Persistent enhancement of ethanol drinking following a monosodium glutamate-substitution procedure in C57BL6/J and DBA/2J mice

Inbred mouse strains such as C57BL/6J (B6) and DBA/2J (D2) and related strains have been used extensively to help identify genetic controls for a number of ethanol-related behaviors, including acute intoxication and sensitivity to repeated exposures. The disparate ethanol drinking behaviors of B6 mice expressing high-drinking/preference and D2 mice expressing low-drinking/preference have yielded considerable insight into the heritable control of alcohol drinking. However, the B6-high and D2-low drinking phenotypes are contrasted with ethanol-conditioned reward-like behaviors, which are robustly expressed by D2 mice and considerably less expressed by B6 mice. This suggests that peripheral factors, chiefly ethanol taste, may help drive ethanol drinking by these and related strains, which complicates mouse genetic studies designed to understand the relationships between reward-related behaviors and ethanol drinking. Traditional approaches such as the sucrose/saccharin-substitution procedure that normally accentuate ethanol drinking in rodents have had limited success in low drinking/preferring mice such as the D2 line. This may be due to allelic variations of the sweet taste receptor subunit, expressed by many ethanol low-drinking/preferring strains, which would limit the utility of these types of substitution approaches. We have recently shown (McCool & Chappell, 2012) that monosodium glutamate (MSG), the primary component of umami taste, can be used in a substitution procedure to initiate ethanol drinking in both B6 and D2 mice that greatly surpasses that initiated by a more traditional sucrose-substitution procedure. In this study, we show that ethanol drinking initiated by MSG substitution in D2 mice, but not sucrose substitution, can persist for several weeks following removal of the flavor. These findings further illustrate the utility of MSG substitution to initiate ethanol drinking in distinct mouse strains.     

Adolescent brain maturation,the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose–time–effect relationship should be central.     

BDNF Release Is Required for the Behavioral Actions of Ketamine

Background:

Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).

Methods:

Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.

Results:

The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.

Conclusions:

Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.     

Oxytocin Reduces Cocaine Seeking and Reverses Chronic Cocaine-Induced Changes in Glutamate Receptor Function

Background:

Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown.

Methods:

In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level.

Results:

Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner.

Conclusions:

These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions.     

Neurodegeneration in the Brain Tumor Microenvironment: Glutamate in the Limelight

Malignant brain tumors are characterized by destructive growth and neuronal cell death making them one of the most devastating diseases. Neurodegenerative actions of malignant gliomas resemble mechanisms also found in many neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases and amyotrophic lateral sclerosis. Recent data demonstrate that gliomas seize neuronal glutamate signaling for their own growth advantage. Excessive glutamate release via the glutamate/cystine antiporter xCT (system xc-, SLC7a11) renders cancer cells resistant to chemotherapeutics and create the tumor microenvironment toxic for neurons. In particular the glutamate/cystine antiporter xCT takes center stage in neurodegenerative processes and sets this transporter a potential prime target for cancer therapy. Noteworthy is the finding, that reactive oxygen species (ROS) activate transient receptor potential (TRP) channels and thereby TRP channels can potentiate glutamate release. Yet another important biological feature of the xCT/glutamate system is its modulatory effect on the tumor microenvironment with impact on host cells and the cancer stem cell niche. The EMA and FDA-approved drug sulfasalazine (SAS) presents a lead compound for xCT inhibition, although so far clinical trials on glioblastomas with SAS were ambiguous. Here, we critically analyze the mechanisms of action of xCT antiporter on malignant gliomas and in the tumor microenvironment. Deciphering the impact of xCT and glutamate and its relation to TRP channels in brain tumors pave the way for developing important cancer microenvironmental modulators and drugable lead targets.     

Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury

Glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor is present in the lungs, and NMDA receptor antagonist MK-801 attenuates oxidant lung injury. We hypothesized that Glu excitotoxicity may participate in the pathogenesis of hyperoxia-induced lung injury. To determine possible pulmonary protective effects, we administered 0.05 ml/kg MK-801 or saline intraperitoneally daily to neonatal rats exposed to more than 95% oxygen in air. After 7 days, MK-801 decreased the hyperoxia-associated elevation of wet-to-dry lung weight, total leukocyte and neutrophil counts, total protein and lactate dehydroase in BAL fluid, total myeloperoxidase activity, and lung pathological injury. MK-801 inhibited hyperoxia-associated increments in reactive oxygen species production and NF-kappaB production. Hence, NMDA receptor antagonist MK-801 ameliorates hyperoxia-induced lung injury in neonatal rats, and is associated with decreased reactive oxygen species and NF-kappaB. We conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor.     

Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus

Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABA_B) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABA_B receptors on GABAergic projections to PO—characteristic of normal animals—was absent in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABA_B receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments.

鸡血藤总黄酮对坐骨神经损伤大鼠机械痛敏影响的实验研究

目的：研究鸡血藤总黄酮对坐骨神经损伤（chronic constriction injury of the sciatic,CCI）大鼠机械痛敏和脊髓谷氨酸含量的影响。方法40只大鼠随机均分为4组：对照组（腹腔注射生理盐水,不手术）、假手术组（分离坐骨神经但不结扎+腹腔注射生理盐水）、模型组（坐骨神经结扎+腹腔注射生理盐水）、鸡血藤总黄酮处理组（坐骨神经结扎+腹腔注射鸡血藤总黄酮20 g/kg）,连续给药4周。运用机械缩足反射阈值检测术后3、7、10、14、21、28 d大鼠机械痛敏。运用高效液相法测定大鼠术后14、28 d脊髓背角中谷氨酸的含量。结果与模型组比较,处理组术后第10、14、21、28天的机械缩足反射阈值明显升高（P＜0.05,或P＜0.01）;在第14天及第28天观测到鸡血藤总黄酮可显著降低大鼠脊髓背角谷氨酸的含量（P＜0.01）。结论鸡血藤总黄酮可减轻神经病理性痛大鼠的机械痛敏,其机制可能与降低脊髓背角谷氨酸的含量有关。