization with a myelin-related peptide as a new therapeutic approach to alleviate chronic consequences of acute psychological trauma, such as those found in posttraumatic stress disorder.