Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions

Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients’ treatment expectations and prior treatment experiences. Animal research confirmed that “enriched environments” support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug × environment interactions to improve trial sensitivity and treatment outcome.     

Chronic MDMA induces neurochemical changes in the hippocampus of adolescent and young adult rats: Down-regulation of apoptotic markers

While hippocampus is a brain region particularly susceptible to the effects of MDMA, the cellular and molecular changes induced by MDMA are still to be fully elucidated, being the dosage regimen, the species and the developmental stage under study great variables. This study compared the effects of one and four days of MDMA administration following a binge paradigm (3 × 5 mg/kg, i.p., every 2 h) on inducing hippocampal neurochemical changes in adolescent (PND 37) and young adult (PND 58) rats. The results showed that chronic MDMA caused hippocampal protein deficits in adolescent and young adult rats at different levels: (1) impaired serotonergic (5-HT_2A and 5-HT_2C post-synaptic receptors) and GABAergic (GAD2 enzyme) signaling, and (2) decreased structural cytoskeletal neurofilament proteins (NF-H, NF-M and NF-L). Interestingly, these effects were not accompanied by an increase in apoptotic markers. In fact, chronic MDMA inhibited proteins of the apoptotic pathway (i.e., pro-apoptotic FADD, Bax and cytochrome c) leading to an inhibition of cell death markers (i.e., p-JNK1/2, cleavage of PARP-1) and suggesting regulatory mechanisms in response to the neurochemical changes caused by the drug. The data, together with the observed lack of GFAP activation, support the view that chronic MDMA effects, regardless of the rat developmental age, extends beyond neurotransmitter systems to impair other hippocampal structural cell markers. Interestingly, inhibitory changes in proteins from the apoptotic pathway might be taking place to overcome the protein deficits caused by MDMA.     

Blueberry supplementation attenuates microglia activation and increases neuroplasticity in mice consuming a high-fat diet

Objectives: Consuming a high-fat diet (HFD) may result in behavioral deficits similar to those observed in aging animals. Blueberries may prevent and even reverse age-related alterations in neurochemistry and behavior. It was previously demonstrated that middle-aged mice fed HFD had impaired memory; however, supplementation of HFD with blueberry reduced these memory deficits. As a follow-up to that study, the brain tissue from HFD-fed mice with and without blueberry supplementation was assessed to determine the neuroprotective mechanism(s) by which blueberry allayed cognitive dysfunction associated with HFD.

Methods: Mice were fed HFDs (60% calories from fat) or low-fat diets (LFD) with and without 4% blueberry (freeze-dried, U.S. Highbush Blueberry Council). Microglia activation was assessed ex vivo and in vitro. The hippocampus was assessed for brain-derived neurotrophic factor (BDNF) and neurogenesis by measuring doublecortin (DCX).

Results: There was significantly less microglia ionized calcium binding adaptor molecule 1 staining and fewer microglia in the brains of mice fed HFD?+?blueberry compared to mice fed LFD and HFD. BV-2 microglial cells treated with serum collected from the mice fed the diets supplemented with blueberry produced less nitric oxide compared to cells treated with serum from mice fed HFD. BDNF levels were higher and the number of DCX-positive cells was greater in the hippocampus of mice fed HFD?+?blueberry compared to mice fed HFD.

Discussion: This study demonstrated that supplementation of a HFD with blueberry reduced indices of microglia activation and increased neuroplasticity, and these changes may underlie the protection against memory deficits in HFD-fed mice supplemented with blueberry.     

Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain

Early, preemptive blockade of nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) attenuates tumor-induced nerve sprouting and bone cancer pain. A critical unanswered question is whether late blockade of NGF/TrkA can attenuate cancer pain once NGF-induced nerve sprouting and neuroma formation has occurred. By means of a mouse model of prostate cancer-induced bone pain, anti-NGF was either administered preemptively at day 14 after tumor injection when nerve sprouting had yet to occur, or late at day 35, when extensive nerve sprouting had occurred. Animals were humanely killed at day 70 when, in vehicle-treated animals, significant nerve sprouting and neuroma formation was present in the tumor-bearing bone. Although preemptive and sustained administration (days 14–70) of anti-NGF more rapidly attenuated bone cancer nociceptive behaviors than late and sustained administration (days 35–70), by day 70 after tumor injection, both preemptive and late administration of anti-NGF significantly reduced nociceptive behaviors, sensory and sympathetic nerve sprouting, and neuroma formation. In this model, as in most cancers, the individual cancer cell colonies have a limited half-life because they are constantly proliferating, metastasizing, and undergoing necrosis as the parent cancer cell colony outgrows its blood supply. Similarly, the sensory and sympathetic nerve fibers that innervate the tumor undergo sprouting at the viable/leading edge of the parent tumor, degenerate as the parent cancer cell colony becomes necrotic, and resprout in the viable, newly formed daughter cell colonies. These results suggest that preemptive or late-stage blockade of NGF/TrkA can attenuate nerve sprouting and cancer pain.     

Decreased serum BDNF levels in major depressive patients

Background

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity. The aim of the present study was to measure serum BDNF levels in depression and to analyze the relationship between BDNF levels and severity of depression.

Methods

Thirty patients meeting the DSM-IV criteria for major depressive disorder and 40 normal control subjects were recruited for this study. Patients had not used psychotropic drugs. The severity of depression was assessed by the Hamilton Rating of Depression Scale (HAM-D). Serum BDNF levels were determined by using ELISA.

Results

HAM-D scores were 17.09 ± 4.96 in depressed patients. We determined that the serum BDNF levels of the depression patients were lower than those of the healthy control group (respectively, 1453.42 ± 144.51 pg/ml, 1632.23 ± 252.93 pg/ml, t = 3.467, p = 0.001, independent t test). No correlation was found between the patients’ serum BDNF levels and HAM-D scores (p > 0.05, Pearson correlation analysis).

Conclusions

Our results suggest that serum BDNF levels are low in depression. However it was not found association between serum BDNF levels and the severity of depression.     

Cajal and brain plasticity: insights relevant to emerging concepts of mind

The main legacies of Cajal are his drawings of brain structure and their connections, and his ideas of brain plasticity, not only in the mature brain but also during development and after brain injury. As the 21st century begins, many scientists are asking an old question: "how does the brain express the mind?" Although most models of mind incorporate the brain connections produced by Cajal, his ideas of plasticity are largely ignored. The purpose of this chapter is to review how some of Cajal's ideas can be useful in understanding the expression of the mind. I have also introduced several concepts and facts not available during Cajal's life. I cover the concept of homeostasis, the global projections of the monoamine neurons, and the actions of "mind-expanding" drugs. The global projecting neurons, because their monoamine transmitters have such a long history, are considered 1st order systems. The point-to-point connections are considered 2nd order systems. Their importance in theories of functional localization studies is briefly reviewed. Finally, a new model is presented called "Plastic Homeostasis," which incorporates the plastic interactions between 1st and 2nd order neurons. It is hoped that this review will encourage others to study the ideas presented by Cajal when considering functions of the brain. The emerging models of the mind would be well served by a review of the theoretical writing of Cajal.     

Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model

Neuroplasticity subsequent to functional angiogenesis is an important goal for cell-based therapy of ischemic neural tissues. At present, the cellular and molecular mechanisms involved are still not well understood. In this study, we isolated mesenchymal stem cells (MSCs) from Wharton's jelly (WJ) to obtain clonally expanded human umbilical cord-derived mesenchymal stem cells (HUCMSCs) with multilineage differentiation potential. Experimental rats receiving intracerebral HUCMSC transplantation showed significantly improved neurological function compared to vehicle-treated control rats. Cortical neuronal activity, as evaluated by proton MR spectroscopy (1H-MRS), also increased considerably in the transplantation group. Transplanted HUCMSCs migrated towards the ischemic boundary zone and differentiated into glial, neuronal, doublecortin+, CXCR4+, and vascular endothelial cells to enhance neuroplasticity in the ischemic brain. In addition, HUCMSC transplantation promoted the formation of new vessels to increase local cortical blood flow in the ischemic hemisphere. Modulation by stem cell-derived macrophage/microglial interactions, and increased beta1-integrin expression, might enhance this angiogenic architecture within the ischemic brain. Inhibition of beta1-integrin expression blocked local angiogenesis and reduced recovery from neurological deficit. In addition, significantly increased modulation of neurotrophic factor expression was also found in the HUCMSC transplantation group. In summary, regulation of beta1-integrin expression plays a critical role in the plasticity of the ischemic brain after the implantation of HUCMSCs.     

Treadmill training for the treatment of gait disturbances in people with Parkinson’s disease: a mini-review

This report reviews recent investigations of the effects of treadmill training (TT) on the gait of patients with Parkinson’s disease. A literature search identified 14 relevant studies. Three studies reported on the immediate effects of TT; over-ground walking improved (e.g., increased speed and stride length) after one treadmill session. Effects persisted even 15 min later. Eleven longer-term trials demonstrated feasibility, safety and efficacy, reporting positive benefits in gait speed, stride length and other measures such as disease severity (e.g., Unified Parkinson’s Disease Rating Scale) and health-related quality of life, even several weeks after cessation of the TT. Long-term carryover effects also raise the possibility that TT may elicit positive neural plastic changes. While encouraging, the work to date is preliminary; none of the identified studies received a quality rating of Gold or level Ia. Additional high quality randomized controlled studies are needed before TT can be recommended with evidence-based support.