Critical reviews in neurobiology最新文献

Oxidative stress has been demonstrated to occur in response to high doses of substituted amphetamines such as methamphetamine (METH) and 3,4-methlyene-dioxymethamphetamine (MDMA). This term represents a set of complex and multi-faceted precursor events that occur in both a parallel and serial manner, eventually converging to produce oxidative damage. This critical review goes beyond the compilation of previously well-documented evidence demonstrating that oxidative stress mediates METH and MDMA toxicity to dopamine and/or serotonin nerve terminals. The diverse causes, effects, and impact of pro-oxidative processes produced by these drugs are highlighted, integrated, and assembled into a proposed temporal sequence in an effort to explain the long-term neurochemical changes produced by amphetamines. Multiple factors are considered, including dopamine, glutamate, impaired mitochondrial bioenergetics, and inflammatory processes, all of which converge and are necessary but alone may be insufficient to cause damage to dopamine and/or 5-HT terminals. In addition, the processes linking inflammation and oxidative stress are considered and described as a feedforward process. The self-perpetuating cycle of inflammation and oxidative stress that is initiated by dopamine, glutamate, and mitochondrial dysfunction may extend well beyond the acute pharmacodynamic effects of the drugs and could represent an underlying and potentially progressive degenerative process.

In 2006, Braun proposed a new model of hemispheric specialization of energy management by the brain, which he termed the "psychic tonus" model of hemispheric specialization. The term "psychic tonus" is deliberately general. It invites further investigation designed to incorporate various behavioral and cognitive modalities. At present, any cognitive operation or behavior likely to require energy expenditure, such as cardiovascular or metabolic, is considered to be at one extreme while any cognitive operation or behavior likely to reduce energy expenditure is considered to be at the other extreme. The model states that the left hemisphere of the brain is specialized to increase psychic tonus and the right to decrease it. The model predicts that the tonus of auditory representation ought to also manifest these hemispheric specializations in the temporal lobes. Specifically, it was predicted that pathological positive auditory tonus (auditory hallucination) ought to be associated more frequently with right temporal lobe lesions. Our analysis of a large number of previously published cases of patients with unilateral lesions supports the prediction.

It is well known that most people who use psychoactive drugs started as teenagers. In spite of this, there has been little preclinical research on the effects of psychostimulants during adolescence. Recently, however, a number of laboratories have begun to focus on drug effects in adolescents as compared with adults. The data show that there are unique responses to drugs during this period of development. This review will focus on our current understanding of neurochemical and behavioral drug effects during adolescence.

G protein-coupled delta-opioid receptors (DORs) participate in opioid-mediated analgesia, and chronic opioid application is well known to produce tolerance, limiting the therapeutic use of these drugs. To control and eventually avoid the underlying adaptive mechanisms, several cellular functions were examined with regard to their roles in tolerance development. Specific interest focused on DOR internalization, and the relevant findings are reviewed here. In general, DOR endocytosis is accomplished by complex interactions of various determinants, each having distinct roles in this process. For instance, DOR activation by certain opioids has been shown to turn on the machinery of endocytosis, whereas other opioids stimulate the receptors but fail to bring about internalization. In addition, receptor phosphorylation by different kinases was commonly found to promote DOR sequestration, but receptor internalization also occurs without their phosphorylation. A central role in DOR endocytosis is referred to the adaptor proteins arrestin-2 and arrestin-3, which bind to receptors and subsequently cause the formation of clathrin-coated pits to trigger dynamin-controlled endocytosis. Distinct sorting proteins, kinases, and phosphatases determine whether internalized DORs are delivered either for proteolytic degradation or for recycling, although the underlying mechanisms are hence not clear. Despite intensive studies, understanding of DOR sequestration, degradation, and recycling becomes increasingly difficult. However, the phenomenon of cellular desensitization is recognized to correspond to the loss of responsiveness as consequence of DOR internalization and degradation. In contrast, DOR endocytosis is also discussed to promote resensitization of cells to opioids by recycling of internalized DORs. Even stimulation of extracellular signal-regulated protein kinases (ERK 1/2) may be accomplished by DOR sequestration. However, opposite findings, as well as the fact that multiple cellular mechanisms underly receptor desensitization, resensitization, and ERK activation, questions whether DOR internalization is essential for these processes. Further investigations in both the cellular mechanism and the consequences of DOR endocytosis might thus reveal new aspects of opioid-controlled functions.

Several lines of evidence support the role of an epigenetic-induced GABAergic cortical dysfunction in schizophrenia psychopathology, which is probably dependent on an increase in the expression of DNA-methyltransferase-1 occurring selectively in GABAergic neurons. The key enzyme regulating GABA synthesis, termed glutamic acid decarboxylase 67 (GAD67) and the important neurodevelopmental protein called reelin are coexpressed in GABAergic neurons. Upon release, GABA and reelin bind to postsynaptic receptors located in dendrites, somata, or the axon initial segment of pyramidal neurons. Because GAD67 and reelin are downregulated in schizophrenia, it is suggested that schizophrenics may express GABAergic deficit-related alterations of pyramidal neuron function. A reduction of dendritic spines is a finding reported in the prefrontal cortex of schizophrenia patients. Because dendritic spines are innervated by glutamatergic axon terminals, very probably this reduction of dendritic spine expression is translated into a functional deficit of glutamatergic transmission. Plastic modifications of neuronal circuits are probably dependent on GABAergic transmitter tone, and it is likely that GABAergic dysfunction is at the root of synaptic plasticity deficits in schizophrenia. Thus, a possible avenue for the treatment of schizophrenia would be to address this GABAergic functional deficit using positive allosteric modulators of the action of GABA at GABAA receptors. Benzodiazepines (BZ) such as diazepam are effective in treating positive and negative symptoms of schizophrenia, but because they positively modulate GABAA receptors expressing alpha1 subunits, these BZs cause sedation and tolerance. In contrast, imidazenil, a full allosteric modulator of GABAA receptors expressing alpha5 subunits may reduce psychotic symptomatology without producing sedation. Hence, imidazenil should be appropriately studied as a prospective candidate for a pharmacological intervention in schizophrenia.

The intrinsic susceptibility of dopaminergic neurons underlies the pathophysiology of Parkinson's disease and is possibly related to developmental injury in schizophrenia. However, the molecular substrates for this susceptibility are not well understood. We review the evidence of selective susceptibility of dopaminergic neurons to excessive glutamate receptor stimulation and discuss the molecular pathways that differentiate between physiological and pathological signaling leading to this particular form of neuronal death. In vitro as well as in vivo, activation of GluRAMPA causes concentration-dependent, severe pruning of neurites and selective death of dopaminergic neurons. In primary cultures of mesencephalon, this form of injury is mediated through release of calcium from intracellular stores (CICR), leading to loss of calcium homeostasis, oxidative stress, and activation of the transcription factor NFkappaB and the cell death protein p53. Post-translational modification of p53 may be an important target for neuroprotection in Parkinson's disease and perhaps in prevention of other neuropsychiatric disorders.

Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.

Adenosine A2A receptor antagonists are regarded as potential neuroprotective drugs, although the mechanisms underlying their effects remain to be elucidated. In this review, quinolinic acid (QA)-induced striatal toxicity was used as a tool to investigate the mechanisms of the neuroprotective effects of A2A receptor antagonists. After having examined the effects of selective A2A receptor antagonists toward different mechanisms of QA toxicity, we conclude that (1) the effect elicited by A2A receptor blockade on QA-induced glutamate outflow may be one of the mechanisms of the neuroprotective activity of A2A receptor antagonists; (2) A2A receptor antagonists have a potentially worsening influence on QA-dependent NMDA receptor activation; and (3) the ability of A2A receptor antagonists to prevent QA-induced lipid peroxidation does not correlate with the neuroprotective effects. These results suggest that A2A receptor antagonists may have either potentially beneficial or detrimental influence in models of neurodegeneration that are mainly due to increased glutamate levels or enhanced sensitivity of NMDA receptors, respectively.

Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suffering and death, excitotoxicity and glutamate uptake deficits have been repeatedly confirmed to play a key role in the pathogenesis of different neurological diseases. Therefore, it is conceivable that assessing the glutamatergic system function directly in patients could be extremely useful for early diagnosis, prognostic evaluation, and optimization of the therapy. A possibility is offered by assessing glutamate levels in biological fluid, such as plasma and CSF, where increased levels of this amino acid have been reported in patients affected by stroke, amyotrophic lateral sclerosis (ALS), and AIDS dementia complex. However, the metabolic role of this amino acid acts as a confounding factor, and the possibility of directly assessing glutamatergic functional parameters, such as amino acid reuptake, would probably mirror closely the actual excitotoxic damage operative in each patient. Here we will describe our findings obtained in peripheral ex vivo cells, such as platelets and fibroblasts, both displaying a functional glutamate reuptake system. Consistent with a systemic-impairment assumption, glutamate uptake was shown to be reduced in peripheral cells of Alzheimer's disease, Down syndrome, Parkinson's disease, ALS, and stroke patients. Different systemic factors might be responsible for this phenomenon, including genetic predisposition, oxidative stress, and inflammatory response, raising new, exciting questions about the relevance of their possible interactions for the pathogenesis of neurological disorders.